2004, Vol.22, Issues 4, Psoriasis

Dermatol Clin 22 (2004) xiii –xiv

Preface

Psoriasis

Alan Menter, MD Jennifer Cather, MD

Guest Editors

This issue of the Dermatology Clinics reviews in peutic era, with hundreds of thousands of patients

a comprehensive fashion the important features of

psoriasis, of relevance to the practicing dermatolo-

gist. All the authors are acknowledged leaders in the

field, having written extensively on various aspects

of psoriasis.

The initial three articles discuss the genetics of

psoriasis, immunopathogenesis of psoriasis, and the

rationale for the use of biologic therapy based on our

current knowledge of both genetics and immunopa-

thogenesis of this prevalent disease. In addition, the

realization of the significant impact that quality of

life issues play in the lives of our psoriasis patients

warrants a full article. All too often we, as busy der-

matologists, do a cursory clinical evaluation without

discussing the day-to-day impact that this highly

visible and distressful disease has on our patients.

Thereafter, the full range of therapeutic modalities

in psoriasis are covered in multiple articles, starting

with a review of the phototherapy arsenal available

to us in clinical practice, together with a comprehen-

sive review of the major systemic tools available to

the practicing dermatologist, prior to the advent of

biologic therapy.

Biologic therapy of psoriasis has become—as with

other immunomediated diseases such as rheumatoid

arthritis and Crohn’s disease—increasingly important.

Dermatology has ‘‘come lately’’ to the biologic thera-

0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right

doi:10.1016/j.det.2004.05.001

already being treated over the past 5 or 10 years

for the two aforementioned diseases. The promise of

biologics, based on our knowledge of the specific

immunopathogenesis of psoriasis reviewed in this

issue, has allowed biotechnology companies to more

specifically target individual molecules involved in

antigen presentation and T-cell interaction with the

release of individual cytokines, particularly tumor

necrosis factor a, thus allowing for more precise

therapeutic options for the practicing dermatologist.

With the first biologic drug Alefacept, having been

released in January 2003, the second, Efalizumab,

in November 2003, and the third, Etanercept, in

May 2004, it is important for the practicing derma-

tologist to have a full understanding of these agents

and subsequent agents likely to be approved in the

months and years ahead. All these biologic agents are

reviewed in individual articles, again by physicians

experienced both in clinical research as well as in the

subsequent therapy of these individual agents.

In addition to our standard tools and the biologic

agents for psoriasis, other new agents have potential

for adding to our therapeutic armamentarium in the

years ahead. Dermatologists are fully versed in reti-

noid therapy for psoriasis, acne, and other dermato-

ses. With the likely advent of future systemic

retinoids, particularly oral Tazarotene, it is important

s reserved.

A. Menter, J. Cather / Dermatol Clin 22 (2004) xiii–xivxiv

that this be reviewed in full in a separate chapter. In

addition, the systemic form of pimecrolimus has re-

ceived a lot of attention and is likewise discussed.

The next two articles review two important issues

for the practicing dermatologist. First, the realization

that psoriatic arthritis is far more prevalent than we

had once believed. Drs. Ruderman and Mease, two

rheumatologists who are fully conversant with psori-

atic arthritis and its impact on the dermatologist, re-

view psoriatic arthritis in a way that will prove of

great value to the dermatologist in clinical practice.

The next article reviews how we as dermatologists can

integrate all these new drugs, particularly the biologic

agents, into our clinical practices.

Finally, Dr. Griffiths, an acknowledged leader

in investigative and clinical research as well as pso-

riasis therapy, gives a fascinating insight into how

psoriasis research and therapy is likely to evolve in the

years ahead.

We sincerely hope that this issue of the Dermato-

logic Clinics, which is designed to familiarize the

reader with the latest updates in psoriasis, will prove

both interesting and valuable as a ready reference for

practitioners who have an interest in psoriasis.

Alan Menter, MD

Jennifer Cather, MD

Baylor University Medical Center

5310 Harvest Hill Road, Suite 260

Dallas, TX 75230, USA

E-mail addresses: [email protected]

(A. Menter); [email protected] (J. Cather)

Dermatol Clin 22 (2004) 339–347

An update on the genetics of psoriasis

Francesca Capon, PhDa,*, Richard C. Trembath, MB, BS, FRCP, FMedScia,Jonathan N. Barker, MD, FRCP, FRCPathb

aDivision of Medical Genetics, Department of Genetics and Cardiovascular Sciences, University of Leicester, Adrian Building,

University Road, Leicester LE1 7RH, UKbDivision of Skin Sciences, St John’s Institute of Dermatology, St Thomas Hospital, Kings College, London SE1 7EH, UK

The existence of a genetic component to psoriasis traditionally been achieved by genotyping markers

has long been recognized, with repeated observations

of familial clustering [1,2] together with increased

concordance rates among monozygotic twins [3]. The

increase in disease risk among patient siblings ranges

from 4 to 6 [4,5], a relatively low ratio, consistent with

a multifactorial mode of inheritance (Fig. 1). These

observations contribute to the widely held view that

psoriasis is a disorder of complex etiology, requiring

the interaction between environmental triggers and

inherited susceptibility alleles. The dissection of such

an intricate model has proved challenging, necessi-

tating the recruitment of increasingly large patient

resources and the development of specifically de-

signed statistical tools. Despite these difficulties, the

last few years have witnessed significant progress in

the field, leading several research groups to close in on

the major psoriasis-susceptibility genes. It seems

timely to review these advances, while highlighting

the controversies and difficulties still to be faced by

the research community.

Chromosome 6p21 harbors the major psoriasis-

susceptibility locus (psoriasis-susceptibility 1)

Defining the psoriasis-susceptibility 1 interval

The first step in the isolation of a disease gene is the

identification of the chromosomal region (locus) bear-

ing the gene responsible for the disorder. This has


doi:10.1016/S0733-8635(03)00125-6

* Corresponding author.

E-mail address: [email protected] (F. Capon).

that cover the entire genome and identifying those that

are co-inherited by affected sib pairs more frequently

than the 50% prior expectation. Such genome-wide

scans have now been performed in several extended

patient cohorts and have repeatedly identified a region

of chromosome 6p21 as a contributor to psoriasis

susceptibility (Table 1). This degree of consistency

among genome-scan results in the analyses of complex

disorders is uncommon. Many studies are typically

plagued by poor reproducibility, caused in part by a

number of recognized confounder issues (Table 2).

Hence, the repeated identification of a 6p21 suscepti-

bility locus (psoriasis susceptibility 1 [PSORS1]) in

several independent samples clearly indicates a major

pathogenic role for this region.

Several attempts have been made to refine the

boundaries of the PSORS1 interval, to define a

minimal target region to focus the search for the

6p21 susceptibility genes. These refinement studies

have sought to identify haplotypes (blocks of markers

grouped together on a chromosome) that are trans-

mitted to affected patients more often than expected

by chance. The rationale behind this approach is that

marker alleles lying in close proximity to a mutation

tend to be in linkage disequilibrium with it (ie, they

are very seldom separated from it by recombination

or cross-over events) (Fig. 2). As a consequence,

marker alleles whose frequency is increased in patient

cohorts may be used to highlight the most likely

location of a susceptibility gene (see Fig. 2).

Three studies reported the fine-scale mapping of

the PSORS1 interval and a consensus minimal region

has emerged. The PSORS1 segment is contained

within a 200-kb block of DNA in the class I major

s reserved.

Fig. 1. A modest degree of family clustering is consistent

with a polygenic mode of disease inheritance. Upper pedi-

gree: an individual affected by a dominant monogenic

disorder caused by mutated allele A transmits the disease to

half (50%) of his offspring. Lower pedigree: an individual

affected by a polygenic disorder requiring the presence of

mutated alleles A, B, and C transmits the disease to one

(12.5%) in eight of his offspring. Square, male; circle, fe-

male; filled symbol, affected; empty symbol, unaffected.

Table 2

Major factors affecting the reproducibility of complex trait

genetic analysis

Confounder Example

Genetic heterogeneity Different genes cause the

same disease, in two

unrelated populations

Lack of statistical power The analyzed sample is

too small to detect the

effect of a given locus

Occurrence of phenocopies Part of the patients are

affected by a nonhereditary

form of the disease

Diagnostic criteria Diverse inclusion criteria

have been used in different

studies

Experimental design Different statistical tools

have been used in various

surveys

False-positives Originally published results

were in fact spurious

In-depth treatises of these issues can be found in Refs.

[73,74].

F. Capon et al / Dermatol Clin 22 (2004) 339–347340

histocompatibility complex (MHC) region (Fig. 3)

[6–8]. One study reported a further refinement of the

critical interval, describing a 60-kb minimal suscep-

tibility region [7] (RH1 segment in Fig. 3). This result

has generated some controversy in the field, however,

with a consensus view that the larger 200-kb interval

may not be discounted at this time [9,10]. The RH1

segment was defined by comparing a number of risk

haplotypes, most of which also contained a second

Table 1

Studies implicating the psoriasis-susceptibility 1 region in

psoriasis susceptibility

Authors Sample origin

Nair et al [65] Germany, United States

Trembath et al [49] United Kingdom

Capon et al [71] Italy

Samuelsson et al [72] Sweden

Lee et al [63] Germany

Veal et al [66] United Kingdom

Zhang et al [67] China

Zheng et al [70] China

conserved block, RH2 (see Fig. 3). The definition of

the minimal PSORS1 region was based on the

observation of a single Cw6-negative risk haplotype

bearing RH1 only (see Fig. 3). A collaborative survey

of an extended patient cohort failed to validate this

chromosome as conferring risk, however, pointing to

a more conservative minimal region, including HLA-

C and RH2, together with RH1 (see Fig. 3) [11].

Psoriasis-susceptibility 1 candidate genes

The consensus 200-kb PSORS1 interval contains

several genes, most of which have been investigated

as positional candidates for psoriasis susceptibility.

HLA-C lies at the centromeric end of the interval and

has long been considered a likely psoriasis-suscepti-

bility gene [12]. The HLA-C gene encodes a MHC

class I antigen participating to the process of immune

system self-recognition and self-tolerance [13]. Class

I molecules also stimulate the response against intra-

cellular pathogens, by presenting nonself cytoplasm

peptides to cytotoxic T cells [13]. HLA-C polymor-

phisms have been investigated in a wide range of

populations and a highly significant association be-

tween the HLA-Cw6 allele and psoriasis has been

repeatedly reported [10,12]. Association studies have

also defined the HLA-Cw6 allele as a factor that

predisposes to early onset disease [14,15] and to the

exacerbating action of streptococcal infections

[14,16]. Despite the significance and consistency of

association findings, it is not known whether the

Fig. 2. Linkage disequilibrium as a tool for the fine mapping of disease loci. The analysis of six polymorphisms spanning a

susceptibility interval shows that patients from unrelated families share a core two-marker haplotype (A7–A2). The preservation

of this genomic segment indicates linkage disequilibrium (ie, lack of recombination because of close proximity) between the two

markers and the susceptibility mutation (asterisk). The conserved haplotype (filled bar) defines the minimal region that is most

likely to harbor the disease-susceptibility gene.

F. Capon et al / Dermatol Clin 22 (2004) 339–347 341

HLA-Cw6 antigen participates in the cellular pro-

cesses that lead to the onset of psoriasis. In the

absence of functional data, it remains possible that

the reported association merely reflects HLA-C prox-

imity to an as yet undisclosed susceptibility mutation.

In addition to HLA-C, the consensus PSORS1

region contains seven known genes (see Fig. 3). Of

these, OTF3 and STG have been considered unlikely

candidates, based on the known characteristics of

their protein products. OTF3 encodes a transcription-

al factor playing a major role in embryonic stem cells

lineage commitment [17], whereas STG codes for an

extracellular protein that is only expressed in the

tongue taste buds [18]. The SC1 and SPR1 genes

seem not to show association with psoriasis [19,20],

and SEEK1 has not yet been characterized in terms of

function, expression pattern, or polymorphism con-

tent. In contrast to this group of genes, both HCR and

CDSN have been extensively investigated and have

been seen in independent reports to show association

with psoriasis. HCR (alpha-Helix Coiled coil Rod

homologue) encodes a highly polymorphic, ubiqui-

tously expressed protein of unknown function, which

is up-regulated in psoriatic epidermis [21,22]. An

association between psoriasis and two HCR variants

first reported in the Finnish population [21] has been

confirmed in studies of several ethnic groups [10,22].

The pathogenicity of these variants remains unclear,

however, not least because haplotypes have been

identified that are overtransmitted to affected patients

but lack the HCR risk alleles [23,24]. A collaborative

analysis of an extended patient resource has also been

reported but failed to discriminate whether the asso-

ciation at the HCR variants was caused by their

proximity to HLA-Cw6 or vice versa [10].

The CDSN gene lies at the distal end of the

PSORS1 interval (see Fig. 3) and codes for corneo-

desmosin, a structural protein that participates in the

process of keratinocyte adhesion and desquamation

[25,26]. Homozygous, nonsense CDSN mutations

Fig. 3. The PSORS1 region refinement proposed by Nair et al [7]. The upper diagram shows the 200-kb consensus minimal

region together with the eight known genes contained therein. HLA-C, HCR, and CDSN are highlighted as genes that have

repeatedly been associated with psoriasis. The lower diagram schematizes the PSORS1 risk haplotypes reported by Nair et al [7],

with different line styles symbolizing regions of haplotype divergence. Following to the exclusion of the bottom haplotype, the

minimal region shared by all risk chromosomes expands to include both HLA-C and RH2.


have been identified in patients with the rare, auto-

somal-recessive disorder hypotrichosis simplex of the

scalp [27]. The observation of CDSN-specific expres-

sion in cornified squamous epithelia [28], together

with its up-regulation and abnormal degradation in

psoriatic epidermis [29–31], have generated a con-

siderable interest in this gene. The CDSN gene is

highly polymorphic, with 37 sequence variants de-

scribed [32,33]. Association analyses have identified

three variants defining an intragenic haplotype that

confers risk to psoriasis in a wide range of popula-

tions [33–38]. The biologic relevance of these find-

ings has been questioned, however, based on the

argument already put forward against the HCR risk

alleles (ie, that the observed association could be

Fig. 4. Both HLA-C and CDSN risk alleles might be required to c

200-kb consensus PSORS1 minimal region. The lower bars schema

and Capon et al [33]. Risk haplotypes carry both HLA-C and CDS

set of risk SNPs (HLA-C or CDSN only) are neutral.

ascribed to linkage disequilibrium with HLA-Cw6)

[39,40].

How many psoriasis-susceptibility 1 genes?

The controversies surrounding the analysis of can-

didate genes have highlighted the difficulties of

carrying out association studies in a region where ex-

tensive linkage disequilibrium between marker alleles

can act as a major confounder. To unravel the rela-

tionship between the HLA-C, HCR, and CDSN

associations, haplotypes spanning the PSORS1 inter-

val and encompassing these three loci have been

generated (Fig. 4) [24]. To maximize the genetic

resolution of the study single nucleotide polymor-

onfer psoriasis susceptibility. The upper diagram shows the

tize the PSORS1 SNP haplotypes reported by Veal et al [24]

N related risk alleles, whereas chromosomes bearing a single

Table 3

Published non–major histocompatibility complex suscepti-

bility loci

Chromosome

(locus name) Sample origin

1p (PSORS7) United Kingdom [66]

1q (PSORS4)a Italy, United States [4,68]

2pa United States, United Kingdom [4,66]

2q United Kingdom [49]

3q (PSORS5) Sweden [51,72]

4q13a United States, Sweden [4,72]

4q31 China [67]

4q34a (PSORS3) Ireland [64]

6qa United States, Germany [65]

7 United Kingdom [49]

8qa United Kingdom [49]

10qa United States, Germany [65]


phism markers distributed across the interval have

been identified. Single nucleotide polymorphisms

occur at a higher frequency in the genome [41], al-

lowing the construction of more dense genetic maps.

In addition, single nucleotide polymorphisms exhibit

a much lower mutation rate compared with micro-

satellite markers [41] and as such are more suited to

the reconstruction of very ancient haplotypes. The

single nucleotide polymorphism–based dissection of

the PSORS1 interval has identified a major risk

haplotype bearing HLA-C, HCR, and CDSN dis-

ease-associated alleles (cluster E in Fig. 4), together

with a minor risk chromosome (cluster D in Fig. 4)

carrying HLA-C and CDSN risk variants only [24].

These observations have subsequently been repli-

cated in an independent population of northern Indian

descent, where two novel haplotypes (G1 and G2 in

Fig. 4) were identified that carried a single set of

risk alleles and did not show any association with

psoriasis [33]. Taken together, these findings have

prompted the intriguing hypothesis that both HLA-C

and CDSN alleles may contribute to psoriasis sus-

ceptibility. The possibility that multiple genes may

underlie a single susceptibility locus is not a novel

concept in the genetics of common multifactorial

disorders, because compound MHC risk alleles have

already been observed within loci conferring suscep-

tibility to type I diabetes [42] and multiple sclerosis

[43]. It is tempting to speculate that further MHC

genes, lying outside of the minimal PSORS1 interval,

might also contribute to or modify an individual’s

genetic susceptibility. In fact, genetic associations

with psoriasis have been reported for a number of

genes lying proximal to HLA-C. These include the

TAP genes, which encode a heterodimeric complex

delivering antigenic peptides to the endoplasmic

reticulum before the assembly of class I molecules

[44,45], and MICA, which codes for a ligand of the

natural killer cell activating receptor NKG2D [46,47].

Significant associations have also been reported for

polymorphisms of the tumor necrosis factor-beta

gene, which encodes the lymphotoxin alpha cytokine

[45,48].
14qa United Kingdom, United States [4,66]
15 Sweden [72]

16qa United States, Germany, Icelandb

[62,65]

17q25a (PSORS2) United States, Germany, Sweden,

China [51,61,65,70,72]

19p13 (PSORS6) Germany, United Kingdom [63]

20pa Germany, United Kingdom, United

States [7,49,65]

a Loci included in the International Psoriasis Genetics

Study [50].b Psoriatic arthritis cohort.

Non–major histocompatibility complex

susceptibility loci: separating the wheat from the

chaff

The non–major histocompatibility complex

contribution to psoriasis susceptibility

The evidence supporting PSORS1 as the major

psoriasis susceptibility locus is by now overwhelm-

ing. PSORS1 accounts for less than 50% of familial

aggregation in psoriasis [49,50], however, hence

other susceptibility loci must contribute to the dis-

order pathogenesis. Genome-wide scans have identi-

fied a number of such non-MHC susceptibility

intervals (Table 3), but the validation of these regions

in independent dataset has proved a challenging task.

Unlike PSORS1, most non-MHC loci have been ob-

served only once and, with the exception of PSORS2,

none of them has been replicated in more than two

populations (see Table 3). The inconsistency of these

findings can be accounted for by confounders that

generally complicate the genetic dissection of com-

plex traits (see Table 2). In the case of psoriasis, the

repeated observation of distinct susceptibility regions

(see Table 3) highlights the likely presence of ge-

netic heterogeneity, well known to affect the repro-

ducibility of localization studies. The small effect of

non-MHC susceptibility loci is also likely to be a

confounder, with undersized patient cohorts lacking

the power to replicate regions of relatively mod-

est effect. Finally, some susceptibility loci might be

unique to the population where they were identified.


This might be particularly true for samples originat-

ing from genetic isolates, such as the cohort from

southwest Sweden in which the PSORS5 suscepti-

bility interval has been reported [51].

Possible approaches to locus validation

The positional cloning of a susceptibility gene is a

labor-intensive and costly endeavor, which is unlikely

to be undertaken unless the chromosomal assignment

of the relevant locus is supported by robust statistical

evidence. The validation of non-MHC susceptibility

loci and the identification of regions warranting fur-

ther investigation are essential steps in the dissection

of psoriasis genetics. To achieve these objectives, an

extended clinical resource was recently established

by integrating the patient cohorts from three research

centers [50]. This pooled sample included 942 affect-

ed sib pairs and, being the largest yet analyzed in a

psoriasis genetics study, was expected to have enough

statistical power to validate non-MHC loci. The pa-

tient data set was typed using 53 markers, which

spanned a number of published susceptibility regions

(labeled with an asterisk in Table 3) and statistically

significant evidence was gathered in support of the

10q and 16q loci [50]. Although these results un-

doubtedly warrant a closer scrutiny of the previously

mentioned regions, they cannot be interpreted as a

definite exclusion of all the remaining non-MHC loci.

In fact, it is entirely possible that even a dataset as

large as the Consortium’s may lack the power to

detect a non-MHC locus in the presence of substantial

genetic heterogeneity. This interpretation is consistent

with independent evidence that has emerged from the

analysis of a distinct inflammatory disorder (atopic

eczema). Indeed, genome-wide searches for loci pre-

disposing to childhood atopic dermatitis have identi-

fied four chromosomal regions closely overlapping

with the 1q21, 3q21, 17q25, and 20p psoriasis-

susceptibility intervals [52,53]. Colocalization of loci

predisposing to different inflammatory disorders is

not unusual and it has been hypothesized that a com-

mon set of genes influencing the immune response

may underlie clinically distinct complex diseases

[54]. The possibility that some of the reported colo-

calizations might be coincidental should always be

considered, however, given the broad extension of the

susceptibility regions detected by genome-wide scans

and the occurrence of false-positive findings in these

studies. Nonetheless, the overlap between atopic der-

matitis and psoriasis-susceptibility regions is thought

to underlie a set of common genetic determinants,

because it has been estimated that the likelihood of

identifying four atopic dermatitis loci colocalizing by

chance with an equal number of psoriasis suscepti-

bility intervals is less than 1:100,000 [52]. Another

possible instance of a shared inflammatory locus

is the chromosome 16q susceptibility region, which

also contains the NOD2-CARD15 Crohn’s disease

gene [55,56]. Case-control and family-based studies

have failed to detect an association between the ma-

jor NOD2 risk allele and psoriasis susceptibility

[57–59]. Preliminary data obtained in the Newfound-

land genetic isolate, however, support an association

between a distinct NOD2 variant and psoriatic arthri-

tis [60].

Summary

It will soon be 10 years since Tomfohrde et al [61]

identified the first psoriasis-susceptibility locus

through a genome-wide scan of eight extended Amer-

ican pedigrees. Nine further genome-scans totaling

almost 800 pedigrees have followed [49,51,62–68]

and at least 500 additional families have been ana-

lyzed in follow-up studies of published loci [50,69,

70]. This major research effort has led to considerable

insights as to the genetic basis of psoriasis suscepti-

bility, notwithstanding the inevitable appearance of

contradictory findings. The evidence supporting a

primary role for the PSORS1 locus is now over-

whelming. Remarkably, psoriasis is the only complex

disorder that has been consistently associated with

an HLA-C allele. This indicates that HLA-Cw6 (or

the undiscovered susceptibility variant that may be

in linkage disequilibrium with it) affects the disease

risk by specifically predisposing to psoriasis, rather

than by conferring a generic susceptibility to inflam-

matory disorders.

Dissecting the contribution of non-MHC loci is

proving a somewhat arduous task, because of their

less prominent role and the likely occurrence of

genetic heterogeneity. Unlike PSORS1, several non-

MHC susceptibility intervals overlap with loci pre-

disposing to other inflammatory or autoimmune

diseases. The identification of the genes underlying

these loci may benefit the understanding of clinically

distinct conditions.

The disease model emerging from 10 years of

genetic analyses is, not unexpectedly, a rather elabo-

rate one, where psoriasis-specific determinants are

likely to interact with a potentially large number of

inflammatory loci and environmental triggers. In this

context, the availability of the human genome se-

quence and the establishment of collaborative pa-

tients’ resources are going to prove essential tools


to disentangle the contribution of individual psoria-

sis-susceptibility genes.

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Dermatol Clin 22 (2004) 349–369

Current concepts in the immunopathogenesis of psoriasis

Michelle A. Lowes, MD, PhDa, Wook Lew, MD, PhDb,James G. Krueger, MD, PhDa,*

aRockefeller University, 1230 York Avenue, Box 178, New York, NY 10021, USAbDepartment of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine,

Yongdong Severance Hospital, 146-92 Dogok-Dong, Kangnam-Ku, Seoul, South Korea

Psoriasis vulgaris affects approximately 2% of the therapy used in individuals with psoriasis is cyto-

US population, and although it varies in severity, it

imposes a great burden on those who have this

disease. Psoriasis was initially considered to be a

primary disorder of keratinocytes, with disturbed

epidermal differentiation leading to keratinocyte

hyperproliferation. Now there is much evidence to

support the involvement of the immune system in the

pathogenesis and maintenance of psoriasis, including

roles for CD8+ and CD4+ lymphocytes, dendritic cells

(DCs), monocytes/macrophages, and natural killer

(NK) and natural killer T (NK-T) cells. Keratinocytes

may still play an integral role, responding to the

leukocyte infiltration and cytokine environment.

Novel anti–T-lymphocyte immunotherapies, and

review of the mechanisms of some traditional anti-

psoriatic medications, have confirmed an important

role of the immune system in psoriasis (reviewed in

reference [1]). Therapies aimed at different immune

targets have proved successful, although there is

variability in clinical response between patients,

reflecting the complexity of psoriasis pathogenesis

and redundancy of immune pathways. The first

such treatment used the immunotoxin DAB389IL-2,

which is a fusion protein carrying a cellular toxin to

interleukin 2R (IL-2R)–expressing cells [2]. This

agent blocks proliferation of activated lymphocytes,

and clinical improvement was associated with reduc-

tion in intraepidermal CD3+ and CD8+ T cells,

therefore supporting the role of these cells in dis-

ease pathogenesis. Another important antilymphocyte


doi:10.1016/j.det.2004.03.010


E-mail address: [email protected] (J.G. Krueger).

toxic T-lymphocyte–associated antigen 4-immuno-

globulin (CTLA4-Ig) [3]. Molecules in the B7

family on the surface of antigen-presenting cells

(APCs) normally engage CD28 on T cells, which

delivers costimulatory signals during T-cell activa-

tion, or CTLA4, which delivers a negative signal.

Blocking this interaction with CTLA4-Ig in indi-

viduals with psoriasis showed a dose-dependent

clinical response associated with reduction of cell

activation markers. Other examples of immuno-

biologic mechanisms are discussed and tabulated in

reference [4], and some are also discussed in other

articles in this issue. The current theories of the roles

of components and the potential functions of the

innate and cell-mediated immune system are dis-

cussed, focusing on current concepts of the immuno-

pathogenesis of psoriasis. The role of xenotransplant

and other mouse models, and the contribution of

recent genomic studies, are also outlined in the con-

text of further understanding psoriasis.

Psoriasis as a type 1 T-cell–mediated autoimmune

disease

There is mounting evidence that psoriasis may be a

type 1 T-cell–mediated autoimmune disease, such as

type 1 diabetes or multiple sclerosis. In such type 1

autoimmune diseases, there is characteristic activation

and proliferation of pathogenic antigen-specific CD4+

or CD8+ T cells, and the responsible lymphocytes are

activated type 1 (interferon g [IFN-g�]–producing)

memory cells. Initially, morphologic studies showed

abundant lymphocytes within lesional skin (along

s reserved.

M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369350

with characteristic neutrophils), but few monoclonal

antibodies were available to classify these cells fur-

ther. Fig. 1 shows the relevant cell types that have

been described in psoriatic tissue and important in-

flammatory products that are likely to play a role in

disease pathogenesis.

Immunohistochemical analysis of these abundant

lymphocytes in lesional tissue and fluorescence-acti-

vated cell sorting (FACS) of epidermal and dermal

single-cell suspensions reveal patterns consistent with

immunologic memory and specialized tissue homing.

There are abundant CD4+ T cells in psoriatic dermis

and CD8+ T cells in the epidermis [5,6]. Lesional

T cells demonstrate the surface marker cutaneous

lymphocyte antigen (CLA), which allows them to

bind to endothelial P- and E-selectin, facilitating

transmigration across the cutaneous vasculature [7].

Epidermal CD8+ T cells are CXCR3+. CXCR3 is a

chemokine receptor that allows these cells to respond

to epidermal chemokine gradients from keratinocyte-

Fig. 1. Psoriasis as a type 1–mediated disease. CLA+ memory

extravasate across inflamed blood vessels, responding to chemokin

dermis, and CD8+ Tc1 cells are found in the epidermis. Both are abl

augment the psoriatic inflammatory process. Activated DCs play a

within the psoriatic lesion by means of type 1 cytokines IL-12 an

direct and downstream effects of these locally produced cytokines

derived monokine induced by IFN-g (MIG) and IFN

inducible protein 10 (IP-10), and migrate into the

epidermis [8]. Many CD8+ lymphocytes bear the

aEb7 (CD103/b7) integrin, which facilitiates move-

ment into the epidermis by way of keratinocyte

E-cadherin [8,9]. Thus, there is specialization in the

surface phenotype of these cells to encourage their

movement into psoriatic lesional tissue.

Lesional epidermal lymphocytes are persistently

activated, as shown by the following: up-regulation of

CD69, a rapidly induced antigen; CD25, the low-

affinity receptor for IL-2 (a chain); and the major

histocompatibility complex (MHC) class II molecule

HLA-DR [6]. Although a universal and specific pso-

riatic antigen has not yet been determined, there is

oligoclonal expansion of CD8+ T-cell receptor (TCR)

b-chain components within psoriatic lesions, particu-

larly of the complementary determining region 3, or

CDR3. The specific TCR chain that is preferentially

expressed is not the same in all patients [10–12]. Over

T lymphocytes and polymorphonuclear (PMN) leukocytes

e gradients. CD4+ Th1 cells are found predominantly in the

e to produce type 1 cytokines IL-2, IFN-g, and TNF-a, whichrole in T-cell activation both in the draining lymph node and

d IL-23. The phenotype of psoriasis is likely caused by the

and chemokines.

M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 351

time, dominant TCR rearrangements persist in re-

lapsing psoriasis [13]. This finding suggests the pres-

ence of ongoing specific antigen, or at least favorable

conditions for clonal in situ T-cell proliferation. Epi-

dermal and dermal CD8+ cytotoxic T-cell (Tc) clones

also have been developed, some of which release

mediators capable of causing keratinocyte prolifera-

tion [14] or producing IFN-g [15].

T-helper (Th) cell (CD4+) differentiation can be

categorized into a type 1 (IFN-g– and IL-2–produc-

ing) versus type 2 (IL-4– and IL-10–producing)

cytokine pattern (Th1 versus Th2, respectively). Simi-

larly, CD8+ cytotoxic T cells can be functionally dif-

ferentiated into two populations, Tc1 and Tc2, which

secrete these two patterns of cytokines [16]. CD4+ and

CD8+ T cells from psoriatic epidermal and dermal

single-cell suspensions produce a type 1 pattern of

cytokines, specifically IFN-g and IL-2, and small

amounts of type 2 cytokines, IL-4 and IL-10 [17].

Tumor necrosis factor a (TNF-a), a cytokine that may

be produced by many cells during innate and cell-

mediated immune responses, is also increased from

lesional lymphocytes. Essentially all type 1 (IFN-g–producing) T cells cosynthesize TNF-a when acti-

vated. Elaborated cytokines are able to orchestrate

further proliferation of antigen-specific T cells, and

activation of effector and responding cells, such as

CD8+ T cells, macrophages, and keratinocytes.

Patients with psoriasis also demonstrate systemic

type 1 immune deviation (Fig. 2), with two- to

threefold expansion of type 1 T cells producing IFN-

g and IL-2 [17–19].

The specific cytokine milieu can determine the

process of type 1 versus type 2 differentiation. IL-12,

produced by activated DCs, stimulates the production

of a type 1 cytokine pattern. IL-13 leads to the

production of IL-4 and IL-10, a more immunosup-

pressive type 2 pattern that is also associated with

antibody production. There are increased IL-12 and

IL-12R found within psoriatic lesions [20,21], which

may drive type 1 T-cell differentiation. One of the

major stimuli for DCs to produce IL-12 is the ligation

Fig. 2. Immune deviation in psoriasis. In homeostatic conditions, th

than type 2 (T2) cytokines (IL-4, IL-10). In diseases characterized b

In type 2 immune deviations, there are more type 2 cytokines tha

of DC CD40 by the CD40 ligand (CD40L) on CD4+

T cells [22,23]. This sets up a scenario where acti-

vated CD4+ T cells engage DCs by means of a

CD40L–CD40 interaction, resulting in IL-12 pro-

duction by DCs and subsequently driving the pro-

duction of the classic type 1 cytokine, IFN-g.This CD40–CD40L interaction also generates the

production of IL-23 [24], another important, recently

discovered type 1 cytokine. IL-23 is a heterodimer

composed of one of the IL-12 chains (p40) and an

IL-23–specific chain (p19; reviewed in reference

[25]). This cytokine shares many features with IL-12,

such as signal transduction pathways, induction of

IFN-g production, target cell proliferation, and up-

regulation of APC costimulatory function. It acts

primarily on memory CD4+ T cells, however, whereas

IL-12 acts on naıve CD4+ T cells. IL-23 is up-

regulated in psoriasis [26] and may be the key

cytokine driving type 1 T-cell expansion and the

production of IFN-g.The current authors believe that IFN-g is a pivotal

cytokine in the development and maintenance of

psoriatic lesions. Fig. 3 outlines a sequential pathway

of type 1 T-cell activation, release of T-cell–derived

cytokines, and production of several inflammatory

mediators that the authors term the type 1 pathogenic

pathway. IFN-g is produced by effector memory

CD8+ T cells, epidermal Tc1, CD4+ T cells, and NK

and NK-T cells. Psoriatic CD8+ Tc1 cell lines and

clones have been shown to produce heterogeneous

levels of IFN-g [15]. There is also evidence of the

effects of IFN-g at the tissue level in psoriatic lesions:keratinocytes show increased levels of HLA-DR,

intercellular adhesion molecule-1 (ICAM-1) [27],

and CD40 [28]; increased CXCR3 expression on

lymphocytes [8]; and greater levels of keratinocyte-

derived MIG and IP-10 [8]. Furthermore, this cyto-

kine may also increase expression of costimulatory

molecules on DCs [29]. IFN-g potently activates

macrophages and may also induce TNF-a release

from monocytes and macrophages, which acts syner-

gistically with IFN-g in an inflammatory response

ere are more type 1 (T1) cytokines (IL-2, IFN-g, and TNF-a)y a type 1 immune deviation, there are more type 1 cytokines.

n normal.

Fig. 3. Type 1 pathogenic pathway in psoriasis. The current authors have proposed that IL-12 and IL-23, primarily DC-derived

cytokines, stimulate type 1 T cells to produce type 1 cytokines. This has many effects at the gene level, and the resultant products

help explain the phenotype of psoriatic lesions. For some genes there is synergy between IFN-g and TNF-a. GAS, IFN-gactivation sequence; ISRE, IFN-stimulated response element.


[30]. Endothelial cells are also responsive to IFN-g,up-regulating several adhesion molecules, such as

ICAM-1 and vascular cell adhesion molecule-1

(VCAM-1), which facilitates the complex process of

leukocyte trafficking into tissues. The sum of cyto-

kines and chemokines made in response to IFN-g and

TNF-a (see Fig. 3) can explain many features of the

pathogenic process: angiogenesis and vascular ecta-

sia, T-cell and neutrophil emigration into lesions, and

some components of the psoriatic epidermal response.

There have been several additional observations

regarding the relationship between IFN-g and psoria-

sis. IFN-g receptors in keratinocytes [31] and IFN-gprotein in papillary dermal cells [32] have been

shown to be up-regulated in lesional skin of patients

with psoriasis. Subcutaneous administration of IFN-gfor the treatment of psoriatic arthritis can lead to the

occurrence of punctiform psoriatic foci at the site of

injection [33]. Patients with immunoblastic lymph-

adenopathy-like T-cell lymphoma showed elevated

serum levels of IFN-g and were reported to develop

psoriasis [34]. For treatment of lepromatous leprosy,

delivery of IFN-g resulted in several features present

in psoriatic lesional skin [35]. As mentioned, a type 1

bias toward activated T cells is indicated by the

overexpression of IFN-g in psoriasis, both lesionally

and in the circulating leukocytes [17]. There are also

preliminary data that blocking IFN-g in patients with

psoriasis may give a beneficial clinical effect [36].

Recent gene expression studies by microchip

analysis have begun to elucidate the pattern of cyto-

kines, inflammatory mediators, and transcriptional

factors within psoriatic tissue at the message level

(discussed later). Interpretation of this vast bank of

data is challenging, but the information can be

ordered on the basis of IFN-g responsive genes

(Fig. 4). After type 2 IFN (IFN-g) is produced, it

binds to the IFN-g cell surface receptor, which is

phosphorylated by janus kinase (JAK) 1 and JAK2

enzymes (reviewed in references [37–39]). This

process makes available a recruitment site for an

important transcriptional factor, the signal transducer

and activator of transcription (STAT). Dimers of

STAT-1 form an IFN-g–activated factor (GAF),

translocate to the nucleus, and activate transcription

from IFN-g target gene promoters containing IFN-gactivation sequence (GAS) elements. Thus, STAT-1

production is an important early indicator of IFN-geffects. Other primary response genes include addi-

tional IFN transcription factors and MIG. Down-

stream effects of IFN-g include the secondary

response genes, which may contribute to the devel-

opment of the psoriatic phenotype, such as IL-8 and

IP-10. Type 1 IFNs (IFN-a and IFN-b) are also able

to induce many genes on the IFN-g pathway, particu-

larly the secondary response genes.

APCs are central to the process of antigen-specific

T-cell activation (reviewed in reference [40]). The

first DC described in normal epidermis, but which

can also be found in the dermis, was the Langerhans’

cell (LC). This cell can be identified by surface anti-

gens MHC class I and II, CD1a, langerin, lag, and

Birbeck granules. LCs are extremely efficient at

capturing local antigen, and after activation, they

migrate to local lymph nodes by way of cutaneous

lymphatics. During migration, they mature for in-

Fig. 4. IFN receptor binding and effects. Binding of IFN-g to its receptor causes STAT-1 phosphorylation and dimerization to

form the IFN-g–activating factor (GAF). GAF is able to translocate to the nucleus and bind to IFN-g activation sequence (GAS)

in promoters for translation of IFN primary response genes. Binding of type 1 IFNs (IFN-a or IFN-b) to the type 1 IFN receptor

causes production of IFN-stimulated gene factor 3 (ISGF3), which is composed of STAT1, STAT 2, and IFN regulatory factor 9

(IRF-9, p48). ISRE is able to bind to the ISRE sequence in gene promoters leading to transcription of IFN-g secondary response

genes in the IFN-g pathway. There is cross-talk between these two IFN systems: STAT1 dimers (GAF) can bind IRF-9 and also

activate ISRE (reviewed in Refs. [37–39]).


creased antigen presentation to lymphocytes, by up-

regulating MHC class I and II, costimulatory mole-

cules B7.1 and B7.2 (CD80 and CD86, respectively),

and CD83. These mature DCs have the capacity to

stimulate resting and memory T cells, unlike other

nonprofessional APCs, such as monocytes or B cells,

which can only activate memory T cells. Inflamed

epidermis has two additional types of DCs [41]. The

inflammatory dendritic epidermal cell, or IDEC, lacks

Birbeck granules; is positive for CD1a, HLA-DR,

CD11b, CD11c; and expresses costimulatory mole-

cules in situ. More recently, the plasmacytoid den-

dritic cell (PDC or DC2) has been identified in

psoriatic lesional skin. PDCs were increased in epi-

dermal single-cell suspensions of psoriasis compared

with other inflammatory dermatoses or normal skin.

This cell has a characteristic ‘‘plasmacytoid’’ mor-

phology, is CD123+ and CD11c�, and makes large

amounts of type 1 IFN on viral infection or stimula-

tion with CpG motifs within microbial DNA. Mature

activated plasmacytoid DCs are functionally special-

ized to prime a Th2 pattern of cytokine production.

Currently, there exists controversy regarding the

capacity for PDC to produce IL-12 and promote an

IL-12–dependent Th1 response [42].

Other DCs that are located in the dermis are factor

XIIIa+ and called dermal DCs (DDC). Factor XIIIa+

DCs were increased in psoriatic skin [43]. These cells

also have an excellent capacity for antigen capture,

migration, and MHC-restricted presentation to lym-

phocytes. DDCs can be further subdivided into three

subsets: CD1a� CD14�, CD1a+ CD14�, and CD1a�

CD14+ [44]. DCs from psoriatic plaques are able to

present to and activate T cells [44,45], concurrently

producing IL-12 and potentially setting up a local type

1 immune response that is perpetuated rather than self-

limited. Psoriatic-derived DDCs were able to stimu-

late spontaneous T-cell proliferation and increase IL-2

and IFN-g production compared with blood-derived

or normal skin–derived DCs. There was involvement

of HLA-DR, B7, and leukocyte function-associated

antigen 1 (LFA-1). There are also activated macro-

phages in psoriatic tissue [46], which may represent a

source of blood-derived APCs. The presence of ma-

ture epidermal and dermal DCs, defined by CD83,

DC-lysome– associated membrane protein (DC-

LAMP), and CD11c positivity [3], supports the con-

cept of the psoriatic lesion becoming more like

peripheral lymphoid tissue, capable of initiation and

maintenance of inflammation. This concept will be

further discussed later.

The study of the actions and role of DCs in disease

states is complicated because there is no uniform

method for generating sufficient quantities of DCs

for study in vitro, and the relationship between these

DCs derived from blood or bone marrow with in vivo

DCs is not yet fully understood. IFN-g can act to

stimulate uncommitted myeloid immature DCs to


produce IL-12 and polarize toward Th1 responses

[47]. An alternative method to study cutaneous DCs

is to culture skin biopsy specimens, which yield DC

‘‘crawl outs’’ [45]. In addition, epidermal and dermal

cell suspensions can give rise to DCs suitable for

surface phenotype analysis or functional studies. Al-

though clinicians still have much to learn about the

roles of different DC subsets in the regulation of

normal and pathogenic immune responses, the DC

repertoire in psoriasis is likely to regulate T-cell

activation and clonal expansion by conventional anti-

gen-presenting mechanisms and type 1 T-cell devia-

tion by cytokines such as IL-12 and IL-23 (see Fig. 3).

In addition, DCs are likely to contribute nitric oxide

(NO) to the inflammatory environment, because in-

ducible NO synthetase (iNOS) is highly up-regulated

in activated DCs, and NO even has been postulated as

a psoriasis-triggering factor [48]. Hence, DCs may be

as important in the maintenance of pathogenic immu-

nity in psoriatic plaques as T cells.

Innate immunity in psoriasis

Despite all the evidence reviewed previously, there

are also data to suggest that the innate immune system

is activated in psoriasis and may play an important

contributory role. Cellular and noncellular compo-

nents of primitive innate immunity give an immediate

or very fast proinflammatory cutaneous response to

microbial infection or nonspecific stimuli, such as

trauma [49]. Leukocytes that contribute to innate

immunity possess several types of pattern recognition

receptors (PRRs) that are individually nonpolymor-

phic, as opposed to adaptive responses where these

receptors are individually variable (eg, TCRs). Pro-

inflammatory molecules and cytokines, such as IL-1

and TNF-a, may be released from keratinoyctes,

macrophages, or DCs, activating endothelial cells

and recruiting additional leukocytes to the site of

inflammation. Pathogens are eliminated by mecha-

nisms such as superoxide anion release, defensins,

phagocytosis, and NK-cell killing. Tissue repair in

the skin is associated with additional changes, such

as epidermal hyperplasia and erythema, but these

changes reverse as homeostasis is restored.

TNF-a is an important cytokine of the innate

immune system, and recent beneficial clinical trials

with anti–TNF-a agents [50] point to its considerable

role in psoriasis. This cytokine may be produced by

many cells, including activated keratinocytes, in re-

sponse to nonspecific injury or stimulation. It induces

complex inflammatory cascades, initially by altering

endothelial cell adhesion molecules, causing neutro-

phil and NK-cell recruitment and stimulating produc-

tion of other cytokines by means of the NFkB pathway

[51]. There is convergence of the TNF-a and IFN-gsignaling pathways mediated by a composite GAS/kBpromoter element, leading to induction of regulatory

components of the IFN-g pathway [30].

Introduction of NK cells to an innate cutaneous

immune response provides a back-up system to the

previously mentioned keratinocyte reaction. NK cells

are bonemarrow–derived large granular lymphocytes,

which make up approximately 10% of circulating

peripheral blood lymphocytes, and probably initially

developed as an early host response to viral infection.

NK cells lack CD3 and T-cell receptor proteins but can

be identified by the following surface markers

(reviewed in reference [52]): CD2+, CD16+, CD56+,

CD57+, CD94+, CD158a+, and CD161. Although

there are diverse NK cell activation stimuli, including

IFNs, cytokines such as TNF-a, IL-2, and IL-15,

chemokines, and membrane-bound molecules on sur-

rounding tissues, effector function is tightly regulated.

NK cells possess low-affinity FcgRIII (CD16),

which enables them to perform one of their hallmark

functions, antibody-dependent cellular cytoxicity, to-

ward cells coated with antibody fragments. They do

this by the release of granzyme and perforin. NK cells

also have an additional function of specific NK-cell

cytotoxicity. NK cells can recognize ubiquitous sur-

face molecules on normal cells by means of receptors

known as killing activating receptors, or KARs. If the

target cell possesses MHC molecule, a killing inhibi-

tory receptor (KIR) is engaged and no attack takes

place. In abnormal cells, however, such as some

virally infected cells or tumor cells that lack MHC

molecules, the KIRs are not activated and perforin

and granzyme are released from the NK cell to effect

target cell death. Another important function of NK

cells is the early production of IFN-g, which may

augment immune responses to deal with the inflam-

matory stimulus. Most studies have shown NK cells

to be increased in psoriatic tissue [53,54] and de-

creased in the circulation [55].

An alternative mechanism to cause type 1 T-cell

activation is by the addition of proinflammatory

cytokines from other cells, such as DCs or keratino-

cytes. A recent important observation is that there is a

TCR-independent process whereby IL-12 can syner-

gize with IL-18 or IL-1b to stimulate production of

IFN-g from T cells by activating transcription factor

GAAD45b [56,57]. IL-18, previously known as IFN-

g–inducing factor, can also stimulate NK-cell IFN-gproduction and cytotoxicity. IL-18 and IL-1b can

both be produced by keratinocytes and macrophages,

monocytes, DCs, and T cells [58]. This finding


provides a mechanism to explain type 1 T-cell acti-

vation and cytokine release in the absence of TCR

engagement, and NK-cell activation.

A model that encompasses the presence of lym-

phocytes and DCs without antigen-specific TCR en-

gagement would require the activation of DCs

by means of non–antigen-specific mechanisms. This

would lead to release of inflammatory mediators, such

as IL-12, and lymphocyte activation and proliferation.

Recent genomics data suggest that DCs may produce

T-cell–activating IL-2 [59]. DCs do bear PRRs for

microbial antigens, which can lead to lymphocyte acti-

vation. Examples of such receptors include the fol-

lowing: mannose receptors; CD14, which binds LPS;

heat shock protein (HSP) receptors, such as CD91;

and Toll-like receptors (TLRs). Engagement of such

PRR causes DC activation, leading to a cytokine

environment that encourages Th1 or Th2 T-cell de-

velopment, depending on the nature of the stimulus.

TLRs are a recently described set of innate im-

mune receptors first discovered based on their ho-

mology with the Drosophilia melanogaster ortholog

protein, Toll. There are currently 10 described TLRs,

with specific ligands for each one, some having more

than one ligand (reviewed in reference [60]). For

example, the respective binding ligands for TLR2,

TLR3, TLR4, TLR5, and TLR9 are as follows: gram-

positive bacterial components, double-stranded RNA,

lipopolysaccharide, bacterial flagellin, and bacterial

CpG DNA. TLR signaling induces APC activation

and maturation, proinflammatory cytokine produc-

tion, such as TNF-a and IL-6, and increased expres-

sion of costimulatory molecules. Ligation of TLR

may induce a type 1 or type 2 cytokine response,

depending on the stimulus. Engagement of TLRs

may also lead to peptide loading of MHC class II

molecules in DCs, with enhancement of CD4+ T-cell

responses [61].

These TLRs are mainly expressed on professional

APCs and endothelial and epithelial cells. Studies

have revealed different patterns of TLR expression in

normal skin. Keratinocytes constitutively express

TLR1, TLR2, TLR4, and TLR5; DCs and DDCs

demonstrate TLR1 and TLR 4; and DDCs also

express TLR2 [62,63]. In psoriasis, there is increased

basal keratinocyte expression of TLR1, TLR2 is

mainly expressed by DDCs, and TLR4 is found on

epidermal DCs and DDCs with mid–epidermal-layer

keratinocytes displaying cell surface staining [62,63].

The alteration of TLRs in psoriasis points to their

possible role in activating DCs and keratinocytes,

leading to T-cell activation independent of the TCR,

which implies the significance of the innate immune

system in the psoriatic lesion.

HSPs are another conserved innate immune mech-

anism which may be involved in skin inflammation

(reviewed in reference [64]). HSPs are abundant,

intracellular, monoallelic proteins that can bind anti-

genic peptides generated within cells. They then

ligate a common receptor CD91 (a2-macroglobulin

receptor) and other receptors found predominantly on

APCs. This process initiates a cascade of innate

events, the earliest of which may be NFkB activation.

Ligation of HSP receptors then leads to secretion of

proinflammatory cytokines (eg, TNF-a, IL-12, IL-1b,and granulocyte macrophage-colony stimulating fac-

tor), chemokine secretion, production of iNOS and

NO, and DC maturation and migration to local lymph

nodes. HSPs may also chaperone their bound pep-

tides for MCH presentation and cross-presentation

and the generation of CD4+ and CD8+ responses.

HSPs 27, 60, and 70 have been found in psoriatic

epidermis. CD91 and other HSP binding receptors are

present on DDCs and fibroblasts (but not keratino-

cytes) in normal skin. DDCs up-regulate their CD91

expression in psoriatic lesions [63].

Nickoloff [65] has proposed an alternative theory

that the primary psoriatic abnormality is in keratino-

cyte response to injury. Normally, nonspecific cutane-

ous stimuli cause keratinocytes to desquamate and

release the contents of their lamellar bodies (pre-

formed lipid and hydrolytic enzymes), IL-1a and

TNF-a. Overall, there is an effort to repair the epider-

mal barrier and maintain cutaneous homeostasis. In

genetically predisposed patients, however, a psoriatic

plaque develops, which, although disfiguring, pro-

vides ongoing resistance to infection. The current

authors have previously reported numerous molecular

similarities between psoriatic lesional epidermis and

acute healing wounds. One idea that bridges these

views is that leukocyte trafficking into the epidermis

induces direct injury to the basement membrane zone

and desmosomes, triggering an exuberant and unnec-

essary wound-healing reaction [1,66,67].

Is psoriasis a disease caused by overlap of innate

and acquired immunity?

The suggestion that the innate immune system

alone can fully explain psoriasis is probably simplis-

tic because it does not take into account clonal

population of T cells, disease transfer by bone mar-

row transplantation [68], resolution of psoriasis after

bone marrow transplant [69], or the beneficial effects

of anti–T-lymphocyte therapies. Trying to separate

the pathogenesis of psoriasis into the innate or

acquired immune system is therefore somewhat arti-


ficial, for there is clearly cross-talk between cells,

mediators, and receptors of these two systems.

TLRs and HSPs are innate system components

that may facilitate type 1 cytokine production. CD91

ligation by HSP plus peptide may generate antigen-

specific responses. Several cellular components may

also link these two systems: the NK-T cells because

they possess cell receptors classically linked to both

systems (discussed further later); DCs because they

may be activated in both antigen-specific and non-

antigen-specific ways to bring about T-cell activation

and type 1 cytokine release; and cytokines, such as

IFN-g and TNF-a, which may be produced by

leukocytes of both systems and may be the final

common pathway for the development of psoriatic

lesions. An alternative possible theory to unite these

two systems is that the innate system is responsible

for the initiation of psoriatic lesions, but during this

process, neoautoantigens become exposed and the

acquired system becomes involved to maintain a

newly developed plaque. Alternatively, a bacterial

antigen or superantigen could initiate the psoriatic

response, which becomes self-perpetuating in the face

of the psoriatic cutaneous microenvironment.

NK-T cells are a recently discovered subpopula-

tion of NK cells that may play an important role in

autoimmune diseases. They are called NK-T cells

because they bear NK-cell receptors, such as CD161.

They and a TCR with an invariant and highly

conserved a chain, Va24, and the b chain is usually

Vb11 [70]. NK-T cells can be identified by the

following surface markers: CD3, Va24, CD56,

CD94, and CD161, and represent less than 1/1000 pe-

ripheral blood lymphocytes in healthy individuals.

Gene rearrangement is not required for their dif-

ferentiation or function. These cells specifically

recognize CD1d+ cells presenting a glycosphingo-

lipid antigen, a-galactosyl ceramide (a-GalCer). It isnot yet determined if a-GalCer is the natural ligand

for these cells, but perhaps this or a similar antigen is

unveiled during cutaneous tissue damage. The non-

polymorphic MHC class I molecule CD1d is found in

normal skin on upper level keratinocytes at a low

level of expression [71] and also on dermal DCs [72].

NK-T cells seem to have several functions: per-

forin/granzyme or fas-mediated cell killing, antiviral

properties, and the capability to produce large

amounts of type 1 and type 2 cytokines. NK-T cells

are a heterogeneous population and distinct subsets

have now been identified. In activated lymphocytes

of healthy adults, CD4+ NK-T cells (defined by

a-GalCer loaded CD1d-tetramer+ and Va24+ cells)

can produce type 1 and type 2 cytokines. However,

the CD4� (CD4�CD8� and CD4�CD8+) NK-T cells

only demonstrate a type 1 cytokine profile (IFN-g andTNF-a) [73,74]. These two populations also demon-

strate different chemokine receptors, integrins, and

NK receptor expression patterns. Cell surface markers

now have been identified to distinguish these two

populations of NK-T cells, with IL-18R being present

on type 1 cytokine-producing cells and ST2L

expressed on type 2 cytokine-producing cells [75].

There have been few studies analyzing NK-T cells

in psoriasis. CD161+ cells seem to be increased in

lesional psoriatic tissue [54,71], but these could be

NK, NK-T, or T cells. There may be a decrease [76] or

increase [75] in NK-T cells in the peripheral circula-

tion; this finding may depend on the surface markers

used to classify the NK-T cells (eg, CD3+ CD56+

versus CD161+ Va24+, respectively). It is not yet

possible to determine if an increase in the tissue is

simply caused by a decrease in the circulation. NK-T

cells did increase slightly with various successful

antipsoriatic treatments, although not to control levels,

and in vitro anti–CD3-activated NK-T cells could not

be detected [76]. These authors hypothesized that an

NK-T cell deficiency is a characteristic and intrinsic

abnormality in patients with psoriasis, and that this

deficiency leads to an imbalance in type 1 and type 2

cytokine profiles, with the excessive activation of type

1 responses leading to autoimmunity. Similarly, a

genetically predisposed excessive NK-T cell response

to infection could trigger psoriasis [65].

Increased CD1d expression is also found through-

out the epidermis in psoriatic tissue. In a positive

feedback loop (shown in vitro), IFN-g treatment of

keratinocytes could induce CD1d expression, which

activates NK-T cells and increases IFN-g production

[71]. A CD94/CD161+ NK-T cell line from a patient

with psoriasis (established by IL-2 and superantigen

stimulation) could be cocultured with CD1d+ kerati-

nocytes and give rise to high levels of IFN-g and

IL-13. This process could be inhibited by anti-CD1d

monoclonal antibodies [77]. This production of both

type 1 and type 2 cytokines suggests that this

NK-T cell line was CD4+. It would be helpful to

know the conditions that encourage development of

different cytokine-producing NK-T cells. Further

work is needed to determine whether NK-T cells

defined by strict criteria, such as Va24+ Vb11+,are genuinely increased in psoriasis lesions.

How can the phenotype of chronic psoriasis be

explained?

The usual response of the skin to an antigenic

stimulus is for an immature DC to acquire the antigen


through constant sampling of the environment, mi-

grate to the local draining lymph nodes, mature with

up-regulation of costimulatory markers, and activate a

naıve antigen-specific T cell. Depending on factors

such as the cytokine microenvironment, Th1 or Th2

cytokine profiles are produced. Antigen-specific lym-

phocytes clonally expand and develop additional skin

homing receptors, which allow them to bind to selec-

tins (eg, CLA+ binds to E- and P-selectin) for initial

tethering and rolling on cutaneous endothelial cells.

Locally produced chemokines cause up-regulation

of T-cell integrins, such as LFA-1 and very late

antigen-4, or VLA-4, for fixed lymphocyte-endothe-

lial cell adhesion, chemotaxis, and extravasation of

lymphocytes into the dermis. Up-regulation of integ-

rin aeb7 on CD8+ T cells allows them to bind to

E-cadherin on keratinocytes with subsequent infiltra-

tion into epidermis. ICAM-1 is often up-regulated on

activated keratinocytes, which can also interact with

lymphocyte LFA-1. Antigen-specific CD4+ and

CD8+ T cells are finally present in the skin, producing

cytokines and inflammatory mediators, ultimately

leading to antigen eradication.

Fig. 5. Epidermal hyperplasia in psoriasis may result from keratino

The pathways diagram inductive effects of IFN-g and TNF-a on ex

keratinocytes. MIG, IP-10, and I-TAC stimulate intraepidermal tr

disrupts the basement membrane and traumatically severs de

Regenerative epidermal hyperplasia may result from physical inj

from the process of IFN-regulated inward migration of leukocytes

In psoriasis, however, the process becomes a

chronic one. Development of lesions requires initia-

tion and maintenance steps. The classic antigen-

driven process just described may indeed take place,

but until a specific antigen is conclusively defined,

other mechanisms must be explored. And although

antigen may initiate the process, physicians need to

be able to explain the chronicity of psoriatic plaques.

There is some evidence that the skin in psoriasis may

actually behave focally like peripheral lymphoid

tissue, which may be a primary or secondary event.

First, psoriatic blood vessels possess the morphology

and cell surface markers found on lymph node high

endothelial blood vessels (HEVs), such as L-selectin,

CD31, CD34, and peripheral lymph node addressin

[1,78]. Second, lymphoid-organizing chemokines

CCL19 and CCL21, and the Bonzo receptor ligand

(CXCL16) recently have been shown to be elevated

in psoriasis [26]. Such factors may help organize

T-cell/DC infiltrates in secondary lymphoid tissues

and produce ‘‘autoimmune’’ inflammation [79].

Third, there are abundant aggregates of T cells and

mature DCs (CD83+/DC-LAMP+) within psoriatic

cyte injury produced by IFN-regulated leukocyte migration.

pression of adhesion molecules and chemokines in epidermal

afficking of CXCR3+ CD8+ T cells. The inward trafficking

smosomes from adjacent connections on keratinocytes.

ury to the basement membrane or keratinocyte membranes

.

Fig. 6. Epidermal mononuclear leukocyte trafficking in

psoriasis. Electron micrographs of lesional psoriatic skin

showing mononuclear leukocyte trafficking through the

epidermis (stars), severing desmosomes on adjacent kerati-

nocytes (arrows). This injury, in conjunction with local

inflammatory cytokines, may initiate a pattern of epidermal

repair and hyperplasia.


lesions that develop spatial arrangements similar to

secondary lymphoid tissue [3]. Keratinocytes may

also play a role in the maintenance of lesions be-

cause once there is an inflammatory cytokine milieu,

keratinocytes up-regulate surface markers such as

ICAM-1 and MHC class II molecules for further sti-

mulation of memory CD8+ and CD4+ T cells. In

addition, keratinocytes may produce inflammatory

cytokines, such as TNF-a, that play a role in DC acti-

vation and maturation. As discussed previously, there

is also persistent T-cell activation in psoriatic tissue

[6], which is able to respond to local, activated APCs.

How do these changes lead to the phenotype of

psoriasis? The major histopathologic features that

need explaining are marked T-cell infiltrate, psoriasi-

form hyperplasia, dilated blood vessels filling the

elongated dermal papillae, increase in mature DCs,

and neutrophil accumulation. An important trigger

for keratinocyte hyperplasia may actually be injury

caused by the passage of lymphocytes through the

epidermis, severing desmosomes as they move

(Fig. 5). Electron micrographs of lesional epidermis

show support for this concept (Fig. 6). As the

desmosomes are disrupted, a pattern of epidermal

repair with keratinocyte hyperplasia may ensue. Oth-

er cytokines may be contributing, such as IL-20

release from dermal macrophages [80], or IFN-g.How does IFN-g contribute to epidermal hyper-

plasia? Conditioned media from CD8+ Tc clones

from psoriatic skin specimens had either proliferative

or antiproliferative effects on keratinocytes, and both

effects were reversed by antiserum to IFN-g [14].

Previous studies, however, have shown that IFN-ghas suppressive in vitro effects on keratinocytes [81].

It is likely that the array of keratinocyte-stimulating

cytokines (Table 1) made in injured skin, such as

transforming growth factor a (TGF-a), amphiregulin,

insulin-like growth factor 1 (IGF-1), and keratinocyte

growth factor (KGF), override any suppressive ef-

fects of IFN-g, resulting in epidermal hyperplasia.

IFN-g may be a key inducer of the overall injury

response pathway, because IFN-g–induced keratino-

cyte production of the chemokines MIG, IP-10,

and IFN-inducible T-cell a chemoattractant (I-TAC)

would set up a chemotactic gradient that regulates

migration of CD8+ T cells bearing CXCR3 into

the epidermis.

The blood vessel changes may be more easily

explained by vascular endothelial cell growth factor

(VEGF) and NO, which cause neovascularization

and dilatation of blood vessels, respectively [82,83].

The most likely candidate for neutrophil chemotaxis

is IL-8, a cytokine that is released by many cells,

including psoriatic keratinoyctes, as an early proin-

flammatory response [84]. There are other cytokines

and inflammatory mediators that may contribute to

the phenotype of psoriasis, which have not been

discussed in this article; these are listed in Table 1.

How do murine models help physicians to

understand the pathogenesis of psoriasis?

There are quite a few ‘‘psoriasis’’ mouse models

with knockouts or overexpression of important epi-

dermal and immune components. One fundamental

problem with these models, however, is that human

epidermis is structurally different to murine, which

Table 1

Changes in cytokines and growth factors with their receptors

in psoriatic lesions

Cytokines and

growth factors/receptors Effect Reference

Inflammatory cytokines

IL-1a +, �, F [101–104]

IL-1b +, � [101–104]

IL-2 + [18,19]

IL-2Ra(CD25) + [21]

IL-6 + [105–108]

IL-7 + [109]

IL-12 + (p40, p70)/

F (p35)

[20,110]

IL-12Rb2 + [21]

IL-15 + [111]

IL-17 + [112]

IL-18 + [58,113]

IL-20/IL-20R +/+ [80,114]

IL-23 + [26]

TNF-a + [115,116]

IFN-g/IFN-gR +/+ [18,19,31,

117,118]

MIF + [119,120]

Inhibitory cytokines

IL-1RII + [121]

IL-1RA +, �, F [121–123]

IL-4 � [18,124]

IL-5 +, F [18,124]

IL-10 F, � [18,110,125]

IL-11 + [106]

IL-13/IL-13R F/+, � [126]

TGF-b +, �, F [127–129]

Hematopoietic cytokines

IL-3 + [124]

GM-CSF + [18,130]

LIF + [131]

OSM + [131]

Chemokines

IL-8/CXCR2 +/+ [26,106,

132–136]

GROa + [26,135–137]

IP-10 + [26,138]

MIG + [26,139]

I-TAC + [26]

MIP3a/CCR6 +/+ [26,140]

RANTES + [141]

MCP-1 + [26,142]

TARC + [8]

MDC + [8,26]

CTACK/CCR10 F, �/+ [26,143]

MIP3b + [26]

SLC + [26]

SDF-1 + [26]

PARC + [26]

Table 1 (continued )

Cytokines and

growth factors/receptors Effect Reference

Chemokines

Bonzo receptor

ligand

+ [26]

ENA-78 + [26]

EMAPII + [26]

HCC-1 � [26]

Keratinocytes/tissue growth factors

TGF-a/amphiregulin/

EGF-R

+/+ [128,144–147]

PDGF-R + [148]

IGF-1R + [149]

KGF/KGF-R +/+ [150]

NGF + [151,152]

bFGF + [153]

Angiogenic factors

VEGF/VEGF-R +/+ [154]

Angiopoitin/tie 2 +/+ [155]

ET-1 + [156]

Angiogenic inhibitors

Thrombospondin � [133]

Abbreviations: bFGF, basic fibroblast growth factor;

CTACK, cutaneous T-cell – attracting chemokine; EGF,

epidermal growth factor; EMAPII, endothelial monocyte–

activating polypeptide II; ENA-78, epithelial cell-derived

neutrophil attractant 78; ET-1, endothelin 1; GM-CSF,

granulocyte machrophage-colony stimulating factor; GRO-

a, growth-regulated oncogenea; HCC-1, hemofiltrate CC

chemokine1; LIF, leukemia inhibitory factor; MCP-1;

monocyte chemoattractant protein 1; MDC, macrophage-

derived chemokine; MIF, migration inhibition factor; MIP,

macrophage inflammatory protein; NGF, nerve growth

factor; OSM, oncostatin M; PARC, pulmonary- and

activation-regulated chemokine; PDGF, platelet-derived

growth factor; R, receptor; RA, receptor antagonist;

RANTES, regulated upon activation normal T expressed

and secreted; SDF-1, stromal cell-derived factor 1; SLC,

secondary lymphoid tissue chemokine; TARC, thymus- and

activation-regulated chemokine; +, increase; �, decrease;F,

no change.


makes extrapolation to human skin disease difficult.

In human skin, there is a clear difference in kerati-

nocyte differentiation of the outer root sheath of the

hair follicle and the interfollicular epidermis. Perifol-

licular ‘‘epidermis’’ is keratin 16-positive (K16+) and

connexin 26+, and in effect represents outer root

sheath differentiation, whereas normal interfollicular

epidemis is K16� and connexin 26�. In psoriasis,

interfollicular epidemis changes to become more


perifollicular-like. But in the mouse, there is less

difference between these two structural areas, and

they are K16�, connexin 26+. Normal murine epi-

dermis is much thinner than normal human interfol-

licular epidermis, with many fewer cell layers.

Clinicians therefore need to be careful describing a

skin lesion in a knockout or transgenic mouse psori-

asis when the murine epidermis already has some

features of this condition, such as connexin 26 posi-

tivity. Another important consideration in the use of

single- or even double-gene manipulations is that

they do not usually reproduce the complete pheno-

type of psoriasis, which is a polygenic disease

[85,86]. Possibly even more important, none of the

transgenic models expresses the primary genes of

psoriasis susceptibility loci and are all downstream

of primary genetic events.

Perhaps the most relevant models are those that

produce regulatory alterations in immune pathways

or other cell growth responses. There is an interesting

murine model of psoriasis: the IFN regulatory factor

2 (IRF-2) knockout mouse [87]. IRF-2 can be in-

duced by IFN-a/b and IFN-g [88] and has a predom-

inantly negative regulatory effect on IFN-a/b–activated IFN-stimulated gene factor 3 (ISGF3).

ISGF3 is a heterotrimer consisting of STAT1, STAT2,

and IFN regulatory factor 9 (IRF-9, p48). Deletion of

the IRF-2 gene caused overexpression of IFN-a/b–inducible genes and led to an erythematous inflam-

matory skin disease with some histopathologic fea-

tures of psoriasis. This includes epidermal acanthosis,

activation of keratinocytes (ICAM-1+), infiltration of

both CD4+ and CD8+ T cells into the basal dermis,

and some CD8+ T cells into the epidermis. There

were additional features not suggestive of psoriasis,

such as alopecia, excoriations leading to ulceration,

and a disorganized muscle layer with associated

fibrosis. Experimental depletion of CD8+ T cells

significantly delayed the onset of skin disease, and

these CD8+ T cells were hyper-responsive to antigen

stimulation, as are psoriatic T cells. There was a

marked polyclonal increase in the population of

memory CD8+ T cells in these mice, and lymphade-

nopathy developed as the skin disease progressed.

Furthermore, not only was there overexpression of

genes usually induced by IFN-a/b by means of

ISGF3 (oligoadenylate synthetase and IRF-7) but

there was also increased cutaneous expression of

genes known to be primarily controlled by IFN-g(MIG and IP-10). The introduction of additional

mutations in IRF-9 in these IRF-2 knockout mice

abrogated the skin disease, genetic overexpression,

and T-cell hyper-responsiveness. Because there is

overlap between the effects of type I and II IFNs,

this model supports the role of overexpression of

IFNs and IFN-related genes in the development of a

psoriasis-like skin disease. In comparison, a study of

transgenic mice with overexpression of epidermal

IFN-g resulted in keratinocyte hyperproliferation,

MHC class II and ICAM-1 induction, and dermal

capillary enlargement. Although there was a dermal

T-cell infiltrate, however, there were no epidermal T

cells [89]. Clinically, there was an ezcematous pro-

cess with hair hypopigmentation and alopecia.

Overexpression of epidermal VEGF (VEGF trans-

genic mouse under-expression of K16 promoter) [86]

led to a psoriatic phenotype at 3 months with wound-

ing (similar to the Koebner phenomenon), or sponta-

neously at 6 months. These mice demonstrated

epidermal hyperplasia with hyperkeratosis, parakera-

tosis, and K6 expression. There was a leukocyte

infiltrate very similar to human psoriasis with neu-

trophil microabscesses within and beneath the stra-

tum corneum, dermal CD4+ T cells, epidermal CD8+

T cells, mast cells, and macrophages. There were

dilated and tortuous dermal papillae blood vessels

with up-regulation of adhesion molecules, such as

ICAM-1, E-selectin, VCAM-1, and platelet-endothe-

lial cell adhesion molecule 1, or PECAM-1. An anti-

VEGF monoclonal antibody (VEGF Trap) was effec-

tive in reversing spontaneous changes of psoriasis

unless the mice developed neutralizing antibodies to

this treatment. High serum levels of E-selectin, a

surrogate marker of disease activity in human disease

and in this K16-VEGF transgenic mouse, were also

reversed by VEGF Trap. Exactly how epidermal

chronic overexpression of a potent angiogenic factor

leads to psoriasis is not yet understood; perhaps it

diffuses to the dermis and primarily creates inflamed

blood vessels, which attract inflammatory leukocytes

and allow cytokine and chemokine changes that lead

to secondary epidermal alterations seen clinically as

psoriasis. VEGF antagonists are obviously an in-

teresting therapeutic modality to investigate further

in patients with psoriasis.

Another useful model to study psoriasis used a

xenotransplant concept, with human skin of varying

clinical types grafted to immunodeficient mice, which

fail to reject it. Initial studies used nude or athymic

mice, which are deficient in T cells. In these mice,

infiltrating human T cells are eliminated from the graft

quite readily. Subacute combined immunodeficiency

(SCID) mice fail to rearrange variable-diversity-join-

ing (VDJ) segments of B- and T-cell receptors, so

these mice lack both humoral and cellular immunity.

SCID mice still make NK and NK-T cells because

these cells do not require TCR gene rearrangement for

their generation. Recombination activating genes


(RAG) knockout mice lack the RAG enzyme, which

is responsible for rearranging TCRs, so these mice

also still have NK and NK-T cells. RAG-deficient

knockout mice now have been generated in conjunc-

tion with deletions of murine type I and II IFN

receptor. Human keratome skin biopsy specimens

have been grafted to these immunodeficient mice

from healthy volunteers, nonlesional skin of patients

with psoriasis, or lesional psoriatic skin. These skin

grafts are allowed to heal and then the mice are

injected with activated human leukocytes to determine

the role of the transplanted cells in the initiation and

maintenance of the psoriatic lesion.

The initial nude mice studies demonstrated that

engraftment of psoriatic skin leads to regression of

histologic and immunologic features of psoriasis,

correlating with elimination of infiltrating human T

cells within the psoriatic skin [90]. Boehncke et al

[91] showed that repeated intradermal injections of

staphylococcal superantigen exfoliative toxin into

grafted nonlesional skin from patients with psoriasis,

along with intraperitoneal administration of autolo-

gous peripheral blood mononuclear cells (PBMCs)

stimulated in vitro with the respective superantigen,

were capable of triggering psoriasis.

Nickoloff et al [92] extended these findings and

continued to develop the SCID mouse model with

injection of activated immunocytes into the graft.

Experiments in 1996 showed that IL-2 and staphy-

lococcal superantigen-stimulated, autologous pe-

ripheral blood-derived immunocytes were able to

induce psoriasis in nonlesional skin of patients with

psoriasis [93]. They next showed that psoriasis could

be induced in normal skin with similarly activated but

allogeneic blood-derived psoriatic immunocytes in

three of six patients [94]. Graft versus host disease

would be expected in this context, but this condition

only developed in one of six transplants. In two

patients, the authors looked at the surface markers of

the human cells in the graft and found that many

possessed NK surface markers (CD94, CD158a,

CD158b, NKB1, and CD161) [95]. They next further

characterized the immunocytes: injection of en-

grafted nonlesional psoriatic skin with activated

CD4+ T-cell lines could induce psoriasis in five of

five cases and in none of five cases, with CD8+ T-cell

lines [53]. Cells with NK markers accumulated early

in the lesion. However, it is difficult to appropriately

activate and differentiate epithelial homing CD8+

T cells in vitro. Finally, the authors characterized a

T-cell line from a psoriatic patient that was capable

of initiating psoriasis in a nonlesional psoriatic skin

graft and demonstrated CD4+ NK-T cell markers

(CD94+, CD161+, Va24�, Vb11+) [77]. A Th1 po-

larized cytokine profile was evident in the lesion

(IFN-g and IL-15).

Gilhar et al [96] also performed early experiments

with SCID mice, demonstrating that intradermal or

intravenous injection of autologous lesional T cells

(cultured for 1 month with IL-2, APCs, and keratino-

cytes) were able to maintain psoriatic grafts. This

group wanted to explore induction of psoriasis using

these IL-2–activated T cells rather than superantigen-

stimulated lymphocytes, and they next used beige-

SCID mice, which have less NK-cell activity [97].

The authors cultured PBMCs with IL-2 for 3 weeks

to generate NK and NK-T cell lines (CD56, CD94,

CD158a, CD158b, CD8, CD4, CD3+ CD161+), which

were IFN-g producing and cytotoxic in vitro. Injectionof autologous NK/NK-T cells initiated psoriasis in

nonlesional psoriatic skin. Unlike Nickoloff’s group,

however, they did not find that that injection of

allogeneic T cells caused psoriasis in nonlesional

psoriatic skin or normal grafts; rather, in these con-

ditions, a psoriasiform dermatitis was seen.

Finally, in a new model using RAG and IFN

receptor–deficient mice, nonlesional psoriatic skin

spontaneously converted to psoriasis in 29 of 30 grafts

[98]. There was an absence of circulating human or

mouse lymphocytes, with up-regulation of HLA-DR

and CD91. CD91 ligands were also present (HSP 27

and 70), and CD91+ cells were adjacent to CD91

ligand-positive keratinocytes. There was expression

of NFkB and TNF-a production, and the effect was

abrogated with anti–TNF-a antibodies in eight of

nine mice. Subsequent work showed blockage of this

effect by CD3 antibodies [99], thus this model is also

T-cell dependent. This finding does not rule out an

important role for IFN-g, because human IFN-g may

still be produced by the graft and react with IFN-greceptors present on engrafted human psoriatic skin.

This is an important report because this is the first

experiment to show that psoriasis could develop

spontaneously in grafts of nonlesional psoriatic skin

without injection of exogenous lymphocytes. This

finding suggests that resident immunocytes are able

to proliferate in situ depending on the local environ-

ment to initiate a lesion, and that once skin homing

(CLA+) memory cells have developed, lymphocyte

trafficking may not be required.

What do recent genomics data add?

Three large-scale analyses of psoriatic disease–

associated genes (mRNA expression) have been pub-

lished recently [26,67,100]. These analyses differ


primarily in their use of various gene chips, with each

study examining an increasingly greater number of

known genes, but also in the samples tested and

approach to analysis. These experiments are not

simple to evaluate because they generate such large

data sets and require specific analytic approaches,

such as hierarchical clustering, nonhierarchical clus-

tering (eg, self-organizing maps [SOMs]), functional

clustering, and principal components analysis (re-

viewed in reference [59]). This line of research will

yield important information and enable further under-

standing about the pathogenesis of skin diseases,

clinical response, and drug mechanisms.

The first study used arrays containing 7000 genes

[67]. An unsupervised cluster analysis approach was

taken, where samples were clustered based on a

hierarchical correlation coefficient (ie, fold change).

Gene expression frequency patterns of normal and

uninvolved skin were grouped together, and they were

clearly different to a separate cluster of expression

patterns of lesional skin. A differential statistical

approach was then taken where average frequency of

gene expression values between uninvolved and

lesional skin were calculated and a paired t test was

performed. Transcript levels that were statistically

different with a confidence level of 95% or greater

were initially identified (426 genes), and this number

was subsequently refined to 159 genes when only

those whose transcript levels differed on average by

twofold or greater were selected. Thus, a disease

classification set for chronic plaque psoriasis was gen-

erated, and these genes could be categorized into di-

verse functional groups. These include transcriptional

regulation, metabolic control, protein processing,

intracellular signaling, cell cycle control, lymphocyte

regulation, and extracellular matrix destruction. Genes

previously known to be differentially expressed in

psoriasis included transcripts such as psoriasin

(S100A7), fatty acid–binding protein (FABP5), elafin

(SKALP, P13), retinoic acid – binding protein

(CRAB2), squamous cell carcinoma antigen (SCCA),

b defensin-2 (DEFB2), keratin 17 (KRT17), and

keratin 16 (KRT16). There were also new genes in

these lists including S100A12 (calgranulin C, EN-

RAGE), matrix metalloproteinases (MMP-12), and

heparin-binding protein 17 (HBP-17). The signifi-

cance of differential expression of many of these

genes will need to be determined in the future.

Findings of expression differences were con-

firmed by performing immunohistochemical analyses

for protein products and reverse transcriptase poly-

merase chain reaction (RT-PCR) on additional sam-

ples where possible. Oestreicher et al [67] next

examined antigen nonspecific gene responses in

delayed-type hypersensitivity (representing T-cell–

driven responses) and in tape stripping (indicative

of active epidermal regeneration) in healthy volun-

teers, and there was some overlap with psoriasis. The

subtraction of overlapping genes from these two

groups and the psoriatic gene set revealed 94 tran-

scripts that were differentially regulated only in

psoriasis, including S100A12 (calgranulin C, EN-

RAGE), RAGE, and GATA3. Finally, the authors

performed similar analyses in samples collected be-

fore, during, and after two immunomodulatory pso-

riasis treatments, comparing expression levels in

lesional skin of the previously identified 159 genes

in responders versus nonresponders. Treatment was

either with the Th2 cytokine IL-11 (which restores

Th1 and Th2 imbalance partially through inhibition

of NFkB nuclear translocation) or cyclosporin A

(which has a T-cell inhibitory effect through blockade

of calcineurin/nuclear factor of activated transmis-

sion IL [NFAT] and p38/JNK signaling pathways).

SOMs were used where the level of expression of

the lesional skin before therapy was normalized to a

value of 1 and the change in expression of the

159 gene set over the course of treatment was

calculated relative to this baseline level. Four patterns

of expression could be identified in responding pa-

tients, with no such change noted for nonresponders.

In responders, gene sets could be observed that

changed (increased or decreased) quickly before

clinical improvement and between rhIL-11 and cyclo-

sporin A treatment. On termination of either treat-

ment, transcripts returned to pretreatment levels. Of

the 41 gene transcripts that increased quickly with

treatment, 12 can be mapped to five of the six known

psoriasis susceptibility loci.

The second study published the same year used

Affymetrix gene chips (Santa Clara, California) with

12,000 known genes and also used gene-clustering

techniques [100]. These authors found a similar

number of differentially expressed gene transcripts

in psoriasis (177 transcripts) compared with normal

skin, independent of demographics or HLA class I

status. These genes were mostly up-regulated, and

approximately 80% had not been described in psori-

asis previously. Some of the 17 genes that showed the

highest level of expression in involved psoriatic skin

were the same as those previously reported and found

in the previously discussed study. The transcript that

showed the greatest increase was transcobalamin

1 (vitamin B12–binding protein), which is found in

mature neutrophils, suggesting an important role for

neutrophil granule proteins. A complete list of genes

in clusters that differentiate involved skin from nor-

mal skin can be found at http://hg.wustl.edu. Several


of these genes have been mapped to regions previ-

ously linked to psoriasis susceptibility.

Using the newer Affymetrix chips containing

63,100 oligonucleotides, the third study further ex-

tended the description of psoriatic gene expression

[26]. The authors used two methods of analysis to

detect differentially expressed genes: first, fold

change combined with t tests comparing differences

in psoriasis and nonlesional and normal skin; and

second, K-means clustering to examine for small fold

changes. A total of 1338 genes were identified, and

these also have been reported on the previously

mentioned Web site. These genes were functionally

categorized according to the Gene Ontology database,

demonstrating disruption of immune and inflamma-

tory responses, response to wounding, response to

pests/pathogens, cell proliferation, the JAK-STAT sig-

naling cascade, cell growth or maintenance, and

several metabolic processes such as NO biosynthesis.

There were 131 genes that were significantly dif-

ferentially expressed (PV 0.05; fold change, > 1.2) in

at least one pairwise comparison among the three skin

groups that were involved in immune signaling. These

were subsequently broken down into three groups:

IL-1 cluster of genes (especially IL-1R antagonists),

those involved in T-cell and DC activation, and che-

mokines in psoriasis. Comparing genes that were

elevated in involved psoriatic skin with normal skin

demonstrated many genes indicative of T-cell activa-

tion, including CD47 (general lineage marker for

blood-derived cells), IL-2Ra, IL-2Rb, CD71, CD69,and IL-7R. Leukocyte integrins LFA-1 (CD11a/

CD18) and Mac-1 (CD11b/CD18), and adhesion

molecules E-selectin, P-selectin, and ICAM were

also elevated. There was up-regulation of genes in-

volved in APC function, such as CD163, CD32,

MHC class I and II, CD83, CD53, and CD24.

Comparison of uninvolved versus normal skin also

revealed some interesting expression changes: un-

involved skin showed increased CD4, CD11c (high-

level expression on monocytes, macrophages, and

NK cells), CD86 (costimulatory molecule), and

CD103 (epithelial homing cells), suggesting a low

level of immune activation.

There were 19 chemokines that were elevated in

this study, including lymphoid tissue chemokines

CCL19 and CCL21. Eleven of these chemokines

had not been previously implicated. CCR7 is the

receptor for CCL19 and it was also overexpressed

(by FACS analysis); its usual role is to allow naıve

and central memory T-cell migration across HEVs

found in lymph nodes. Along with prior reports,

these findings provide evidence for the suggestion

that psoriatic skin behaves as secondary lymphoid

tissue, which could sustain chronic T-cell activation

within focal skin regions. Increased CCL18 may

be important for recruiting naıve T cells to skin

draining lymph nodes, and CXC16 (expressed on

CD11c+ DCs) is important for epidermal recruitment

of CD8+ T cells.

Further analysis revealed the importance of the

IFN-g or type 1 pathway, consistent with the current

authors’ hypothesis that this is a key cytokine in

psoriasis. There was increased expression of the IFN-

g transcript, along with primary IFN-g– induciblegenes TRIM22 and STAT-1, and the chemokines

IP-10 and MIG. In fact, more than 5% of elevated

genes (>60) related to IFN signaling were identified

in this study. Finally, large-scale promoter analysis

demonstrated 13 coexpressed gene clusters and

shared transcription factor–binding sites (TFBS),

including the IFN-g–inducible TFBS motif IRF2-

ISRE (IFN-stimulated response element). A recent

review described 200 genes that are considered to be

regulated by IFN-g in various cell types and lines

[37], and in psoriasis, there are 60 IFN-g–regulatedgenes that can be extrapolated from the literature.

This overlap supports the hypothesis that IFN-g is

functional and produced by activated T cells in

psoriasis; however, it is curious that the overlap is

not more complete. There could be several reasons

for this finding: the chronic process of psoriasis may

result in different gene activation than can be found in

a short-term in vitro analysis; direct IFN-g effects in

skin, an organ rather than cell type or line, have not

been studied; and other cytokines may be inducing

the JAK-STAT pathway rather than IFN-g.

Summary

This article has focused on the innate and acquired

immune systems, their overlap, and the role of these

components in the pathogenesis of psoriasis. Recent

data on mouse models have been presented, empha-

sizing xenotransplant models as more representative

of psoriatic lesions than knockouts or transgenic

mice. Finally, a summary of recent genomics data

in psoriasis was discussed to introduce these impor-

tant studies and the data they generate. The authors’

belief of the importance of IFN-g as a pivotal

cytokine in the initiation or maintenance of psoriatic

lesions has been supported with evidence throughout

the article, while acknowledging that TNF-a plays an

important and probably synergistic role. There are

topics that have not been covered but some of these

are done so elsewhere in this issue, such as the

genetics of psoriasis. The role of specific antigens


(autoantigens, superantigens, or microbial antigens)

in triggering or maintaining lesional activity is an-

other area that has not been discussed and requires

further experimentation and attention.

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Dermatol Clin 22 (2004) 371–377

From laboratory to clinic: rationale for biologic therapy

Stephanie Mehlis, MDa, Kenneth B. Gordon, MDb,*

aDepartment of Dermatology, Northwestern University Medical School, 675 N. St. Clair Street, Chicago, IL 60611, USAbDivision of Dermatology, Department of Medicine, Loyola University, Stritch School of Medicine, 2160 South First Avenue,

Building 112, Room 342, Maywood, IL 60153, USA

Although topical therapy can be extremely effec- The pathogenesis of psoriasis

tive in cases of limited psoriasis, systemic therapy is

often needed for severe cases to give patients appro-

priate relief. Traditional systemic medications for

psoriasis include systemic retinoids, methotrexate,

cyclosporin, and psoralen plus UVA. All of these

treatments have well-documented side effects, the

frequency of which increases with increasing length

of exposure [1]. Dermatologists have devised meth-

ods including intermittent and rotational strategies to

avoid these side effects [2].

Because psoriasis is a chronic disease, there has

been an increased demand to develop therapies that

can be used for the lifetime of the patient. The

development of new treatments has been facilitated

by advances in immunology and an increased under-

standing of the basic pathophysiology of the disease.

This information, and the advent of genetic engineer-

ing techniques, has led to the creation of new targeted

medicines termed ‘‘biologic therapies’’ that inhibit

the basic pathologic processes while remaining rela-

tively free of interactions with other organ systems.

These treatments are proteins produced by living

organisms to target specific points of the inflamma-

tion cascade, including antibodies against cell surface

markers, cytokines, and adhesion molecules. This

article discusses the pathogenesis of psoriasis, looks

at the immunologic factors that contribute to form-

ing a psoriatic plaque, reviews how novel biologic

therapies are made, and explores how biologics can

target each of these specific parts of the immuno-

logic cascade.


doi:10.1016/S0733-8635(03)00124-4


E-mail address: [email protected] (K.B. Gordon).

The clinical and histolopathologic presentation of

psoriasis is dominated by the obvious changes in the

keratinocyte of the plaque when compared with

uninvolved skin. The clinical scaling and induration

associated with psoriasis can be seen on biopsy as

parakeratosis, acanthosis, and loss of the granular

layer. Keratinocytes proliferate rapidly, with an eight-

fold shortening of the epidermal cell cycle [3].

Additionally, these cells mature abnormally. These

keratinocyte changes are accompanied by an inflam-

matory infiltrate composed primarily of mononuclear

cells and neutrophils. The lymphocytes are primarily

T cells with a predominance of CD4+ T cells in the

dermis and many CD8+ T cells in the epidermis.

Some of the T cells in the epidermis express natural

killer cell markers and are thought to be resident to

the skin. Additionally, activated Langerhans’ cells,

macrophages, and dermal dendritic cells are present

in the psoriatic plaques.

Animal and human models have helped to clarify

the significance of the inflammatory infiltrate in the

development of psoriatic plaques. Most experiments

have focused on the role of these activated T cells and

the cytokines they produce as the driving force for the

induction and maintenance of psoriatic plaques [4,5].

In a model first developed by Wrone-Smith and

Nickoloff [6], symptomless skin (psoriatic patient/

nonindividual skin [PN]) from a psoriatic patient was

transplanted onto an immunodeficient (severe com-

bined immunodeficiency) mouse. T cells from the

same patient were activated in vitro and then injected

into the xenografted skin. In time, the graft became

histologically identical to skin from a plaque of

psoriasis, complete with keratinocyte and vascular

s reserved.

S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377372

changes. This change did not occur in skin from

patients without psoriasis (non-psoriatic patient/non-

involved skin [NN]) or when the T cells were not

activated in vitro. The introduction of activated T cells

was sufficient to induce psoriasis in genetically

susceptible skin [7].

One question this model does not answer is the

role played by local cells in the skin including resi-

dent T cells and antigen-presenting cells (APC). Re-

cently, a model has been identified that addresses this

issue. Boyman et al [8] have identified a novel im-

munodeficient mouse called the AGR mouse. When

susceptible skin is transferred to the mouse, it spon-

taneously develops into a plaque of psoriasis. This

response can be blocked by the addition of medi-

cations that inactivate tumor necrosis factor-alpha

(TNF-a), a cytokine central to the immune process

in psoriasis. What the results of these experiments

suggest is that local cells in the skin, when properly

activated, may be sufficient in themselves to create a

psoriatic plaque without the requirement of inflam-

matory cells being introduced from the circulation.

Moreover, TNF-a is a major cytokine produced by

APC, including dendritic cells and macrophages. The

activation of these inflammatory cells may play a

major role in the early development of lesions.

Additional evidence for the fundamental role of

the inflammatory response, particularly of T cells,

comes from the efficacy of T cell–specific immuno-

modulation in the treatment of psoriasis. Cyclosporin

has immunosuppressive effects by decreasing prolif-

eration and cytokine production of T cells. It was

incidentally noted to improve psoriatic lesions in pa-

tients on cyclosporin after solid organ transplantation

[9]. Further study has definitively proved that this

T cell–specific medication is extremely effective as a

treatment for psoriasis [10]. Psoralen plus UVA and

UVB have also been shown to deplete affected skin

of T cells [11]. Finally, treatment with biologic agents

that decrease the number of effector T cells in

psoriasis (denileukin diftitox and alefacept) has dem-

onstrated efficacy. Further evidence for the critical

role the immune response plays in psoriasis is shown

by a cure of psoriasis after reconstruction of a pa-

tient’s immune system from an allogenic bone mar-

row transplant, and the development of psoriasis in a

patient who had a bone marrow transplant from a

psoriatic donor [12,13]. All of these therapeutic

results help to prove the important role the T cell

plays in the pathogenesis of psoriasis.

T cells can be classified into two major pheno-

types characterized by the cytokines they produce.

Type 1 helper T cells and cytotoxic T cells (Th1 and

Tc1) secrete interleukin (IL)-2, TNF-a, interferon

(IFN)-g, and IL-18, and stimulate cell-mediated im-

munity and T-cell cytotoxicity. IgE-mediated allergic

and mucosal responses are generated from the type 2

T cells (Th2 and Tc2) through release of IL-4, IL-5,

and IL-13. Cytokines released by type 1 reactions

inhibit type 2 reactions and vice versa [14]. The T cell

response in psoriasis is primarily a type 1 reaction.

Skin in psoriatic lesions has increased TNF-a and

IFN-g compared with nonlesional skin [15] and IL-2

has been shown to flare psoriasis. Moreover, circu-

lating T cells of patients with psoriasis have a higher

ratio of IFN-g to IL-4 than normal patients [16].

These data all help to demonstrate that the T cell–

directed immune response in psoriasis is primarily a

type 1 reaction [17].

T cells and psoriasis

Many of the new biologic treatments of psoriasis

have targeted blocking the inflammatory response

of the T cells. To understand how these therapies

work, an analysis of the steps necessary for T cells to

induce a psoriatic plaque must be understood. For

ease of understanding, this complicated process can

be simplified into three basic steps: (1) the initial acti-

vation of T cells, (2) the migration of T cells into the

skin, and (3) reactivation of the memory T cells and

the magnification of the immune cascade by cyto-

kines on various cells in the psoriatic plaque.

Activation of T cells

T cells must be activated by APC. In the skin, the

APC are Langerhans’ cells that are constantly exposed

to infectious and other protein antigens from the

environment. When Langerhans’ cells are exposed

to an antigen and have an appropriate signal to mature,

they display the peptides from these antigens on either

class I (for intracellular antigens) or class II (for

extracellular antigens) major histocompatibility com-

plex. These mature APC migrate out of the skin and

into the skin’s lymphatic system. It is here that a

mature APC binds to a naıve T cell through adhesion

molecules [18]. One of the first interactions between

these cells is the binding of the leukocyte function-

associated antigen 1 (LFA-1) and its two subunits

(CD11a-CD18) to the intracellular adhesion molecule

(ICAM or CD54) on the APC. Additionally, CD2 on

the T cell binds to LFA-3 on the APC to complete the

initial recognition process [19].

Once bound, there must be a process of antigen-

specific recognition, referred to as ‘‘signal 1.’’ The

major histocompatibility complex presents antigens

S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377 373

on the surface of the APC, and T cells sample

these until there is a ‘‘fit’’ between the antigen-spe-

cific T-cell receptor and the major histocompatibility

complex–antigen complex. The major histocompat-

ibility complex I recognizes the CD3-CD8 T-cell

receptor of cytotoxic T cells, whereas major histo-

compatibility complex II recognizes the CD3-CD4 T-

cell receptor of helper T cells [18]. Binding still plays

an important role in this step, because it keeps the

cells together while the T-cell receptor is sampling

the various major histocompatibility complex–anti-

gen complexes.

The third and final step in T-cell activation is

referred to as ‘‘signal 2’’ or co-stimulation. This is a

not an antigen-specific reaction, but it is necessary for

T-cell stimulation. If antigen recognition takes place

without co-stimulation, the T cell does become active.

In fact, in the absence of co-stimulation the T cell is

forced to die through apoptosis or be rendered unre-

sponsive in the future (anergy). One of the most im-

portant co-stimulatory molecules is CD28 on the

T cell. CD28 binds to both CD80 and CD86 on the

APC (molecules that are up-regulated during matu-

ration). The T-cell receptor and CD28 synergistically

make the T cell produce cytokines that promote ac-

tivation, including IFN-g, TNF-a, and IL-2 [20]. If

this response takes place in the presence of IL-12, the

T cell differentiates into a type 1 cell. The activated

T cell also begins to express the high-affinity IL-2

receptor (IL-2R or CD25) and promotes its own ac-

tivation and clonal proliferation though IL-2 [21].

Other important co-stimulatory molecules include

CD2–LFA-3 and CD40L-CD40 [22–24]. Although

it has traditionally been thought that this initial ac-

tivation step takes place in the draining lymph nodes

of the skin, the AGR mouse suggests that this could

also take place with resident T cells in the skin.

Migration of T cells into the skin

After the initial clonal proliferation of T cells in

the lymph node, most of the newly active cells un-

dergo apoptosis. A minority, however, become mem-

ory cells that express markers like CD45RO and

migrate out of the lymph node and into the circulation

and tissues. For these cells to induce lesions of pso-

riasis, they must migrate to the skin and be reacti-

vated locally. This trafficking back into the skin is yet

another multistep process, this time between the T

cell and the endothelium. Perhaps the most important

of these regulators is the cutaneous lymphocyte

antigen. Cutaneous lymphocyte antigen is a skin-

specific adhesion molecule that binds to selectins

including both E-selectin and P-selection [25,26],

molecules that are greatly up-regulated on endothelial

cells during cutaneous inflammation [27]. This cell-

cell interaction slows the memory T cells in the

bloodstream and allows these cells to undergo a sec-

ond adhesion event called adherence [25,26]. Chemo-

kines secreted in the local inflammatory reaction

induce the T cell to increase expression of the integ-

rin molecules LFA-1 and very late antigen-4. These

molecules bind respectively to ICAM and vascular

cell adhesion molecule-1 on the endothelium and

cause the T cell literally to stick to the blood vessel

wall. Finally, a flattening and migration of the T cell

through the blood vessel wall occurs in a process

called diapedesis. From here they follow various

chemotactic molecules into the dermis [28].

There are multiple chemokines that are thought to

play a role in inflammation in psoriasis. Chemokines

were originally described as primary chemoattract-

ants, but have also been found to promote a variety of

other inflammatory functions. Initially, chemokines

help with adhesion and the ‘‘rolling’’ of cells along

the endothelium. They can also have direct effects on

T-cell differentiation by altering cytokine expression

and inflammatory receptors [29]. The major influence

for the secretion of chemokines (by various cells

including endothelial cells, keratinocytes, monocytes,

and Langerhans’ cells) is the synergistic action of

TNF-a and IFN-g from type 1 cells. Endothelial cells

secrete chemokines RANTES and TARC further to

attract more type 1 cells out of the vasculature [30].

The CD8+ cells need to migrate all the way up into

the epidermis. This is accomplished though the inter-

action of the chemokines MIG and IP-10 produced by

epidermal keratinocytes to the CXCR3 receptor. In

fact, CXCR3 CD8 cells are 10 times more likely to be

found in psoriatic plaques than in the peripheral

blood of psoriatic patients [31].

Immune cascade in the skin

The keratinocyte changes of psoriasis are a re-

action to the immune response in the skin initiated by

activated T cells but involving many different types

of inflammatory cells. The T cells are believed to

promote these changes by secreting a variety of cy-

tokines. These cytokines induce the other cells found

in the skin, including epidermal keratinocytes, den-

dritic cells, and macrophages, to produce their own

cytokines. This positive feedback cycle maintains the

chronic psoriatic plaque. The type 1 cytokines induce

ICAM-1, CD40, and major histocompatibility com-

plex II proteins on epidermal keratinocytes. ICAM-1

makes it possible for the T cells to migrate into the

epidermis through LFA-1–ICAM-1 interaction [30].

Table 1

Cytokines and chemokines that play a role in the immunologic cascade of psoriasis

Cytokines and chemokines Produced by Effects

TNF-a [54,55] Type 1 T cells, macrophages,

keratinocytes

Promotes type 1 differentiation of T cells; induces ICAM,

VCAM, and E selectin

IFN-g [29,30] Type 1 T cells Keratinocyte proliferation; increases MHC I and II expression;

Ag presentation attracts macrophages and release of TNFa;induces ICAM, VCAM, and E selectin; inhibits IL-4 (and Th2

expression)

IL-2 [29] Type 1 T cells Promotes CD28-CD80-CD86 interaction and clonal proliferation

of Th1 cells; activates macrophages and Tc1

IL-3 [29] T cells Growth of dendritic cells and macrophages

GM-CSF [29] T cells Activates neutrophils and mononuclear cells

IL-12 [29,56] APC Promotes Th1 differentiation

VEG-F [33,52] Keratinocytes, T cells Promotes angiogenesis

RANTES [29,30] Keratinocytes Induces IL-12; attracts lymphocytes

MIG and IP-10 [29,31] Keratinocytes Increases leukocyte adhesion

IL-8 [51,53] Neutrophils, keratinocytes Attracts lymphocytes and neutrophils; induces vascular response

Abbreviations: APC, antigen-presenting cells; GM-CSF, granulocyte macrophage colony–stimulating factor; ICAM, intra-

cellular adhesion molecule; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TNF, tumor necrosis

factor; VCAM, vascular cell adhesion molecule; VEG-f, vascular endothelial growth factor.


IFN-g produced by the Tc1 cells induces keratinocyte

proliferation and differentiation.

The IFN-g also is a potent stimulator for macro-

phages to release TNF-a. Neutrophils are attracted

into the dermis by the IL-8 chemokine, released by

differentiated keratinocytes as a result of multiple

inflammatory cytokines [32]. Vascular growth and

remodeling seen in psoriasis are likely caused by the

T cell release of vascular endothelial growth factor

[33]. A more extensive list of cytokines and chemo-

kines is provided in Table 1.

Creating a novel biologic therapy

The simplified immunologic cascade described

previously presents a basic understanding of the

different molecules and signals behind the develop-

ment of a psoriatic plaque. Each of these is a potential

target for the new biologic therapies. The develop-

ment of these novel biologics, however, poses a chal-

lenge. After an appropriate target is chosen, whether

it is a cell surface receptor or an extracellular cyto-

kine, it must interact with that target appropriately to

induce the proposed response.

Kohler and Milstein [34] described the first bio-

logic therapies with monoclonal antibodies in 1975.

The spleen of a mouse immunized with a specific

antigen is mixed with human myeloma cells (immor-

tal cells). To ensure that the myeloma cells do not

overgrow the fused cells, only myeloma cells that are

deficient in HGPRT, a crucial enzyme in the prolif-

eration of cells, are mixed in with the mouse spleen

cells. The medium itself does not allow spleen cells to

grow. Myeloma cells cannot reproduce on their own

without HGPRT. Only the hybrid of the myeloma and

spleen cells is able to grow in the medium. This hy-

bridoma is then cloned, and large amounts of mono-

clonal antibodies are produced.

The problem with the use of these monoclonal

antibodies in humans, however, is the potential for

patients to develop immune reactions against the

mouse protein. This reaction manifests itself as hu-

man antimouse antibodies. More recently, methods

have been developed to decrease or eliminate these

reactions by fusing parts of human antibodies with

these mouse antibodies. Chimeric antibodies (drugs

ending with -ximab) take the antigen-binding portion

of mouse antibody and fuse it to a constant region of

human antibody. Humanized antibodies (drugs end-

ing with -umab) use the framework of a human

antibody and selectively place it in small amino acid

sequences from murine antibodies into the variable

region. Fusion proteins (often ending in -cept) are

receptor domains or cell surface markers of human

proteins that are fixed to the constant portion of an

immunoglobulin [35]. For example, if a medication is

needed to block TNF-a, using an antibody that is

bound to the TNF-a receptor blocks the activation of

that receptor.

The rational for synthesizing these proteins with

the constant chain of human immunoglobulin (usu-

ally IgG) is to improve the half-life of the drug. The

drug lasts longer in the circulation if it appears to be a

human immunoglobulin. Organs that clear proteins,

like the spleen and liver, recognize it as foreign if

S. Mehlis, K.B. Gordon / Dermat

most of the antibody is murine. This allows for longer

periods between dosing and easier use for patients.

Targets for biologic therapies

The authors have developed a model, published

previously [36,37], that uses the simplified vision of

the immunopathogenesis of psoriasis to develop four

potential areas as target strategies for biologic im-

munotherapy. Strategy 1 is to decrease selectively

the number of pathogenic T cells. Strategy 2 inhibits

T-cell activation or reactivation in the lymph nodes or

skin. Strategy 3 attempts to alter the cytokine profile

of the effector T cells from type 1 to type 2, a process

called immune deviation. Finally, strategy 4 inac-

tivates specific cytokines that play a major role in

the immunologic cascade of psoriasis. This section

briefly discusses how some of the newer biologics

may fit into this framework.

Strategy 1: targeting pathogenic T cells

Psoriasis is a T-cell –mediated disease. Elimi-

nating pathogenic T cells from the periphery or the

skin should decrease disease activity. One of the first

biologics studied for psoriasis was denileukin difitox,

a fusion protein that combines an enzymatically

active diphtheria toxin with the coding sequence of

IL-2. This protein binds avidly to the IL-2 R and

rapidly gets internalized. The active diphtheria toxin

inhibits protein synthesis and ultimately results in cell

death [38]. It has no effect on any other cells other

than an activated T cell that expresses the high

affinity IL-2 receptor [39]. In clinical trials with this

drug in psoriasis, there was an improvement in

psoriasis, leading researchers to focus on blocking

T cells and their function for biologics [40,41].

Another method of blocking T cells is to induce

apoptosis of the cell itself by surface receptors or

by activating natural killer cells or macrophages to

induce their death. Alefacept, a fusion protein of

LFA-3 and human IgG, works in two separate ways.

First, the LFA-3 portion binds to its match on the

T cell, the CD-2 receptor, blocking co-stimulation.

The constant portion IgG engages the FcgIII receptoron natural killer cell, however, which induces apo-

ptosis by the perforin-granzyme system [42]. It also

reduces the number of activated T cells found in the

circulation, and the response to therapy correlates to

this decrease in the periphery and especially the skin

[42,43].

Strategy 2: blocking T-cell activation

Strategy 2 blocks cell-cell interaction in any of the

three steps outlined in T-cell activation: (1) binding,

(2) antigen-specific activation, and (3) co-stimulation.

It could also target the trafficking of the T cells back

into the skin. Efalizumab is a humanized monoclonal

antibody that binds to the CD11a portion of the LFA-

1 surface molecule found on T cells [44]. By blocking

the interaction with ICAM, efalizumab blocks the

initial binding of T cells to the APC [45], migration

into the skin by ICAM on endothelial cells [46], and

Tc1 adhesion to keratinocytes [45].

Strategy 3: immune deviation away from type 1

T cells

There is an inverse relationship between the bal-

ance of Th1 and Th2 cells. Promoting a Th2 response

by the addition of Th2 cytokines should decrease the

activity of Th1 cells. Several different biologic agents

work to upset the Th1 balance. IL-4 is the primary

cytokine that inhibits the activity of type 1 T cells.

Small studies have demonstrated some efficacy with

acute treatment with recombinant IL-4. IL-10 is an

important Th2 cytokine, and subcutaneous injection

of recombinant IL-10 has been shown to decrease

Th1 cytokines and improve psoriasis [47]. Recombi-

nant IL-11 has similarly induced a Th2 response and

improvement in psoriatic plaques [48].

Although the induction of immune deviation has

traditionally been limited to treatment with type 2

cytokines to down-regulate type 1 cells, very prelim-

inary data from another approach suggest potential

effects with immune deviation. The presence of IL-12

is necessary for type 1 T-cell differentiation. Early

studies suggest a monoclonal antibody directed

against IL-12 could have some efficacy in psoriasis.

By blocking type 1 differentiation, a novel form of

immune deviation in psoriasis, it may be possible to

improve disease.

Strategy 4: inactivating cytokines and chemokines

The final strategy uses antibodies to target inflam-

matory mediators that are still bound to cells or have

been excreted. There are a variety of different cyto-

kines and chemokines implicated in the pathogenesis

of psoriasis, and any of the candidates in Table 1 can

be a potential target. Etanercept is a dimeric fusion

protein that binds to soluble TNF-a to neutralize it

[49]. Infliximab also targets TNF-a. It is a chimeric

antibody that targets both soluble and bound TNF,

and can neutralize the effects of TNF and can also

ol Clin 22 (2004) 371–377 375


result in compliment-mediated fixation and antibody-

dependant toxicity of T cells [50]. Other cytokines

that have been targeted include IL-8 [51] and IFN-g.

Summary

Traditional systemic therapy for psoriasis is

limited by either lack of efficacy or the long-term

side effect profile of the medications used. Newer

information about the pathophysiology of the disease

has led to new perspectives on developing novel

techniques for attacking psoriasis. In particular, spe-

cifically targeting the areas in the immunologic

cascade that may be the central drivers for the

development of psoriasis could lead to better therapy.

The techniques of genetic engineering and the tech-

nology to produce bioengineered molecules in large

quantities have given clinicians the ability specifi-

cally to target psoriasis and other inflammatory dis-

eases. These biologic medications truly bridge the gap

between the identification of the pathophysiologic

processes of psoriasis and the treatment of patients

suffering from this disease.

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Dermatol Clin 22 (2004) 379–388

Review of therapy of psoriasis:

the prebiologic armamentarium

David S. Aaronson, MD, Mark Lebwohl, MD*

Mount Sinai School of Medicine, 5 East 98th Street, Box 1048, New York, NY 10029-6574, USA

To appreciate the evolving treatments for psoriasis diflorasone diacetate in optimized base, to the weaker

in the current biologic era, it is important to first

examine traditional therapies. This article reviews the

prebiologic armamentarium and addresses the follow-

ing treatments: (1) topical agents, including topical

corticosteroids, tars, anthralin, vitamin D analogs,

retinoids, and salicylic acid; (2) systemic agents, such

as oral acitretin, methotrexate, and cyclosporine; and

(3) phototherapy with ultraviolet B (UVB) light,

narrowband UVB, and psoralen with ultraviolet A

(PUVA) light.

Topical therapy

Topical therapy is considered the first line in

psoriasis treatment. The various side-effect profiles

of these agents, however, often require their rotation

throughout the course of the disease. The following

sections describe the medicines in this category, their

side effects, and the current data on their efficacy.

Corticosteroids

Corticosteroids persist as the mainstay for the

topical treatment of psoriasis despite the existence

of safer therapies with lesser side effects. Topical

corticosteroids are categorized by the Stoughton-

Cornell classification system, based on the vasocon-

striction of small blood vessels in the upper dermis

[1]. This system ranges from the superpotent class 1

steroids, such as clobetasol, halobetasol propionate,

betamethasone dipropionate in optimized base, and


doi:10.1016/j.det.2004.03.012


E-mail address: [email protected] (M. Lebwohl).

class 7 steroids, such as 1% hydrocortisone. They all

reduce inflammation but vary in strength, vehicle,

and cost. Many forms of topical corticosteroids exist,

including solutions, foams, lotions, creams, emollient

creams, gels, ointments, sprays, and tape.

Topical corticosteroids come with bothersome and

occasionally serious side effects that limit their long-

term use in the treatment of psoriasis, however. The

hypothalamic–pituitary–adrenal axis can be sup-

pressed by medium-potency or stronger topical cor-

ticosteroids. This potential side effect is most

worrisome for children because their ratio of surface

to body mass is increased. Conversely, iatrogenic

Cushing’s syndrome is also a rare potential side effect

of topical corticosteroids. More common side effects

occur locally at the site of topical corticosteroid

application resulting in cutaneous atrophy. This pro-

cess leads to skin fragility and tearing of dermal

connective tissue, which causes irreversible striae.

Telangiectases also arise, which can rupture and form

purpura. These findings are most often seen when

high-potency corticosteroids are used on the face and

intertriginous areas for prolonged periods of time.

One other major complication of topical cortico-

steroids is tachyphylaxis. Tachyphylaxis is defined as

the cessation of therapeutic response to a substance as

treatments with that substance are continued. This

phenomenon is seen scientifically as the reduction

or loss of small vessel vasoconstriction induced by

topical corticosteroids [2]. Clinically, however, it has

been questioned whether tachyphylaxis exists [3]. To

avoid tachyphylaxis and other side effects, Katz et al

[4] demonstrated that a regimen of three applica-

tions of superpotent betamethasone dipropionate over

24 hours per week led to improvement of psoriasis for

up to 6 months in 60% of patients versus 20% of

s reserved.

D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388380

patients in the placebo group. This method has been

termed pulse therapy or weekend therapy. Other

methods to limit the side effects from topical cortico-

steroids include the introduction of novel agents,

such as fluticasone propionate, mometasone furoate,

prednicarbate, and tipredane, and novel vehicles, such

as betamethasone valerate in a foam and diflorasone

diacetate in an optimized base in a gel.

Anthralin and tars

Anthralin use has declined in Europe with the

introduction of topical vitamin D analogs for psoria-

sis. Anthralin can be moderately irritating and can

stain skin, clothes, and furniture. Micanol with 1%

anthralin in a new temperature-sensitive vehicle acti-

vated at skin temperature was recently released to

avoid these drawbacks. It only prevents staining of

clothes and furniture, however, not skin. To reduce

skin irritation, short contact regimens of anthralin

have been explored to minimize exposure to the

staining and irritating effects. Despite these efforts,

and the equal efficacy shown for 0.25% to 2%

dithranol cream applied once daily for 30 minutes

versus 3 mg/g of calcitriol ointment twice daily, the

quality of life in the calcitriol group was perceived as

much better [5]. Application of triethanolamine after

removal of anthralin may prevent irritation and stain-

ing of the skin [6].

Topical vitamin D analogs

The vitamin D3 analog calcipotriene was intro-

duced in Europe in the early 1990s in a 0.005%

ointment formulation. Calcipotriene binds to the

vitamin D receptor found in keratinocytes, halting

proliferation and causing terminal differentiation [7].

It is currently used to treat moderate to severe plaque

psoriasis alone, but primarily in combination with

other treatment modalities.

Side effects from vitamin D analogs are minimal

when compared with topical corticosteroids and

anthralin. Vitamin D analogs can cause irritant con-

tact dermatitis, however, particularly on the face and

in intertriginous sites. Yet, they are highly effective in

alleviating psoriasis. Studies suggest that dilution of

calcipotriene with petrolatum, when used on the face

or intertriginous areas, or the addition of superpotent

halobetasol ointment may prevent irritant contact

dermatitis [8,9]. Another side effect, hypercalcemia,

is seen rarely in case reports but is invariably asso-

ciated with excess use over large surface areas [10].

In general, long-term studies of calcipotriene have

shown that it is well tolerated with few adverse

effects [11,12].

Calcipotriene, when compared with topical corti-

costeroids in clinical trials, was shown to be as

effective as class 2 (fluocinonide, 0.05%) but not as

effective as class 1 corticosteroids [13]. In combina-

tion, calcipotriene plus limited application of the

superpotent topical corticosteroid halobetasol worked

better than either one alone, with no incidence of

cutaneous atrophy [14]. Furthermore, a new combi-

nation of calcipotriol and the betamethasone dipropio-

nate ointment used once daily was shown to be more

effective than either one alone in a randomized

double-blind study [15].

These studies led to the examination of combination

preparations containing calcipotriene. Halobetasol

(0.05%) ointment or cream and 5% tar gel (Estargel)

in combination with calcipotriene (0.005%) ointment

remained stable for a minimum of 13 days at room

temperature. One study found, however, that 6% sali-

cylic acid or 12% ammonium lactate lotion inactivated

calcipotriene completely or by more than 30%, respec-

tively [16].

Calcipotriene also has been combined with photo-

therapy. The Canadian Calcipotriol and UVB Study

Group has shown in a multicenter, prospective, ran-

domized, parallel-group, vehicle-controlled, single-

blind study that calcipotriol cream plus twice-weekly

broadband UVB reduced the UVB exposure to

achieve total psoriasis clearance [17]. Narrowband

UVB plus calcipotriol, however, does not improve

psoriatic response when compared with narrowband

UVB alone [18]. Importantly, calcipotriene is not

inactivated by UVB and may increase the minimal

erythema dose [19].

PUVA in combination with calcipotriene also has

been studied. One promising study by Speight and

Farr [20] showed that application of twice-daily

calcipotriene ointment versus placebo to symmetri-

cally located plaques of psoriasis on the same patient

decreased the UVA dose by 26.5% without affecting

time to relapse. This regimen has the advantage of

reducing the long-term skin aging and carcinogenic

effects of UVA. Calcipotriene is inactivated by UVA

and should therefore be applied only after photo-

therapy [21].

Retinoids

Tazarotene is a specific retinoic acid receptor

(RAR) ligand and has no binding activity with the

retinoic X receptor. It specifically binds b and gsubtypes of RAR and is believed to reduce inflam-

mation and cause epidermal differentiation [22,23].

D.S. Aaronson, M. Lebwohl / Derm

Tazarotene is available in gel and cream formulation

at 0.05% and 0.1% concentrations.

Tazarotene was introduced because it is less

irritating when compared with topical application of

nonspecific retinoids and has little of their systemic

effects. Still, its major side effect is cutaneous irrita-

tion, which is worse with the more effective higher

concentration [24]. Like the vitamin D analogs, it

does not cause the more troublesome side effects of

topical corticosteroids.

Efforts have been undertaken to minimize the

irritating nature of retinoids and enhance their action

by combining topical corticosteroids. Tazarotene used

with the topical corticosteroids, 0.1% mometasone

furoate cream (class 4) or 0.05% fluocinonide (class 2),

improved psoriatic plaques with reduced retinoid

dermatitis [25]. Furthermore, a small-scale pilot study

postulated that 0.1% tazarotene can actually reduce

epidermal atrophy induced by 0.05% diflorasone

diacetate ointment [26]. Regimens of 0.1% tazarotene

and the corticosteroids, 0.1% mometasone furoate or

clobetasol ointment, also have shown increased effi-

cacy and decreased side effects compared with either

treatment alone [27,28].

Tazarotene with phototherapy also has been

examined. The addition of tazarotene to UVB quick-

ened psoriasis improvement when compared with

UVB alone but caused increased sensitivity to burn-

ing [29]. There have been recommendations to reduce

UV doses by one third to avoid burning with com-

bination tazarotene [30].

Phototherapy

UV light causes DNA damage to cutaneous

tissue. It also is a proven effective psoriasis treat-

ment. William Goeckerman [31] first introduced

phototherapy at the beginning of the 20th century.

Goeckerman’s regimen consisted of a day and night

crude coal tar bath followed by exposure to a hot

quartz mercury vapor lamp. At that time, patients

only received phototherapy in the inpatient setting.

Ingram [32], who substituted anthralin for crude

coal tar, made an important modification in the

1950s. Levine et al [33] made additional modifica-

tions in the 1970s when they discovered that out-

patient treatment 3 times per week and a clear

lubricating base instead of crude coal tar was as

effective as an equal number of inpatient treatments.

Over the years, additional advances in phototherapy

have occurred with the use of systemic and topi-

cal medicines.

Ultraviolet B

Discussion of phototherapy in the more modern

era must first start with broadband UVB. UVB dose

is based on minimal erythema dose or Fitzpatrick skin

types [34]. UVB has enhanced efficacy with a thin-

layer application of clear emollients, such as petrola-

tum and mineral oil, because of improved optical

transmission to the skin [35]. Thick application of

these same emollients and other topical treatments

already discussed can block UVB [36]. Attention

should be paid to agents that block or enhance UVB.

The side effects of UVB are skin burning and

photosensitivity. Unlike UVB in sunlight, evidence

suggests that broadband UVB in phototherapy does

not lead to carcinogenesis [37]. The combination of

UVB with other topical and systemic treatments for

psoriasis has been shown to increase skin burning and

photosensitivity, and with some treatments, actually

reduces the time to relapse. Care must be taken when

combined treatment is considered. The benefits of

combination therapy with calcipotriene or tazarotene,

however, are accelerated efficacy and increased skin

clearing [29,38,39].

Systemic therapy with methotrexate or acitretin in

combination with UVB is another effective treatment

of psoriasis. The addition of a systemic agent reduces

the total cumulative dose of UVB, and conversely,

addition of UVB to systemic therapy reduces drug

dosages [40,41]. The synergy between systemic and

UVB therapy is a critical observation when the side

effects of methotrexate and oral retinoids are consid-

ered. This synergy includes reduction in liver biop-

sies performed for methotrexate and the hair loss,

cheilitis, myalgias, and pyogenic granulomas caused

by oral retinoids.

Psoralen plus ultraviolet A

PUVA is a major treatment of widespread or re-

sistant psoriasis. Psoralen, 8-methoxypsoralen, when

targeted with UVA, causes the formation of pyrimi-

dine dimers and reaches peak cutaneous concentra-

tions between 1 and 4 hours. Pyrimidine dimers lead

to cross-linkage of DNA strands. Cross-linkage of

DNA strands leads to genomic instability and inflam-

matory cell death. Psoralen is typically given orally

2 hours before UVA in a crystalline form (Oxsoralen)

at 0.6 mg/kg or 90 minutes before UVA in an encap-

sulated liquid form (Oxsoralen Ultra) at 0.4mg/kg.

PUVA increases the incidence of squamous cell

carcinoma (SCC) and, to a lesser extent, malignant

melanoma. One study showed that patients treated

with 260 individual PUVA sessions compared with

atol Clin 22 (2004) 379–388 381


fewer than 170 sessions had an 11-fold increase in

SCC [42]. Male genitalia should be shielded during

UVA exposure because of the tendency to develop

carcinoma in that region [43]. One study reported that

malignant melanoma increased several-fold in indi-

viduals treated with more than 250 PUVA ses-

sions, and that study included individuals treated at

the onset of PUVA therapy with higher doses [44].

Notwithstanding, it is important for all patients re-

ceiving PUVA therapy to have periodic skin exami-

nations to monitor for new lesions.

In addition to cancer, lesser side effects, such as

premature cutaneous aging, nausea, headache, and

burning, can be prominent. It is important to take

psoralen with food to reduce the incidence of nausea,

or particularly sensitive patients can bathe in psoralen

[45,46]. Also, avoidance of sun exposure should be

stressed. Unlike normal sunburn, PUVA-induced

burns appear within 24 hours, but peak around

48 hours. For this reason, PUVA therapy should

never be given 2 days consecutively.

The combination of PUVA therapy plus other

topical agents has been explored to reduce the cumu-

lative dose of UVA. PUVA and corticosteroids have

yielded conflicting results [47,48]. Studies of the

combination of PUVA and anthralin have not been

undertaken, most likely because of the potential for a

UVA-photosensitizing effect. The combination of

PUVA and calcipotriene has met with greater success

and was discussed earlier. It causes quicker clearing

with lower UVA doses than with PUVA alone. The

combination of PUVA and tazarotene gel is not

widely published, but tazarotene may enhance PUVA

with the caveat that tazarotene gel reduces the amount

of UVA necessary [30]. The combination of PUVA

with oral retinoids provides not only synergy but also

a reduction in one another’s side-effect profiles. This

effect is partially brought about through a reduced

need for UVA exposure to achieve the same clearance

of psoriasis [49,50]. The addition of oral retinoids is

termed PUVA-sparing therapy. There has been work

showing that the addition of oral retinoids reduces the

incidence of skin cancers because the development

of UVA-induced skin cancers is dose-dependent

[51–53]. Another systemic agent, methotrexate, also

has been proven effective in combination with PUVA

in the treatment of psoriasis [54]. Yet, methotrexate is

a known risk factor for SCCs and requires liver

function monitoring.

Narrowband ultraviolet B

Narrowband UVB (Tl-01) is a wavelength of ap-

proximately 311 nm that maximizes psoriasis clear-

ance compared with its erythrogenic potential.

Narrowband UVB has the disadvantage of producing

more severe and longer-lasting burns than broadband

UVB, however, and its long-term effect on carcino-

genesis remains unknown. Its overall safety is sus-

pected to be much greater than PUVA.

Narrowband UVB has been proven superior to

broadband UVB [55] and is as effective as or less

effective than PUVA [56,57]. The better safety profile

of narrowband UVB, especially when administered at

an optimized dosage, has led to its increased use over

the last few years. Studies with narrowband UVB in

combination with other agents are underway.

Systemic therapy

Systemic therapy for psoriasis in the prebiologic era

consists of Food and Drug Administration (FDA-)–

approved drugs, such as methotrexate, acitretin, and cy-

closporine, and nonapproved drugs, such as tacrolimus,

mycophenolate mofetil, hydroxyurea, 6-thioguanine,

and sulfasalazine. Typically, these systemic therapies

are used for severe disabling psoriasis or psoriasis

refractory to topical or phototherapeutic modalities.

Methotrexate

Methotrexate was implemented as an effective

treatment of psoriasis back in the 1970s, and at the

present time, remains widely used [58]. It also has

FDA-approved uses for the treatment of neoplastic

and rheumatologic disease. It reversibly inhibits

dihydrofolate reductase, which is an enzyme required

for the reduction of folic acid to tetrahydrofolic acid.

This inhibition limits the quantity of one-carbon units

needed to form purines and transform deoxyuridylate

into thymidylate. Through this mechanism, metho-

trexate prevents the synthesis of DNA and cell

replication. Inflammatory cells and cells with high

turnover, such as hematopoetic and gastrointestinal

cells, are most affected by systemic methotrexate

therapy. It is methotrexate’s effects on these cell types

that cause most of its side effects; most recently,

attention has been drawn to the immunosuppressive

effects of methotrexate. Methotrexate is 50% protein

bound in plasma and primarily excreted by the

kidneys. In addition, it interacts with many other

drugs, making it crucial to get a complete list of pa-

tient medications.

Methotrexate has a multitude of side effects, rang-

ing from benign to life threatening. The most com-

mon side effects are nausea, vomiting, anorexia,

D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388 383

stomatitis, macrocytic anemia, and phototoxicity.

Stomatitis and macrocytic anemia can be prevented

with oral folic acid in dosages of 1 to 5 mg daily [59].

Methotrexate phototoxicity is a unique side effect and

has been given the name ‘‘radiation recall,’’ which is

the development of erythema at previous sights of

radiation or sunburns [60].

Methotrexate can also cause fatal seizures, hepa-

totoxicity, renal failure, bone marrow suppression,

and pulmonary fibrosis. Consequently, methotrexate

is contraindicated in patients who have renal or

hepatic impairment or profound bone marrow sup-

pression. It is also necessary to stop methotrexate in

the event of infection or other illness requiring an

intact immune response.

The pulmonary side effects can be deadly. If a

patient complains of new-onset shortness of breath or

cough, methotrexate should be discontinued [61].

Persistent or worsening symptoms should be evalu-

ated with a chest radiograph.

Much like other immunosuppressive drugs, metho-

trexate has been reported to cause lymphoprolifera-

tive disorders. These lymphoproliferative disorders

have disappeared with methotrexate cessation, sug-

gesting possible causality [62,63].

Hepatotoxicity is the most serious long-term side

effect, and how best to monitor patients taking

methotrexate is a topic of much debate. It is well

agreed on, though, that those patients already predis-

posed to cirrhosis of the liver, such as alcoholic,

obese, or diabetic patients, should take methotrexate

with extreme caution or not at all. Roenigk et al [58]

have published guidelines on monitoring patients

taking methotrexate. Patients with hepatic risk factors

should have a liver biopsy after 2 to 4 months of

methotrexate therapy with signs of psoriatic improve-

ment. A biopsy should be repeated after a 1- to 1.5-g

cumulative dose has been reached. Patients with no

hepatic risk factors should have a liver biopsy at a

1–1.5-g cumulative dose and thereafter for every

1.5 g of methotrexate. Previously, a baseline liver bi-

opsy was indicated for every patient starting metho-

trexate. Rheumatologists do not recommend routine

liver biopsy for patients treated with methotrexate for

rheumatoid arthritis (RA), however. Patients with

psoriasis, however, are more likely to have histologic

progression or cirrhosis than patients with RA [64].

There are several confounding factors that may ex-

plain this difference, including use of nonsteroidal

anti-inflammatory medicine and oral steroids, popu-

lation bias, and dosage.

One final contraindication to the administration of

methotrexate is pregnancy. It is a class X drug and

therefore highly teratogenic and known to cause

miscarriages [65]. Methotrexate may also temporarily

affect male fertility. Therefore, methotrexate therapy

should be halted several months before conception,

and all patients should be advised about its deleteri-

ous effects.

Despite numerous side effects and the required

monitoring of toxicity, methotrexate is effective.

Psoriatic arthritis may be most alleviated with metho-

trexate. Methotrexate is also useful for the long-term

management of severe psoriasis, especially the eryth-

rodermic and pustular variants. Newer studies in

comparing the biologics are currently underway.

Retinoids

Retinoids can be applied topically or systemically

to treat psoriasis. Topical retinoids were discussed

previously. Systemic usage is indicated for the treat-

ment of severe psoriasis, including the erythrodermic

and pustular types. There are four FDA-approved

retinoids available, but only three are used in the

treatment of psoriasis. Isotretinoin is useful for acne

and pustular psoriasis in monotherapy [66]. It can

also be combined with PUVA and UVB for enhanced

effects [67,68]. Etretinate and acitretin are the other

two FDA-approved systemic retinoids for the treat-

ment of psoriasis. Acitretin is the active metabolite

of etretinate.

Retinoids are highly teratogenic and persist in

fatty tissue long after they are discontinued. Further-

more, etretinate was withdrawn from the market once

the shorter-lived acitretin was introduced. All women

considering this agent must be warned that retinoids

should not be taken if they plan to become pregnant

while they are taking this medication, or even 3 years

after they discontinue the medicine. Most physicians

expect patients to use some sort of birth control to

prevent accidental pregnancy. Prolongation of reti-

noid teratogenicity may occur if acitretin is taken

with alcohol because it is esterified to longer-lived

etretinate [69]. Therefore, female patients of child-

bearing potential must also cease drinking and be

watchful of over-the-counter medications and foods

containing alcohol.

Acitretin is usually well tolerated at low doses, but

at doses of greater than 50 mg per day, mucocutane-

ous lesions may develop, including hair loss, dry lips,

cheilitis, dry skin, and ‘‘sticky skin’’ (retinoid-type

dermatitis). Elevation of serum lipids and liver func-

tion tests are common. Triglyceride elevation can be

partially negated by use of gemfibrozil or atorvastatin

[70]. No cases of hepatitis have been reported, but

liver function should be monitored. Other concerns

after long-term treatment with retinoids include the


following: the development of pseudotumor cerebri,

although this is rare and has only been associated

with isotretinoin; osteoporosis [71]; and the develop-

ment of ligamentous calcifications and skeletal ab-

normalities [72].

Despite these minor side effects, acitretin is a

highly effective systemic treatment modality for se-

vere erythrodermic or pustular psoriasis in mono-

therapy or in combination with other treatment

modalities. Plaque and guttate psoriasis are slower

to resolve with acitretin therapy alone. In combina-

tion with PUVA or UVB, however, excellent results

can be achieved with lower doses of UV light

[49,50,73]. One study showed that retinoids may

suppress development of cutaneous malignancies

associated with UVA [74]. Acitretin in combination

with calcipotriol ointment has improved resolution of

psoriatic plaques and reduces total cumulative dose of

acitretin to reach clearance [75].

Cyclosporine

Cyclosporine is an immunosuppressive agent

originally created in the 1970s for the prevention of

kidney transplant rejection. Its mechanism of action

is not completely understood, but cyclosporine is

known to cause inhibition of the antigenic response

of helper T lymphocytes by reducing the production

of interleukin 2 (IL-2) and interferon g (IFN-g). Theoral microemulsion formulation is FDA-approved for

the treatment of psoriasis in doses of up to 4 mg/kg

daily. It is highly effective for all forms of psoriasis

but must be administered by knowledgeable physi-

cians [76,77].

Cyclosporine can cause nephrotoxicity, hyper-

tension, hyperlipidemia, hypomagnesemia, hyper-

kalemia, increased susceptibility to infection, and

malignancy. The risk of malignancy, however, proba-

bly is only increased in those patients who are

undergoing long-term treatment. Skin cancer and

lymphoproliferative disorders have been witnessed

in transplant patients on long-term, high-dosage cyclo-

sporine [78,79]. In patients treated with cyclosporine

for RA for a mean of 1.6 years, but at an average dose

of only 2.6 mg/kg daily, the incidence of malignancy

was no different from that in the control group [80].

A recent report found that a patient treated for

recalcitrant psoriasis with cyclosporine developed a

primary, cutaneous, large T-cell lymphoma that re-

solved clinically and histologically with discontinua-

tion of therapy after 2 months. The lymphoma

recurred 3 years later, however [81].

The nephrotoxicity of cyclosporine is perhaps the

most worrisome side effect of this powerful drug.

Histologic changes consistent with interstitial fibrosis

and renal tubular atrophy have been demonstrated in

individuals treated for more than 2 years [82,83].

Nephrotoxicity is best minimized by maintaining

doses of less than 5mg/kg per day and monitoring

serum creatinine for a change from baseline that is

greater than 30%. Patients must also be monitored

periodically for hypertension, although this common

side effect can be alleviated by the addition of a

calcium channel blocker. It has been suggested that

calcium channel blockers may actually prevent cy-

closporine nephrotoxicity [84]. Hyperlipidemia can

be managed with a statin-type drug. Hyperkalemia

can be avoided through low-potassium diets or the

use of hydrochlorothiazide.

Serum levels of cyclosporine are greatly affected

by numerous medicines. With proper monitoring,

however, cyclosporine dosage can be altered accord-

ingly. Unlike methotrexate and acitretin, cyclosporine

is not teratogenic and is not myelosuppressive [85].

Cyclosporine is a highly effective agent for the

treatment of severe psoriasis. Debate concerning

intermittent versus continuous treatment has resulted

in numerous studies. The use of intermittent cyclo-

sporine is recommended; although it may be less

effective, the added side effects do not warrant con-

tinuous therapy [86,87]. The administration of cyclo-

sporine should stop or be tapered once psoriatic

clearance has occurred.

Tacrolimus (FK506)

Tacrolimus is a macrolide antibiotic used as an

immunosuppressive agent for organ transplant. It is

structurally distinct from cyclosporine but behaves in a

similar manner by suppressing T-lymphocyte activa-

tion. When compared with cyclosporine, it is 100 times

more potent in its ability to inhibit IL-2 and IFN-gsecretion [88,89]. Tacrolimus is not FDA-approved for

psoriasis but is indicated in the treatment of atopic

dermatitis as a topical agent.

Tacrolimus has a side-effect profile similar to

cyclosporine. The monitoring of renal, hematopoetic,

and hepatic function is necessary if a patient is put

on tacrolimus.

A multicenter, double-blind, placebo-controlled

study involving 50 patients with severe recalcitrant

plaque psoriasis demonstrated a significant improve-

ment based on the Psoriasis Area and Severity In-

dex [90]. The reported side effects were not severe.

Greater experience needs to be gained with tacroli-

mus for the treatment of psoriasis. To date, no

comparisons to cyclosporine have been undertaken

in patients with psoriasis.

Dermatol Clin 22 (2004) 379–388 385

Mycophenolate mofetil

Mycophenolate mofetil is an oral immunosup-

pressive agent that is hepatically metabolized to its

biologically active mycophenolic acid. It currently is

FDA-approved for prophylaxis against rejection of

organ transplants. Mycophenolate mofetil has been

used to treat severe psoriasis, with long-term remis-

sion and minimal side effects [90,91]. Its mecha-

nism of action is the noncompetitive inhibition of

inosine monophosphate dehydrogenase, thereby pre-

venting DNA synthesis and cellular proliferation. Its

other non–FDA-approved uses are for the treatment

of bullous pemphigoid, pemphigus vulgaris, and

atopic dermatitis.

Like all immunosuppressive agents, its use must

be monitored. Notably, nephrotoxicity is not asso-

ciated with this drug. There is a risk of increased sus-

ceptibility to infection and malignancy, however [92].

Hydroxyurea

Hydroxyurea is an antimetabolite that is FDA-

approved for the treatment of cancer and sickle cell

anemia. It inhibits ribonucleotide reductase, a crucial

enzyme necessary for the conversion of DNA bases.

Its use in the treatment of severe psoriasis is not

FDA-approved, but it has a three-decade history as a

monotherapy for psoriasis [93,94].

Doses needed to develop psoriatic improvement,

however, cause nearly 50% of patients to experience

bone marrow toxicity. In addition, long-term treat-

ment has been associated with lymphoproliferative

disorders [70]. Mucocutaneous lesions can also arise

as a common side effect.

6-Thioguanine

The agent 6-thioguanine is a purine analog that

inhibits DNA and RNA synthesis by incorporating

into native strands. It is an approved antineoplastic

drug, with a nonapproved indication in the treatment

of severe psoriasis.

Its side effects primarily involve the gastrointes-

tinal tract, but severe myelosuppression can occur. Fur-

thermore, initial trials with 6-thioguanine were limited by

bone marrow toxicity. Silvis and Levine [95] reported

that weekly dosing could achieve similar clearance of

psoriasis with nearly no myelosuppression.

Sulfasalazine

Sulfasalazine is a conjugation of 5-aminosalicylic

acid and sulfapyridine. It is indicated in the use of

D.S. Aaronson, M. Lebwohl /

ulcerative colitis but also has been implemented in

the treatment of psoriatic arthritis. The mechanism of

action is unknown although it is believed to disrupt

prostaglandin synthesis and the arachidonic acid

pathway. Multiple double-blind studies have shown

moderate results in the treatment of psoriatic arthritis.

One study comparing cyclosporine versus sulfasala-

zine in 99 patients through an open, prospective,

randomized, controlled format significantly demon-

strated better results with cyclosporine [96].

Summary

The prebiologic armamentarium discussed in

this article has a significant role in certain patients

for the treatment of psoriasis. With the creation of

the newer ‘‘biologics’’ and their comparatively les-

ser toxicity, however, the treatment of psoriasis is

being re-evaluated.

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Dermatol Clin 22 (2004) 389–395

Quality-of-life issues in psoriasis

Rita Mukhtar, BA, Jane Choi, MD, John Y.M. Koo, MD*

Psoriasis and Phototherapy Treatment Center, Department of Dermatology, University of California,

515 Spruce Street, San Francisco, CA 94118, USA

Although most skin conditions are not life threat- riasis in such terms can be helpful in formulating a

ening, they can strongly affect how patients perceive

and interact with their environment, giving such dis-

eases the potential to alter every aspect of a patient’s

life. There is a common tendency among the general

public, health professionals, and policymakers, how-

ever, to view skin disease as merely a ‘‘cosmetic’’

problem. When it comes to determining morbidity,

more weight is generally assigned to the physical

sequelae of disease, based on the assumption that the

psychosocial impact somehow deserves less attention.

Increasingly, however, studies of psoriasis show

that skin disease has serious consequences for those

afflicted. Psoriasis, as a disease, typically affects the

skin, but as an illness, it can affect a patient’s

relationships, finances, leisure activities, and mental

health. The words of one psoriasis sufferer illustrate

the significance of the disease:

Skin is contact. It is my closest contact with my

surroundings. Expressions of love, etc., revolve

around skin. . . . it is frustrating to have a damper

placed on one’s contact with people. [1]

The visibility of skin gives it a prominent role in

social interactions. One study examining the psycho-

dynamic characteristics of life stressors raises this

issue, suggesting that the skin lesions of psoriasis

might not simply be of biologic significance but carry

psychologic meaning as well [2]. Thinking about pso-


doi:10.1016/j.det.2004.03.016

Conflict of interest: Dr. Koo has been a clinical re-

searcher, consultant, and speaker for Allergan, Amgen,

Biogen, Bristol-Myers Squibb, Centacor, Connetics, Elan,

Fujisawa, Galderma, Genentech, GlaxoSmithKlein, ICN,

Novartis, and Roche.


E-mail address: [email protected] (J.Y.M. Koo).

concept of how a patient might experience the disease.

Although clinicians who care for people with skin

disorders are most likely to be cognizant of some of

the difficulties their patients face, there remains a

notable gap between the patient’s experience of

disease and the dermatologist’s perception thereof.

A comparison of physician and patient responses to

surveys showed significant differences between phy-

sician and patient assessments of patient quality of

life (QOL). Physicians tended to underestimate the

impact of severe skin disease, and overestimate the

impact of mild disease (the authors suggested that

some patients might downplay morbidity as they

become accustomed to having disease) [3]. Similarly,

a survey of members of the National Psoriasis Foun-

dation (NPF) revealed the prevalent view among

patients that physicians fail to appreciate the full

impact psoriasis has on their lives [4,5].

It is, then, the inner world of the patient with

psoriasis to which clinicians need access. Understand-

ing exactly how psoriasis affects the patient is the

purpose of queries about QOL. It has been argued that

QOL assessment is the most important measure of

disease severity because reductions in QOL define the

patient’s actual experience of living with the illness.

The concept of ‘‘quality of life’’ attempts to account

for several dimensions of well-being in an individual.

The domains that are often assessed include physical,

psychologic, social, and general well-being, and cog-

nitive functioning [6]. Health-related QOL (HRQOL)

is more narrowly defined and encompasses those

factors specifically relating to the disease process or

its treatment. In the absence of a permanent cure, as is

the current case with psoriasis, the clinician strives to

reduce the severity of disease with the goal of pre-

venting reduction in QOL [7].

s reserved.

R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395390

Increasingly, QOL is being used as a measurement

tool in the evaluation of health care outcomes [6].

Krueger et al [8] argued that although body surface

area (BSA) is often used to define severity in clinical

trials, such a definition fails to be sensitive to indi-

vidual differences between psoriasis sufferers. De-

pending on which region of the body the psoriasis

affects, a low BSA can correspond with very severe

functional impairment, whereas a higher BSA can

have very little impact on an individual’s day-to-day

life. For example, psoriasis affecting the dominant

hand might receive a low BSA but hinder an indi-

vidual’s ability to perform basic tasks, whereas pso-

riasis affecting a larger region of the body, such as the

back, might not affect functioning as much. Because

it is ultimately the impact of psoriasis on activities of

daily living that matters to patients, QOL becomes a

critical measure of disease severity.

Measuring QOL not only gives clinicians access

to important information about the individual patient,

it also allows for comparisons to be made between

psoriasis and other chronic medical conditions.

Knowing which diseases have the most impact on pa-

tient QOL helps ensure proper allocation of research

and treatment resources. In addition, accurately mea-

suring QOL allows clinicians to assess the efficacy of

new therapies and provides a patient-oriented means

of measuring disease status [9].

Tools for measuring quality of life

As the importance of measuring QOL has been

increasingly recognized, researchers have developed

several instruments to assess the impact of skin dis-

eases, including psoriasis, on patients. These instru-

ments can be divided into generic, specialty-specific,

or disease-specific classes, such that an instrument

might be applicable to patients with any systemic ill-

ness, patients with skin disorders in general, or pa-

tients with only psoriasis. In addition, questionnaires

designed to measure HRQOL are categorized as either

discriminative or evaluative. Discriminative instru-

ments attempt to differentiate between individuals at

one point in time, whereas evaluative instruments are

useful in quantifying change in the same individuals

over time [7]. To be useful, these tools must be valid,

reliable, and responsive to change, meaning that they

actually measure what is intended to be measured,

yield consistent results on repeated use, and are able

to detect clinically meaningful changes [10]. Using

a general measure along with a psoriasis-specific

measure has been recommended to better assess

the full impact of psoriasis on HRQOL [6].

Generic measures that have been used in studies

of psoriasis include the Short Form–36 Health Sur-

vey (SF-36), a commonly used survey developed as

part of the Medical Outcomes Study, which consists

of 36 questions that address eight domains of

HRQOL [11]. These categories can be combined to

create a physical component summary score and a

mental component summary score, with higher scores

indicating better HRQOL [12]. Like the SF-36, sur-

veys such as the UK Sickness Impact Profile (UKSIP),

the Nottingham Health Profile, and the General Health

Questionnaire allow for comparisons to be made

between different diseases but can often be quite long

and time-consuming to complete [7]. Dermatology-

specific tools that have been developed are discussed

in the following sections.

Dermatology Life Quality Index

Finlay and Khan [9] developed the Dermatology

Life Quality Index (DLQI), a 10-item questionnaire

with the aim of creating a simple, compact measure

of QOL applicable to patients with any skin disease.

A Spanish study using a translated version of the

DLQI found it to be generally reliable, valid, and

responsive to change [13]. A pediatric version of the

DLQI also exists [7].

Dermatology Quality-of-Life Scales

Developed from patient-generated items, the Der-

matology Quality-of-Life Scales are intended to

complement the DLQI with more emphasis on the

psychosocial domain of QOL, with a psychosocial

score composed of four subscales of embarrassment,

despair, irritableness, and distress, along with addi-

tional items addressing physical activities and symp-

toms [14].

Next, this article discusses disease-specific assess-

ments that focus on the effects of psoriasis on HRQOL.

Psoriasis Disability Index

The Psoriasis Disability Index (PDI), a 15-item

questionnaire, was developed with patients who have

psoriasis to assess QOL by looking at the following

areas: daily activities, work or school matters, per-

sonal relationships, leisure, and treatment [15]. Pa-

tient scores on the PDI correlate with their scores on

the UKSIP, a general measure of QOL, supporting the

validity of the PDI in measuring QOL [16]. It has

been argued, however, that use of the PDI in the

United States might be limited by the disparity

between the British patients with whom the test was

R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395 391

developed and the typical American patient with

psoriasis, as the differing structures of health care

systems mean that dermatologists in the two countries

have access to different populations. Although der-

matologists in the United States treat many mild to

moderate cases on an outpatient basis, dermatologists

in the United Kingdom have more limited access to

the average patient with psoriasis, instead seeing

more patients on the severe end of the disease

spectrum [5].

Psoriasis Quality-of-Life Questionnaire–12

The Psoriasis Quality-of-Life Questionnaire–12

(PQOL-12) is a 12-item self-administered, disease-

specific, psychometric instrument created to specifi-

cally assess those QOL issues that are most important

to the largest proportion of patients with psoriasis. It

was developed using both nationwide, randomized

psoriasis population samples and multicentered clini-

cal trial subjects [17,18]. The original 41-item, two-

factor domain (psychosocial and physical) version

was created by testing many questions in a sample of

patients with psoriasis drawn from a nationwide

survey [5]. Psychometric analysis showed the origi-

nal PQOL-41 had satisfactory reliability, validity,

and responsiveness to change [19]; however, it was

too lengthy to be practically administered in a

clinical setting and there was some overlap between

its questions.

Therefore, a three-center study to determine va-

lidity and correlation with the Psoriasis Area and

Severity Index (PASI) was conducted. A total of 474

subjects participated who had disease ranging from

mild to severe. As a result of this study, a shortened

version of the questionnaire was developed that

contained only 12 items with one factor/domain.

The PQOL-12, produced by Koo et al [17,18], is a

valid, reliable, and responsive subset of the original

PQOL, with a Cronbach’s a of 0.95 and a mean

interitem correlation of 0.62. Because this instrument

was purposely designed to assess issues that were

scientifically proven to be of most relevance to the

largest population of patients with psoriasis, it shows

a predictable correlation with PASI. Simultaneous

assessment of PASI and PQOL-12 demonstrated that

for every 1-point increase in PASI score, the mean

PQOL-12 score increased by 6 to 11 points. There

was a similar correlation found with BSA measure-

ments and simultaneously administered DLQI sur-

veys. The PQOL-12 takes approximately 5 minutes to

complete and is appropriate to use in both clinical

practice and research. In addition, it can be used

across the spectrum of disease severity.

Physical impact of psoriasis

You have a disgusting body covered by marks and

lesions. You feel like a leper . . . I feel unclean and

sticky. Touching the rash disgusts me. [1]

In Koo’s [5] nationwide population study, psori-

asis sufferers reported that the worst and second

worst things about psoriasis were (1) itching and

scratching and (2) appearance. At least two other

studies reported on the high prevalence of pruritus in

psoriasis, with 76% of sufferers experiencing pruritus

‘‘frequently’’ or ‘‘all the time’’ in one study, and 79%

reporting pruritus in another [4,20]. Itching and skin

soreness have been found to have a negative impact

on the mental component of the SF-36 [21]. Because

of the high prevalence of pruritus and its negative

impact on the QOL of psoriasis sufferers, it has been

suggested that physicians pay more attention to con-

trolling this symptom [22].

In addition, Krueger et al’s [4] survey of the NPF

found that 94% and 71% of patients experienced

scaling and skin redness, respectively, with 39% of

the total group describing involvement of more than

10% of their bodies. The location of these physical

signs affects how the patient feels emotionally, with

more discomfort resulting from the involvement of

the face, scalp, or hands [1]. Messy, sticky, and

malodorous treatments can be physically unappealing

for patients as well [23].

Those individuals with psoriatic arthritis face

additional physical challenges. The NPF’s 1998 sur-

vey reported that roughly two thirds of these patients

have difficulty using their hands, standing for long

periods of time, and ambulating [4].

Mental health impact of psoriasis

I often have a feeling of being inadequate. The

disease brings defeat after defeat. I am ashamed of

being different. [1]

Research has shown that psoriasis has deleterious

effects on an individual’s psychosocial functioning.

In a national study in which 67% of the original

50,000 subjects returned surveys, people with psori-

asis were more likely to feel self-conscious, helpless,

embarrassed, angry, and frustrated than those with-

out psoriasis. Those who considered their psoriasis to

be more severe were more likely to feel uncomfort-

able or apprehensive about their appearance [5].

Patients with psoriasis also report significant levels

of social embarrassment, life disruption, and social

withdrawal [24].


In a study of 64 patients with psoriasis, 56%

reported being markedly to extremely anxious and

46% reported moderate to extreme depression during

flares of the disease. During these periods of exacer-

bation, 33% of patients remained housebound, with

15% of patients being essentially housebound even in

between flares [24]. McKenna and Stern [25] fol-

lowed up with 1113 patients who had previously been

enrolled in the long-term psoralen plus ultraviolet A

light, or PUVA, cohort study in 1976. Of those

patients, 44% felt physically unattractive, sexually

undesirable, or both, whereas 29% felt shame or

embarrassment because of their psoriasis. As self-

reported disease severity increases, so does use of

alcohol, cigarettes, tranquilizers, sleeping pills, and

antidepressant drugs [26].

Of particular concern is the increased depression

and suicidal ideation found in patients who have

psoriasis. Psoriasis sufferers have significantly higher

rates of depression and problems with body cathexis

than do control subjects [27]. One small-scale study

found a 37% prevalence of depression in its sample of

psoriasis sufferers, and an association between active

flares of skin lesions and higher stress levels, suggest-

ing that stress might play a causal role in psoriasis

activity and initiate a self-perpetuating cycle of stress,

flare, and subsequently, more stress [28]. Krueger et al

[4] found that in those patients aged 18 to 34 years,

54% reported feeling depressed. Another study found

links between pruritus, sleep difficulties, and depres-

sion, and reported that active suicidal ideation is found

in more than 5% of patients with psoriasis [29].

Similarly, Gupta and Gupta [30] found a 5.5% preva-

lence of acute suicidal ideation and a 9.7% prevalence

of a death wish in patients with psoriasis.

One gets a sense of just how life-altering psoriasis

can be by how much time and money patients would

be willing to invest in a cure. Forty-nine percent of

patients surveyed were willing to spend 2 to 3 hours

each day on treatment if it would result in normal

skin for the rest of the day [31]. In another study,

patients with psoriasis were willing to pay 9% to 14%

of their income each month for a cure, roughly the

same amount patients with asthma were willing to

pay [32].

Social interactions and psoriasis

I want to do many things; I want to be a positive

person and talk to other people. But the psoriasis

stops me from seeking the contact I want with others.

I’m afraid of rejection . . . I feel sort of alone with my

disease . . . I also feel like I want to hide. [1]

Many studies have shown that the shame and

embarrassment patients with psoriasis feel does not

evolve simply out of self-consciousness but from

actual experiences of rejection from others. Krueger

et al [4] found that 40% of those with severe psoriasis

had experienced problems receiving equal service or

treatment in places like hair salons, barbershops,

public pools, and health clubs. In a study of 137

patients with moderate to severe psoriasis, Gupta

et al [33] found that 26.3% of patients with psoriasis

had had an episode in the previous month where

‘‘people made a conscious effort not to touch them.’’

Although these experiences can depend on the pa-

tient’s perception of the social interaction, Ginsburg

and Link [34] reported that 19 of 100 subjects studied

had experienced a total of 50 episodes of frank rejec-

tion from a gym, pool, hairdresser, or job, despite the

fact that many of these patients with psoriasis avoid

these places to begin with for fear of such reactions.

Even in their intimate personal relations, sufferers

are not spared the negative impact of their disease. Of

120 patients with psoriasis surveyed, 40.8% reported

being affected sexually, with a decline in the amount

of sexual activity. These patients reported more joint

pains, somewhat increased severity of disease affect-

ing the groin region, greater scaling, and greater

pruritus severity than psoriasis sufferers who were

not affected sexually. Sixty percent of those affected

attributed the decline in their sexual activity to the

appearance caused by their psoriasis [35].

Patients with psoriasis often respond to difficulties

in social interactions by avoiding them altogether.

They engage in anticipatory and avoidant behavior,

such as not going to a swimming pool, even if they

haven’t experienced rejection previously [29]. The

stress of avoiding negative reactions from others has

a huge impact on the psyche of patients with psori-

asis. Furthermore, stress resulting from anticipating

other people’s reactions to psoriasis has been found to

have more effect on day-to-day QOL than any other

factor taken into consideration, including medical

and health status [36]. This finding has led Lebwohl

and Tan [37] to argue that interventions that can

reduce this fear of negative evaluation can improve

patient QOL.

Several studies have shown that younger patients

with psoriasis are more acutely affected by the

difficulties they face in social interactions than older

patients. Patients aged 18 to 54 years report a greater

impact of psoriasis on the psychosocial aspects of

their lives than do respondents aged 55 years and

older, describing more difficulty in sexual activities,

embarrassment, feelings of being unattractive, and

frustration [4,26]. Gupta and Gupta [38] reported that


patients aged 18 to 45 years have more problems with

appearance, socialization, occupation, and finances

than those older than 45 years. Younger patients also

have been found to be less compliant than older

patients [39]. The increased QOL impact of psoriasis

coupled with poor compliance warrants clinicians

paying particular attention to younger patients, espe-

cially children and adolescents [40].

Seeking social support, expressing emotions, tell-

ing others that psoriasis is not contagious, and en-

dorsing beliefs in the controllability of the disease

lessen the negative impact of psoriasis on QOL [41–

43]. Furthermore, the following have been found to

be significantly associated with a negative impact on

QOL: telling others about psoriasis without address-

ing its noninfectious nature, covering the lesions, and

avoiding people [41].

Financial impact of psoriasis

The only thing you think of is scratching, bathing,

and putting on ointment, then putting on more

ointment, bathing, scratching, and slathering on

ointment yet again. It’s in your head 24 hours a

day. [1]

Psoriasis presents direct costs to the patient and

health care system in terms of treatment and indirect

costs in terms of time lost from work and difficulties

with employment in general. In 1993, the outpatient

cost of psoriasis in the United States was conserva-

tively estimated to be between 1.6 and 3.2 billion

dollars annually. The mean annual direct cost for an

individual patient is estimated at $800 per year [44].

In one study, of the 54% of subjects who were not

working or retired, 34% attributed their employment

status to their psoriasis. Of those who were working,

59.3% had lost a mean of 26 days from work during

the previous year because of their disease [31]. In

addition, patients with severe psoriasis rate the qual-

ity of their work life lower than do control subjects

[44], and 6% report discrimination at work [4]. Men

tend to have greater work-related stresses because of

their psoriasis than do women, reporting more fear of

losing their job and more criticism for taking time off

to go to medical appointments [38]. Psoriasis can, in

fact, be so severe as to make working impossible for

some patients [22].

The financial effects of psoriasis overlap with

other aspects of QOL as well, with one study finding

that unemployed patients suffer from more desqua-

mation than employed patients [21]. Patients with

lower family incomes not only are more affected by

the cost of psoriasis treatment but also spend more

time caring for psoriasis. In addition, they perceive

more interference with work and activities around the

home [44].

How psoriasis compares with other diseases

Using the SF-36 to compare QOL impact between

different conditions, Rapp et al [21] found that

patients with psoriasis report reductions in physical

functioning and mental health comparable to that

seen in patients with cancer, arthritis, hypertension,

heart disease, and diabetes. Furthermore, patients

with psoriasis had among the lowest SF-36 scores

of all groups. Only patients with congestive heart

failure scored lower on the physical component score,

and only patients with depression or chronic lung

disease scored lower on the mental component score

[20]. The negative effects of psoriasis on the physical,

psychologic, and social aspects of life can be worse

than those caused by life-threatening illnesses [22].

For a sense of comparison, 46%, 42%, and 32% of

severe psoriasis sufferers considered it ‘‘better’’ or

‘‘the same’’ to have diabetes, asthma, or bronchitis,

respectively. Of those subjects who happened to

have both psoriasis and the comparative disease,

the percentages rose to 87%, 80%, and 77%, respec-

tively [29].

Summary

A preponderance of evidence clearly shows that

understanding the true impact of psoriasis on patients

requires assessing their QOL. Better QOL tools are

necessary to further reduce the gap that exists between

patient experience and clinician perception of the

illness. Knowing the impact of disease on QOL can

help clinicians and patients when grappling with

treatment options and performing risk–benefit analy-

ses. Using tools like BSA measurements only skim

the surface without really getting to the core of the

illness [45]. HRQOL measurements reveal that psori-

asis sufferers face challenges that demand that psori-

asis be viewed and aggressively treated as a serious

disease. Patients with psoriasis deserve as much

attention from clinicians and policymakers as patients

with other systemic illnesses. It is hoped that such

mindfulness will lead to better treatments and in-

creased public awareness of this noncontagious, dis-

abling disease. This result, in and of itself, might help

ameliorate some of the negative impact of the disease.


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Dermatol Clin 22 (2004) 397–406

Phototherapy arsenal in the treatment of psoriasis

Michael Zanolli, MDa,b,*

aDermatology Consultants, PC, 4230 Harding Road, Suite 609 East, Nashville, TN 37205, USAbDivision of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

An essential method of treatment for psoriasis tant psoriasis, and can be used with precautions and

vulgaris in the twenty-first century will remain the

option for UVB light therapy and photochemother-

apy. During the last half of the twentieth century, the

use of UVB therapy was one of the mainstays of

treatment for psoriasis. During the last quarter cen-

tury, photochemotherapy in the form of psoralen plus

UVA (PUVA) emerged as one of the most effective

modalities of treatment for psoriasis. Accompanying

the advent of the most recent era of psoriasis with

targeted biologic therapies has been a decline in the

frequency of phototherapy. This does not diminish its

known clinical effects and, because of a better un-

derstanding of photobiology, the therapeutic ap-

proach to treatment of psoriasis with UV light has a

common basis for treatment of psoriasis along with

and in combination with new biologic agents [1].

Individuals affected with psoriasis vulgaris know

the natural effect of sunlight can improve psoriasis in

most cases. This use of limited amounts of natural

sunlight will continue as a practical approach to treat-

ment of psoriasis for patients. Refinement of the

delivery and methods for the most effective wave-

lengths of UV light in treating psoriasis will continue

into the twenty-first century. This is evidenced by the

continued prevalence of the availability of narrow-

band UVB, which has been recognized as more

effective than broadband UVB, in addition to the

devices that deliver the most effective range of UV

light to the skin in a localized manner. The efficacy of

PUVA for the treatment of psoriasis has not been

surpassed by any other form of phototherapy. It still

plays a significant role, especially in extensive resis-


doi:10.1016/j.det.2003.12.003

* Dermatology Consultants, PC, 4230 Harding Road,

Suite 609 East, Nashville, TN 37205.

E-mail address: [email protected]

limitation of total dose with excellent response. The

long-term experience with the use of photochemo-

therapy has been important in helping to understand

potential risks and side effects for that modality. It is

similar to other psoriasis treatments in that caution

must be used when PUVA and other forms of photo-

chemotherapy are used.

Natural phototherapy

Natural sunlight for treatment of psoriasis has

been used throughout the ages, even before the

advent of Westernized medicine. It is common

knowledge, evidenced by experience and observa-

tion, that a vacation to more southern latitudes or to

areas of recreation, such as beaches, tends to help

patients with psoriasis and in many cases contributes

part of an annual practice to help clear up limited thin

plaque-type psoriasis. The closer one is to the equator

and the lower the latitude, there is more energy in the

terrestrial light in UVB range. This is caused by the

angle of incidence of the sun to the earth’s surface.

As such, there are special geographic locations in

the world today that further enhance the effects of UV

light and are frequently used as a therapeutic ap-

proach to treatment. Specifically, the UV light that

reaches the earth’s surface at the Dead Sea, which is

below sea level, is unique in its spectrum [2]. Be-

cause the Dead Sea is below sea level, the terrestrial

light at this location has less of the 290 to 300 nm

wavelengths of light. This slight shift in the spectrum

more toward the mid range of UVB enhances the

ability for a person to incur less sunburning and

obtain more therapeutic UVB as it relates to treatment

of psoriasis. This is very beneficial because of the

known enhanced effects of wavelengths closer to

s reserved.

M. Zanolli / Dermatol Clin 22 (2004) 397–406398

310 to 315 nm. One can consider the Dead Sea to be

more of a natural location for therapeutic UVB

unique in the world. Use of this therapeutic spa and

scientific investigations that have been ongoing for

decades at the Dead Sea attest to this being a very

special place to receive UV light in combination with

the specialized salts found in the Dead Sea. The

remissions obtained and the clearing percentage for

persons attending the spa for 2 to 4 weeks has not

been achieved at any other natural therapeutic resort

for treatment of psoriasis.

Box 1. Broad band UVB protocol byMinimal Erythma Dose (MED)

1) Obtain MED using the followingdoses (mj/cm2): 20, 40, 60, 80,100, 120

2) Start at 70% of MED3) Increase by 20% of MED each

treatment4) Treatment frequency of

3–5X/week

Artificial UVB

Amainstay of therapy for psoriasis during the mid-

portion of the twentieth century was the use of UVB

produced by an artificial light source, either alone or

in combination with other agents. The refinement of

this modality of therapy using either a discontinuous

spectrum from hot quartz lamps or the use of fluores-

cent tubes has gradually evolved and facilitated ease

of use in an office-based setting. The current mainstay

of therapy for office-based UV light is the fluorescent

tube. The fluorescent tube has the benefit of ease of

mass production and depending on the phosphor used

to line the inner surface of the fluorescent tube, can

also have more specific emissions spectrum. The

broad-spectrum fluorescent tubes remain important

and contain a relatively wide range of UV light. They

contain higher-energy, lower-frequency UV light, and

carry a greater potential for a sunburning-type reac-

tion and erythemogenic response.

The availability of narrowband UVB on a com-

mercial scale was made possible because of the

specialized lamps produced by Phillips having the

narrow spectrum between 300 and 313 nm. Because

of their specialized use, however, the production of

these lamps has not been a major emphasis by this

company. The lamps have a relatively shorter work-

ing life of 500 to 1000 hours of operation as com-

pared with the more durable broader-spectrum UVB

lamps that can maintain fairly consistent output with

thousands of hours. This fact requires that the nar-

rowband UVB lamps be replaced more often because

their fluence diminishes with less use as compared

with broad-spectrum UVB lamps.

Traditional broadband UVB therapy

The use of conventional broadband UV light

therapy is dependent on an induction phase during

the initial response with thinning of the psoriatic

plaques and then a variable duration of approximately

15 to 25 treatments before full therapeutic efficacy.

The most efficient approach to treatment with any

UVB protocol for the practitioner is first to determine

the minimal erythema dose (MED), which is depen-

dent on the response a person experiences to that

particular light unit. The determination of the MED

shows a dose response and allows for more precise

and more aggressive therapy with UVB, which facili-

tates more rapid clearing and better final results.

Investigation comparing erythemogenic and sub-

erythemogenic UVB delivery demonstrates that the

more aggressive monotherapy with broadband UVB

produces a quicker response rate and a better overall

response. With that type of approach, however,

patients may experience mild discomfort because of

the pink erythema that is consistently produced by the

advancement of therapy on a daily basis. Patients can

improve while undergoing broadband UVB light

therapy without having to incur the maximal MED

on each visit [3]. It is customary to obtain a MED and

proceed by starting at 70% to 75% MED and in-

creasing by up to 50% of the MED each visit.

Aggressive treatment with UVB therapy is possi-

ble because the maximal erythema reaction of the

effects of UVB on the skin is seen between 12 and

18 hours. Patients demonstrate the reaction on their

return even if treatments are given on consecutive

days. Such an aggressive treatment protocol custom-

arily uses an average of 15 to 25 treatments during

the course of therapy to achieve maximal benefit.

Protocols and approaches to treatment may vary from

region to region and a more simplified and slightly

less aggressive approach to treatment for broadband

UVB is set forth in Box 1.

Narrowband UVB

Narrowband UVB has finally achieved general

recognition in North America as advancement in the

further refinement of UV therapy for treatment of

Box 3. Narrow band UVB protocol byMinimal Erythma Dose (MED)

1) Obtain MED2) Start at 50% of MED3) Increase by 10% of MED each

treatment4) Treatment frequency of

3–4X/week

M. Zanolli / Dermatol Clin 22 (2004) 397–406 399

psoriasis. Before the availability of narrowband UVB

in North America in 1998, Europeans had been using

narrowband UVB with regularity and good success.

The original reports reflecting the efficacy and pref-

erence of narrowband UVB emerged in the mid-

1990s. Comparison trials with right- and left-sided

controls on the same individual demonstrated that

narrowband UVB is more effective than broadband

UVB and eliminated the need to produce erythema at

each visit [4–6].

Delivery of broadband UVB is best initiated with

determination of the MED, as with any UVB treat-

ment. This is especially important because the do-

simetry between the broadband and narrowband is

different and to be able to have a dosage measured in

millijoule per square centimeter, one needs to have

the proper photometers or accurate readings of the

irradiance from the lamps themselves provided by the

manufacturer. This information enables one to deliver

incremental doses just below the range known to

cause erythema for the Fitzpatrick’s skin type deter-

mination of patients being treated. This is important

because the more limited wavelengths of the narrow-

band spectrum emitted by these specialized fluores-

cent tubes require a much higher energy because of

the absence of the more erythemogenic shorter wave-

lengths from 310 nm and below. The dosage range

for the determination of MED by skin type is included

in Box 2. There can certainly be production of ery-

thema using narrowband UVB, and this is also on a

reproducible dose response curve in an individual.

As with any erythema dose response within the

UV range, the higher the skin type, the higher the

average mean of the millijoule per square centimeter

is needed to produce erythema. Each skin type has a

broader range for MED with narrowband UVB than

with broadband UVB, which further illustrates the

importance of determining MED before initiation of a

treatment protocol.

A series of experiments done in the 1990s to

maximize therapeutic benefits of narrowband UVB

shows therapy done three times weekly is essentially

as effective as broadband UVB done five times per

Box 2. Dose range for MED testing fornarrow band UVB

� Six test sites of 1.5 cm2 each� For skin types I–III (mj/cm2): 400,600, 800, 1000, 1200, 1400

� For skin types IV–VI (mj/cm2): 600,800, 1000, 1200, 1400, 1600

week and is certainly more convenient for the patient

[7]. A more aggressive approach that maximizes the

erythemogenic potential of narrowband UVB does

not offer substantial benefit over trying to maximize

the amount of erythema produced at each visit. The

less aggressive approach is certainly preferred by the

patients receiving treatment.

The use of lubricants that help transmit UV light

on top of the skin’s surface and decreases reflectance

from the psoriatic scale is also considered standard

therapy. The protocol for the use of narrowband UVB

in an office-based setting is outlined in Box 3. There

is some variability of the starting dose of narrowband

UVB, either at a more conservative 50% or slightly

more aggressive 70% of the MED. The onset of

erythema following narrowband UVB occurs within

8 to 24 hours.

One of the practical advantages of using limited

narrowband UVB wavelengths delivered to the skin

surface is that phototoxic or photoallergic drug reac-

tions do not occur as frequently as with the broader-

spectrum broadband UV, and with UVA light used

with photochemotherapy. There have been reports of

photoallergic reactions in patients who are receiving

narrowband UVB, but the occurrence of drug reac-

tions while receiving narrowband UVB is uncommon.

Localized UVB

The traditional use of localized delivery of UV

light for treatment of hands and feet has been facili-

tated by the availability of 2- to 3-ft fluorescent tubes

with broadband wavelength. Similar systems are used

for localized bath PUVA therapy with irradiation or

systemic PUVAwith irradiation of just the hands and

feet. The use of UVB for hyperkeratotic thick plaques

on the distal extremities has limited response, and

combination therapy with a systemic retinoid is

frequently used to enhance the efficacy of the treat-

ments. There is more success with the use of systemic

administration of psoralen with localized delivery

of UVA to the hand and feet but this approach also

is enhanced with addition of systemic retinoids to


decrease the thickness of the plaques before and

during phototherapy.

The application of localized delivery of laser light

near the optimal wavelength for maximal efficiency

in the treatment of psoriasis led to clinical investiga-

tions regarding the excimer laser for treatment of

psoriasis [8]. Because noninvolved skin is left unir-

radiated, this offers the opportunity to test for the

optimal method of delivery and dose for treatment of

psoriasis without involving the surrounding skin.

Using multiples of the MED when treating psoriasis

has been found to enhance the benefits and therapeu-

tic response to laser light. The durability of the

clearing was also correlated with the more aggressive

treatment using 4x, 6x, and 8x multiples of the MED.

As expected, using multiples of the MED produced

very pronounced effects of marked erythema and

blistering at the sites of delivery, although scarring

at the sites was not observed. Another aspect of this

approach to treatment is the reduction in the number

of treatments needed to achieve the response [9].

Generally 8 to 10 treatments can attain clearing of

plaques. Continued experience with this method of

treatment using multiples of the MED with localized

treatment makes it obvious that certain locations

tolerate a higher dose of UV light, such as the knees

and elbows. In those locations multiples of 6 to 8x

MED should be used as compared with 4 to 6x MED

on more sensitive non-UV hardened skin, such as the

intertriginous skin or buttocks.

The same principles used with the laser-generated

coherent light at 308 nm have been applied to the

localized delivery of broader band UVB generated by

a filamentous light source delivered through optics to

a small spot target area. Less complicated technology

using a high-intensity lamp as the light source has

been developed and brought to the market for treat-

ment of psoriasis and other photoresponsive derma-

toses. The two main devices are being marketed

through Lumenis and Theralight corporations. There

are differences between the coherent light at 308 nm

from the excimer laser and the range of the UVB

delivered by the other localized delivery systems for

UVB. Both light units have the same filamentous light

source, but the Lumenis system, B Clear, transmits the

light through a fiberoptic cable to a very functional

handheld delivery, whereas the Theralight unit uses a

liquid medium in a flexible cable to a cylindrical

pencil-grip type handpiece. The Theralight system

has the ability also to switch to a low-fluence UVA

if localized PUVA is a consideration for therapy.

Basic principles of localized delivery of UVB are

the same as with the excimer laser. First, an MED

needs to be obtained; then, choices for the multiple of

the MED to be used for the site to be treated are se-

lected by the clinician. The actual setting on the

device is very easy to determine on the Lumenis

system, which gives a numerical reading of the actual

dose to be delivered. The Theralight system requires

reference to a chart to set the machine, but follows the

same principles of the multiples of the MED. Once a

phototherapist becomes accustomed to the use of any

of the devices the actual operation becomes routine.

Photochemotherapy

The development of photochemotherapy for treat-

ment of psoriasis comprises a major advance in

therapy and efficacy of treatments for psoriasis

worldwide. For centuries it was known that agents

with photosensitizing compounds in the class of

psoralen drugs could be used for treating vitiligo

and other skin disorders. The discovery, however,

that the ingestion of certain psoralen molecules when

combined with UV light has dramatic effects on

psoriasis improved the effective available treatments

further. These advances were championed primarily

in the United States by Fitzpatrick and Parrish but

also were recognized by European colleagues who

developed the use and protocols for delivery of

PUVA [10]. This therapy generated intense clinical

research during the late 1960s and early 1970s.

One reason that photochemotherapy is so impor-

tant is that the duration of remission following

clearing with PUVA is more durable than with

UVB light. Refinements of photochemotherapy and

improvements in the bioavailability of the chemical

after ingestion help make this therapy one of the

standard treatment options in the arsenal for treatment

of psoriasis. Specifically in North America, 8-me-

thoxypsoralen has been the psoralen used for PUVA

therapy. In Europe this has also been a mainstay but

there has been more use in the recent decade of

5-methoxypsoralen, which has therapeutic efficacy

and fewer gastrointestinal side effects [11].

As with the acceptance of UVB therapy for treat-

ment of psoriasis, the adoption and development of

photochemotherapy occurred because of the observed

beneficial therapeutic effect on people with psoriasis.

The exact mechanisms of the psoralen molecule as it

relates to treatment of psoriasis have not been entirely

clear. In fact, further insights are gained into the

mechanism of action for both UV light and photo-

chemotherapy because of a better understanding of

the pathogenesis of psoriasis. The known effects of

photochemotherapy are dependent on both the availa-

bility of the psoralen molecule at the site of action

Box 4. Precautions in selection of PUVApatients

� Skin types I and II� Previous history of skin cancer� Previous or current immunosuppres-sive therapy

� Cumulative number of previousPUVA treatment >200


and stimulation by wavelengths of UV light within its

absorption peaks. It is known that the psoralen mole-

cule intercalates between DNA base pairs through a

concentration gradient. There is no biochemical inter-

action between the psoralen molecule and DNA itself

without activation or absorption of photons of UV

light. If there is absorption of photons of UV light

there is a photochemical reaction with the psoralen

molecule and a pyrimidine base and DNA cross-links

can occur. For a true cyclobutane ring to form another

photochemical reaction must occur. If a cross-link

does form, this is one of the theoretical reasons for

increased development of squamous cell carcinomas

with repetitive therapy over years.

A second mechanism of action of PUVA therapy

on inflammatory skin disorders is oxygen-dependent

photochemical reactions (ie, reactive oxygen species

are formed when the psoralen molecule absorbs

photons in the presence of oxygen). This type of

oxygen-dependent reaction causes membrane and cell

damage and may be central to the observable effects

of UV light on the skin. It seems that antigen-

presenting cells and T lymphocytes are more sus-

ceptible to these oxygen-dependent reactions than

keratinocytes, and the underlying mechanism of ac-

tion of psoriasis photochemotherapy may be inhibi-

tion of immune activation and immune recruitment

of additional T cells into the skin [12].

Taking this one step further one could speculate

that long-term remissions induced by PUVA may be

caused by depopulating the epidermis of antigen-

presenting cells, natural killer T cells, and cutaneous

lymphocyte antigen (CLA)-positive lymphocytes.

These effects decrease the recruitment of additional

cells and reduce the stimulus for the ongoing pso-

riasis reaction instead of just interfering with the

activation of lymphocytes or cytokine messaging. A

short-term remission is expected if message interfer-

ence occurred. A long-term remission is expected if

the cells stimulating the reaction of T lymphocytes

and immune competent cells in the epidermis and

dermis are reduced in number or eliminated.

The use of PUVA gained more widespread availa-

bility throughout the last quarter of the twentieth

century in North America. It is still a vital tool in

therapy, but the availability of PUVA has declined

over the past decade for two main reasons. First, other

therapies have become available that are potent and

modify the immune system. Examples are the known

effect of the cyclosporine class of drugs and more

recently the biologic protein medications that show

efficacy without the need for specialized equipment

and specialized personnel. The second reason is the

30 years of experience with PUVA and the known

increased risk of squamous cell carcinoma that occurs

especially in fair-skinned individuals with greater

than 250 treatments over time [13]. There have been

reports also of increased risk of melanoma in this

special population by following over three decades a

cohort of patients registered in North America [14].

This group of patients has confounding factors, such

as other treatments for psoriasis including systemic

immunosuppressive therapy and the fact that the early

protocols for PUVA used high-dose PUVA, which is

not done to such a degree today. Nonetheless, now

that these important observations and statistical analy-

sis of a specialized group of patients have been done,

clinicians are better able to use this tool in a way that

is safer and with parameters that help ensure the

overall well-being of patients. Precautions and limi-

tations of the use of PUVA over time are listed

in Box 4.

The delivery of PUVA is more complicated than

UVB therapy even though both must have ocular

protection to prevent corneal burns in the case of

UVB and lens and retinal changes more specifically

with the use of PUVA. PUVA requires additional

protection from any other sources of UVA light for

18 to 24 hours following treatment. In my opinion,

PUVA has been a great success story in preventive

medicine over time because of the awareness of the

potential for ocular side effects and the institution of

standardized protocols and mechanisms for proper

eye protection following a treatment.

A manageable but frequent side effect of psoralen

is caused by the nausea that the psoralen compound

commonly produces especially with the use of

8-methoxypsoralen. There is a dose-response rela-

tionship with the degree of nausea that occurs and

peak blood levels of the psoralen compound that

occasionally is so pronounced that patients withdraw

from therapy. Management of the nausea is to take

the psoralen exactly the same way at the same time of

day, preferably in the afternoon, and to have a small

bit of food with the psoralen dose [15]. A slight

reduction in the dose can also be attempted; however,

Box 5. PUVA protocol by skin type

1) Dose of 8-MOP = 0.5 mg/kg2) Ingest psoralen 1.5 hours prior to

treatment3) Take psoralen at same time of day

with liquid4) If nausea take psoralen with some

food5) Dose of UVA

Skin type I–III Initial = 2 J/cm2

Skin type IV–VI Initial = 4 J/cm2

Increase by 1 J/cm2 each treatment6) Frequency of treatments 3X/week


care must be taken not to reduce the dose below the

therapeutic range.

There is variability from person to person in the

gastrointestinal absorption of the psoralen molecule.

The range for dosing and the timing of dosing should

remain constant for each individual throughout their

particular course of therapy. Although protocols vary

between regions of the country and between conti-

nents, one of the standard protocols is included in

Box 5. Different psoralen molecules have been used

in Europe primarily to reduce the gastrointestinal side

effects while maintaining efficacy. The most widely

used psoralen molecule besides 8-methoxypsoralen is

5-methoxypsoralen. It still has potential to form

cyclobutane rings and with excessive long-term use

is also expected to increase the risk of squamous

cell carcinoma. The efficacy of 5-methoxypsoralen

is approximately that of 8-methoxypsoralen, however,

with much fewer complaints of gastrointestinal

side effects [16]. The 5-methoxypsoralen is not

available in the United States as a commercial prod-

uct, however, and requires clinical trials to demon-

strate its efficacy before approval by the Food and

Drug Administration.

Combination therapy

Phototherapy historically has been used, especially

in this modern era, in combination with both topical

and systemic agents. In fact, it is unusual not to have

some sort of combination therapy in the form of

concomitant topical agents while the patient is un-

dergoing induction and treatment with either UVB

modalities or PUVA. There are myriad combinations

that have been used, with some known to enhance the

therapeutic effect while reducing the dose and total

number of treatments required for response. This

section highlights the best and most common com-

bination therapies to use with phototherapy and

specifies important nuances in understanding the

maximum benefit and the most efficient delivery of

the combinations.

Topical agents plus phototherapy

Patients must understand that certain topical agents

used with phototherapy may either inhibit the effects

of the UV light by blocking UV light at the surface of

the skin and not allowing it to penetrate to the proper

site of action or inactivate the drug through absorption

of UV light. Topical steroids are still the most com-

mon treatment for mild plaque-type psoriasis and can

be used safely in combination with phototherapy.

Although there might be some initial reduction in

the thickness and a more rapid initial response for

plaque-type psoriasis, continued use of the topical

steroids throughout the course of a full therapeutic

regimen with UVB does not necessarily add much

long-term benefit. When superpotent topical cortico-

steroids are used, a regimen of using the initial

treatment for induction followed by tapering and

discontinuation of topical steroids should be used.

This is the most effective approach to combination

treatment and seems to have the best initial benefit.

Calcipotriene with both UVB and PUVA therapy

has also been used. Calcipotriene can enhance photo-

therapy; however, certain precautions must be taken

to ensure that their combined use does not inhibit or

alter the calcipotriene molecule. Specifically, if calci-

potriene is applied immediately before UV light

therapy, inactivation of the molecule may result. To

realize the enhanced effect of this topical combination

with phototherapy, one should deliver the UV light

treatment first and then use the topical agent later that

day or at least 2 hours before treatment [17]. This

helps ensure the modest benefit that might be

obtained with this combination therapy. Topical for-

mulations of retinoids have also been used to help

enhance the effects of UV therapy [18]. As with the

vitamin D derivatives, application should not imme-

diately precede the delivery of the UV light. Caution

should be used when advancing the dose of UVB or

PUVA in this circumstance because of the retinoid

effect on the plaques of psoriasis.

Systemic retinoids plus UV therapy

The best combination therapy with UV light,

whether UVB or PUVA, is with systemic retinoids

Box 6. Retinoids and UV therapy

� Dose of Acitretin and UVB or PUVA10 or 25 mg/day

� Use the retinoid two weeks prior toinitiation of UV therapy

� Obtain MED with UVB treatments� Select a lower skin type determina-tion when using PUVA

� Adding acitretin to an ongoing photo-therapy treatmentReduce the dose of UV light therapy

by 50%Keep the dose of the UV the same for

six treatments


[19]. Various systemic retinoids are used in combi-

nation with UV light therapy, and numerous studies

have demonstrated their positive effects. The treat-

ment rationale for combining retinoids with UV light

is to enable reduction of the total energy delivered to

the skin and enhance the therapeutic regimen by

decreasing the total number of treatments needed.

The approach to such treatment is to initiate

therapy with the retinoid for at least 7 to 14 days to

establish the retinoid effect on the skin and its

modification of psoriatic plaques. The observed effect

of retinoids on plaque-type psoriasis is to reduce the

thickness of the plaque and help reduce scaling

through their inherent mechanisms of helping to

normalize differentiation of the keratinocytes. The

exact effect of retinoids relates to cellular differentia-

tion through impact on retinoid receptors, both local

and circulating. Retinoids probably also have an

effect on the immune mechanisms involved with

psoriasis. This cumulative effect of the retinoids helps

to decrease the thickness of the plaques and the

scaling, allowing the UV therapy to be more effective

and encounter less blocking and scattering of light at

the skin surface. The retinoid effect increases suscep-

tibility to erythema from UVB and makes one more

prone to phototoxic effects from PUVA. It is not a

direct effect from UV light on the retinoid molecule

itself that produces the increased susceptibility to UV

treatment. It is the effect on the skin, primarily the

epidermis, which enhances the UV light combination.

When using a systemic retinoid 2 weeks before

initiation of UV therapy, caution must be used during

the initiation and induction period of phototherapy.

This is another incidence in which determining the

MED before UVB therapy, whether broadband UVB

or narrowband UVB, is very helpful because using

only skin type to determine the dose is not as ac-

curate, and a starting point has to be estimated

without any objective measurement. The dose of

the retinoid can be reduced when combined with

phototherapy as compared with the dose of retinoid

if used only as a monotherapy. A simplified modifi-

cation of the dosage of retinoid when used in com-

bination with UVB or PUVA is contained in Box 6.

Caution must be applied when considering adding a

retinoid to a UV treatment program if a patient has

already received multiple doses of UV light. The

tolerance to UV, whether UVB or PUVA, is decreased

within 1 week of introduction of the retinoid and

unexpected phototoxic reactions may occur even

without increase in the dose of UV light. If a retinoid

is to be introduced to an ongoing protocol for photo-

therapy it is recommended the dose of the UV light

be reduced by 50% at the start of retinoid therapy and

kept at that level for 2 weeks before increasing the

dose of UV light.

Various individual retinoid molecules have been

used in combination with phototherapy. Currently, the

most used retinoid is acitretin [20–22]. The basic

principles for the use of retinoids in conjunction with

phototherapy have been applied to the combination of

acitretin plus narrowband UVB, although there are no

studies that have actually been performed in a pro-

spective manner.

Thirteen-cis-retinoic acid (Accutane) can also be

used in combination with phototherapy, but requires

adhering to the general precautions needed for all the

retinoids and their use. This is especially true with

regard to informed consent and the special precau-

tions necessary for avoidance of pregnancy. There

may be times when 13-cis-retinoic acid is preferred

over acitretin because of the problems with long-term

bioavailability of acitretin metabolites when com-

bined with alcohol. With even minimal ethanol con-

sumption a potential for long-term fat storage of the

teratogenic metabolite occurs, which requires pro-

longed years of strict adherence to contraception.

Other systemic agents and UV therapy

There are other systemic agents that have been

tried and used with phototherapy. Particular features

of some of the more common systemic agents deserve

mention when used in combination. Methotrexate has

frequently been used in combination treatment for

psoriasis [23,24]. Short-term UV light therapy may

be particularly helpful in aborting psoriasis flares,

which can then be brought under control with long-

term use of methotrexate with appropriate monitor-

ing. Methotrexate by itself does not inhibit the

M. Zanolli / Dermatol Clin404

efficacy of UV treatments. In fact, if methotrexate is

used before UV light, some of the same plaque-

thinning benefits realized by retinoids can occur,

helping with the induction of UV light response. It

is more common, however, to have UV light used as

an adjunct to long-term methotrexate treatments.

Early studies show that the combination can be very

helpful with application of routine broadband UVB.

One must prevent a generalized phototoxic reaction

with excessive UV light therapy during the course of

treatment. This is true whether a therapeutic use of

UV light is used or a patient sustains a sunburn

reaction from natural sunlight. This situation can

provoke what is known as a ‘‘recall reaction’’ with

methotrexate and normal doses of light subsequent to

the burn. Although it is an infrequent and unexpected

side effect, if the recall reaction occurs, it may be as a

result of normal doses of therapeutic UV light.

The combination of methotrexate and PUVA has

also been used. This alternative is not considered a

very common treatment choice because of the in-

creased incidence of squamous cell carcinoma known

to occur with long-term PUVA therapy with the

additional relative immunosuppression of methotrex-

ate. Short-term it can be used with caution for very

resistant cases having significant plaque-type pso-

riasis. This is another instance in which methotrex-

ate can be used during the pretreatment phase and

then tapered before induction with PUVA. The ap-

propriate procedure is to limit methotrexate use to

the 1 or 2 months before induction and maintenance

with PUVA.

Another conventional therapy used for resistant

plaque-type psoriasis is cyclosporine. Combination

therapies with cyclosporine should be used very

cautiously because the particular combination of

cyclosporine and PUVA therapy, if used long-term,

leads to increased risk of squamous cell carcinoma

over and above the risk inherent in PUVA itself [25].

Whether broadband or narrowband, UVB combina-

tion therapy with cyclosporine generally should not

be used in the long-term. If there are resistant

plaques, possibly just a short-term course of UV light

therapy should be considered. Of particular concern

here is historical use of PUVA, especially in patients

who had long-term maintenance with PUVA therapy

before the advent of the use of cyclosporine. In this

instance, even use of cyclosporine post-PUVA carries

increased risk of developing or facilitating squamous

cell carcinomas years posttherapy as demonstrated by

the results of long-term follow-up of the PUVA

cohort. Patients having a history of years of PUVA

treatment should be considered to have a relative

contraindication for any follow-up with cyclosporine.

Biologics in combination with UV light

Over the next 2 to 5 years more information about

use of biologic agents with UV light therapy, particu-

larly narrowband UVB, will be available. The regu-

lations regarding phase 2 and phase 3 clinical trials

require that phototherapy be excluded as concomitant

therapy during the clinical trials determining the

dosage, frequency, efficacy, and safety of the biologic

agents that have become part of treatment for psori-

asis over the last 2 years. Small pilot studies are now

starting to appear concerning UV combination treat-

ments with alefacept and etanercept. These initial

reports are few and do not define the nuances of

phototherapy, which may be important for the most

effective and efficient delivery of UVB therapy. The

important factors are whether or not there is change in

the MED with concomitant use of the biologic

treatment and if there is any actual significant en-

hancement of effect in conjunction with UVB therapy.

The general principles underlying combination ther-

apy with UV therapy are to decrease the total dose of

millijoule per square centimeter for an individual and

to decrease the total number of treatments needed to

obtain the desired effect. Subsequent trials will pro-

vide further insights concerning these issues.

Theoretically, there could be great advantage to

the combination therapy with biologics and UV light.

The biologics may have actions that vary from

inhibiting circulating T cells from entering the der-

mis, such as with efalizumab, or decreasing circulat-

ing CD4 lymphocytes, as with alefacept. The use of

narrowband UVB could compliment these effects

through known mechanisms of decreasing CD3 lym-

phocytes in the epidermis [26], thereby having po-

tential for attacking the cutaneous immune system

from the surface of the skin while the biologic agents

act on cells in the circulating CLA, CD45RO+

lymphocyte pool. Although the frequency of office-

based UV light treatment has diminished over the

past 5 years in North America there is great potential

for short-term intermittent combination therapy for

patients who may be on long-term therapy with one

of the new biologic agents.

22 (2004) 397–406

Summary

Ultraviolet light has been the most used and

effective treatment of psoriasis over the centuries.

The beneficial effects of natural sunlight for clearing

of psoriasis on the exposed skin do not depend on

technology or insight into the known pathogenesis of

the disease. In fact, an understanding of the patho-


genesis was not necessary to recommend one of the

traditionally effective treatments of psoriasis with

long-term remissions, as was done with the Goecker-

man therapy for psoriasis in the mid portion of the

twentieth century. Even the current advancements in

therapeutics enjoyed today with the advent of the

biologics and other immunomodulating systemic

agents do not surpass the overall response rate and

duration of remission of the previous standard of

therapy that was had in the 1950s. Refinements in

the delivery of UVB light, the development of photo-

chemotherapy with PUVA, and the more recent

focusing of the spectrum of UVB to the most effec-

tive region between 310 and 313 nm for narrowband

UVB have given clinicians additional options in the

arsenal of therapeutics to attack psoriasis. Further

refinements of the delivery systems for UVB in the

form of lasers and localized delivery through fiber-

optics are beneficial in helping to reduce the overall

exposure of noninvolved skin and permitting more

aggressive doses of UV to the sites of disease while

sparing noninvolved skin.

Enhancement of the different modalities of UVB

and PUVA has been demonstrated with systemic

agents, such as retinoids, but also in combination

with immunosuppressive agents for short-term treat-

ment to hasten the initial response to treatment. The

advent of the biologic agents in treating psoriasis also

introduced the opportunity for combination therapy

and the theoretical advantage of managing T cells and

antigen-presenting cells in the epidermis with UV

light, and activated T cells in the circulation.

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Dermatol Clin 22 (2004) 407–426

Current concepts and review of alefacept in the treatment

of psoriasis

Gerald G. Krueger, MD

Department of Dermatology, 4B454 School Medicine, University of Utah Health Sciences Center, 30 N 1900 E,

Salt Lake City, UT 84132-2409, USA

Alefacept is the first and only biologic agent ap- marker that can be targeted by therapeutic agents.

proved by the US Food and Drug Administration for

the treatment of adult patients with moderate to severe

chronic plaque psoriasis who are candidates for sys-

temic therapy or phototherapy. Several reviews have

been published on alefacept and new treatment options

for psoriasis [1–4]. This article provides updated in-

formation on alefacept with regard to the following:

� Mechanism of action� New data analyses from the psoriasis clinical

program� Rationale and design of two recently completed

pilot studies, one evaluating alefacept/ultraviolet

B (UVB) light combination therapy for psoriasis

and the other investigating the effects of adding

alefacept to methotrexate in patients with active

rheumatoid arthritis (RA)� Description of an ongoing psoriasis study in

which alefacept is used concurrently with other

systemic therapies and phototherapy� Initial findings in patients with psoriatic arthritis

Mechanism of action

Psoriasis is an immune-mediated disease, with

memory T cells playing a key role in disease patho-

genesis [3,5]. The costimulatory molecule CD2 is

highly expressed on activated memory T cells [6–8].

This increased expression of CD2 provides a specific


doi:10.1016/j.det.2004.03.014

Conflict of interest: the author has been a long-term con-

sultant for Biogen and a lead investigator or an investigator

in some of the clinical trials.


Alefacept is a bivalent recombinant fusion protein

composed of the first extracellular domain of lym-

phocyte function-associated antigen 3 (LFA-3) fused

to the hinge, CH2 domain, and CH3 domain of human

IgG1. The results of experiments in vitro and in

rodents have shown that alefacept has a dual mecha-

nism of action. The LFA-3 portion of alefacept binds

to CD2 receptors on T cells, thereby blocking their

natural interaction with LFA-3 on antigen-presenting

cells. The IgG1 portion of alefacept binds to the FcgRreceptor on accessory cells (eg, natural killer [NK]

cells) to cause T-cell apoptosis [9,10]. Cytotoxic

assays have shown the apoptotic effects of alefacept

to be selective for the activated memory T-cell

population [6], presumably because of the CD2 up-

regulation associated with this cell type.

Recent experimentation using mutant LFA-3/IgG1

isoforms and cell depletion or antibody blockade

strategies indicates that alefacept immunomodulation

reflects its ability to mediate cognate interactions

between cells expressing human CD2 and human

CD16 (FcgRIII) [11]. To address the molecular and

structural basis for the mechanisms of action of

alefacept, its signal-inducing properties were investi-

gated in transfected Jurkat cells and in interleukin

2–expanded NK cells, which express both CD2 and

CD16. Alefacept induced the activation of intracel-

lular signaling pathways (eg, phosphorylation of

extracellular signal-regulated kinase, up-regulated ex-

pression of the cell surface activation marker CD25,

and release of granzyme B). The binding of alefacept

to both CD2 and CD16 was required for pharmaco-

logic activity, although most of the signaling was

mediated through CD16. Thus, alefacept acts as an

effector molecule, mediating cognate interactions of

s reserved.

Activation

CD2

CD2

CD16CD16TNF

TNF-R

Apoptosis

Apoptosis

CD2+ target cell

NK cell

Caspase- independent pathway

Caspases

GRANZYME/PERFORIN

Alefacept Alefacept

Fig. 1. Model for the activation of apoptosis of sensitive CD2+ cells by alefacept. The LFA-3 portion of alefacept binds CD2

(eg, T cells), and the IgG1 portion binds CD16 on accessory cells (eg, NK cells). Binding of alefacept to both CD2 and CD16

is necessary for pharmacologic activity. NK cells then secrete granzyme/perforin to induce activated CD2+ target cells to undergo

apoptosis. The apoptotic effects of alefacept are selective for the activated memory T-cell population because of its high level of

CD2 expression. Naıve T-cell, NK-cell, and B-cell counts are not significantly affected by alefacept therapy.

G.G. Krueger / Dermatol Clin 22 (2004) 407–426408

cells expressing CD2 and FcgR to activate FcgR+

cells (eg, CD16+ NK cells). These cells secrete

granzyme/perforin to induce activated CD2+ target

cells (eg, T cells) to undergo apoptosis as measured

by annexin V staining (Fig. 1). The prolonged remis-

sions observed in patients with psoriasis who respond

to alefacept (see ‘‘Duration of response’’ section) are

likely the result of this targeted apoptosis.

Alefacept in chronic plaque psoriasis

The clinical profile of alefacept for the treatment

of psoriasis has been extensively studied. Three

studies provide the primary clinical data: one phase

2 study [12] and two phase 3 studies [13,14]. These

studies consistently showed improvements in psoria-

sis that were superior to placebo, durable (even

following treatment cessation), and associated with

improvements in patients’ quality of life (QOL).

Importantly, the effect of alefacept continued well

into the postdosing period, which provided confirma-

tion of the remittive action of the drug and the

importance of evaluating its effect over time.

The efficacy and pharmacodynamic and QOL

effects of alefacept that are presented in the following

sections are primarily based on the results of the two

multicenter, double-blind, placebo-controlled, paral-

lel-group, phase 3 studies involving 1060 patients with

chronic plaque psoriasis. In the intramuscular (IM)

study, patients were randomized to placebo (n = 168),

alefacept (10 mg; n = 173), or alefacept (15 mg; n =

166) for a single course [14]. In the intravenous bolus

(IV) study, patients were randomized to one of three

cohorts: alefacept (7.5 mg) in courses 1 and 2 (cohort

1, n = 183), alefacept (7.5 mg) in course 1 and placebo

in course 2 (cohort 2, n = 184), or placebo in course 1

and alefacept (7.5 mg) in course 2 (cohort 3, n = 186)

[13]. In both studies, each course consisted of

12 once-weekly injections of the study drug followed

by 12 weeks of observation.

Recent analyses of safety data from the phase 3

studies are also presented. In addition, the tolerability

of alefacept over up to six treatment courses is

reported based on a pooled analysis of all studies in

the alefacept clinical program. The latter sections

describe the rationale and design of a study evaluat-

ing combination treatment with alefacept and UVB,

and the design of an ongoing trial that allows alefa-

cept to be administered concomitantly with other

psoriasis systemic and phototherapies.

Efficacy

The benefits of targeted therapy with alefacept are

evident in the overall response rates for reductions in

0

10

20

30

40

50

60

70

80

28

40

71

56

≥50% PASI Reduction

% P

AS

I Red

uct

ion


1 Course of IV Alefacept

2 Courses of IV Alefacept

Fig. 2. Overall response rates for a �50% reduction in PASI and a �75% reduction in PASI with one and two courses of

IV alefacept. (Data from Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN, for the Alefacept Clinical

Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses

of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47(6):821–33.)

G.G. Krueger / Dermatol Clin 22 (2004) 407–426 409

the baseline Psoriasis Area and Severity Index (PASI)

from the two phase 3 studies (Figs. 2 and 3). With

either IM or IV administration, most patients treated

with a single course of alefacept achieved at least a

50% reduction in PASI (PASI-50), and a second

course of therapy provided further benefit by increas-

ing response rates and prolonging the duration of off-

treatment response [13–15].

The following sections summarize new analyses

regarding the efficacy of alefacept among important

subpopulations of patients who participated in these

0

10

20

30

40

50

60

70

80

69

57


% P

AS

I Red

uct

ion

Fig. 3. Overall response rates for a �50% reduction in PASI an

IM alefacept. (Data from Lebwohl M, Christophers E, Langley R

Clinical Study Group. An international, randomized, double-blind,

patients with chronic plaque psoriasis. Arch Dermatol 2003;139:7

pivotal trials. The results demonstrate that alefacept is

efficacious in a broad spectrum of patients with pso-

riasis and that it provides long-lasting off-treatment

responses, regardless of the route of administration.

Patients with severe disease

At baseline, the severity of psoriasis was defined in

both phase 3 studies according to PASI, body surface

area (BSA) involvement, and Physician Global As-

sessment (PGA). The PASI is based on a formula

encompassing disease severity and extent of lesions,

33

43


1 Course of IM Alefacept

2 Courses of IM Alefacept

d a �75% reduction in PASI with one and two courses of

, Ortonne J-P, Roberts J, Griffiths CEM, for the Alefacept

placebo-controlled phase 3 trial of intramuscular alefacept in

19–27.)

66

3341

29Pat

ien

ts (

%)

Alefacept15 mg IM

(n=44)

Placebo IM(n=43)

Alefacept7.5 mg IV(n=111)

Placebo IV(n=56)

0

20

40

60

80

100

Fig. 4. Percentage of patients who achieved a �50% reduction in PASI at any time during treatment or the follow-up period

(overall response rates) for patients with severe disease at screening (PASI, > 20). Results shown are from the two phase 3

studies of alefacept (course 1 data are presented). (Data from Vaishnaw AK, Ticho B. Alefacept is efficacious in a broad spec-

trum of patients with psoriasis, including those with severe disease. Presented at the 61st Annual Meeting of the American

Academy of Dermatology. San Francisco, March 21–26, 2003.)


weighted by the proportion of BSA involved [16].

Scores range from 0 to 72, with the highest score

reflecting complete erythroderma. A PASI greater than

20 generally has been used to define severe disease.

Patients who participated in the phase 3 studies

had a median baseline PASI ranging from 13.2 to

15.2, and a median baseline BSA involvement of 22%

to 24% [17]1. Based on physician assessment, which

is likely to account for multiple factors (eg, severity,

disability, and psychosocial impact), more than 80%

of patients were considered to have moderate, mod-

erate to severe, or severe disease. Among those with a

screening PASI of greater than 20, more patients

treated with alefacept (15 mg given IM or 7.5 mg

given IV) achieved a 50% or greater reduction in PASI

(PASI-50) during treatment or during the follow-up

period (overall response rate) than those who received

placebo (Fig. 4). Results were similar when psoriasis

severity was defined by a BSA of greater than 30% or

a PGA of moderate or worse.

Prior treatment history and response

In the two phase 3 studies, patients were queried

about their prior therapies for psoriasis and then,

during randomization, stratified according to their

histories of prior systemic or phototherapy [18].

Patients were also asked to classify their responses

to each prior systemic or phototherapy as follows: no

1 Data on file, Biogen, Inc.

change, worsening of disease, or improved. The

treatment groups were well balanced with respect to

prior treatment history; 77% and 78% of patients,

respectively, in the IM and IV studies had received

prior systemic or phototherapy. Substantial percent-

ages of patients reported either no change or wors-

ening of their psoriasis after treatment with prior

therapy. Prior therapies consisted of the following:

cyclosporine (21% and 28% of IM and IV patients,

respectively), psoralen plus ultraviolet A light (PUVA;

26% and 36%), methotrexate (32% and 35%), UVB

(35% and 45%), and retinoids (44% and 50% of

IM and IV).

Regardless of prior treatment history, the percent-

ages of patients who achieved a PASI-50 at any time

during treatment or during the follow-up period were

higher in the alefacept group (15 mg IM or 7.5 mg IV)

than in the placebo group (Fig. 5) [18]. Similar

proportions of treatment-naıve and previously treated

patients had a clinically meaningful response to IM or

IV alefacept. As expected, treatment-naıve patients

had slightly better response rates than patients who

had tried other therapies before enrolling in these

studies. In the alefacept 15-mg IM group, 39% of pa-

tients who reported no change or worsening of disease

during prior systemic or phototherapy achieved a 75%

or greater reduction in PASI (PASI-75) compared with

28% of patients who improved on prior therapy. The

corresponding results in the alefacept 7.5-mg IV group

were 36% and 23%, respectively. Importantly, a sub-

stantial number of patients who had not responded to

0

20

40

60

80

100

60 61

24

Pat

ien

ts (

%)

Alefacept15 mg IM(n=47)

PlaceboIM

(n=46)

Treatment–Naïve Prior Systemic Therapy

Alefacept15 mg IM(n=119)

PlaceboIM

(n=122)


PlaceboIV

(n=46)


PlaceboIV

(n=140)

Treatment–Naïve Prior Systemic Therapy

37

24

54

34

55


(overall response rates) in treatment-naıve patients and those who received prior systemic psoriasis therapies or phototherapy.

Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (Data from van de Kerkhof P,

Vaishnaw AK, Kragballe K, Ortonne J-P. Alefacept is efficacious in a broad spectrum of patients with psoriasis. J Eur Acad

Dermatol Venereol 2003;17(Suppl):55.)


prior therapies responded to alefacept. Furthermore,

patients who reported responding to prior therapies

had a lesser overall response to alefacept. This finding

is not understood and requires future study.

Patients who were refractory to or who had

contraindications to conventional systemic psoriasis

therapies or phototherapy

Data from both phase 3 studies were pooled to

determine whether a single course of alefacept was

effective in the subset of patients who were refractory

to or had contraindications to other systemic psoriasis

therapies or phototherapy [19]. Patients who reported

no change or worsening of disease while on such

treatment were considered to be refractory. The most

common contraindication was a history of hyperten-

sion (21%). Among patients who were refractory to or

had contraindications to one or more systemic psoria-

sis therapies or phototherapy, 53% of alefacept-treated

patients and 26% of placebo-treated patients achieved

a PASI-50 during treatment or the follow-up period.

The corresponding results were 52% versus 25%

among patients who were refractory to or had contra-

indications to two or more systemic psoriasis thera-

pies or phototherapy, and 50% versus 21% among

patients who were refractory to or had contraindica-

tions to three or more systemic therapies or photo-

therapy. The efficacy results were comparable to those

observed among patients who were not refractory and

who had no contraindications to other systemic pso-

riasis therapies or phototherapy.

Duration of response

The remittive effect of alefacept has been demon-

strated following IV administration [13]. Recently,

data from the phase 3 IM study have been analyzed

and confirmed this effect [20]. In the phase 3 IV study,

patients who received alefacept in course 1 and

placebo in course 2 (cohort 2) were observed to de-

termine the duration of their off-treatment response.

Per the prespecified analysis, patients in this cohort

who achieved a PASI-75 after the first dose main-

tained a PASI-50 for a median of more than 7 months

(216 days). In addition to improving PASI response

rates, two courses of alefacept (cohort 1) provided a

longer duration of response compared with a single

course. The median duration of response could not be

determined because more than 50% of the patients

who received two courses of alefacept had maintained

their PASI-50 at the final study endpoint, nearly 1 year

after the first dose.

Patients who completed the phase 3 IM study

were eligible to enroll in a separate double-blind

extension study. Patients treated with 15 mg of

alefacept in the phase 3 study received another course

of alefacept at the same dosage. In this treatment

group, those who achieved a PASI-75 after the first

dose in the phase 3 study maintained a PASI-50 for a

Alefacept 15 mg (n=166) Placebo (n=167)

Study Week

Mea

n C

ou

nt

(cel

ls/µ

l)

CD4+ Memory T Cells

600

500

400

300

200

100

A.

0 12 24

CD4+ Naïve T Cells

Mea

n C

ou

nt

(cel

ls/µ

l)

0 12 24

600

500

400

300

200

100Dosing PeriodDosing Period

Fig. 6. Effects of IM (A) and IV (B) alefacept on circulating CD4+ memory and naıve T cells. Similar results were seen for

circulating CD8+ memory and naıve T cells (data not shown). Results shown are from the two phase 3 studies of alefacept.

(Reprinted from Gordon KB, Vaishnaw A, O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of

clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563–70; with permission; and

Ortonne J-P, Lebwohl M, Griffiths CEM. Alefacept-induced decreases in circulating blood lymphocyte counts correlate with

clinical response in patients with chronic plaque psoriasis. Eur J Dermatol 2003;13(2):117–23; with permission.)


median of approximately 7 months (209 days) [20].

These observations confirm and extend the data that

show the duration of response to alefacept is pro-

longed and provides patients with an extended treat-

ment-free period.

Pharmacodynamics

As expected from its mechanism of action, alefa-

cept reduces total lymphocyte and CD4+ and CD8+ T-

cell counts [21,22]. Reductions are selective for

memory T cells, with relative sparing of naıve T cells

(Fig. 6) and no notable effects on CD19+ B cells or

CD16+/CD56+ NK cells [21,22]. Importantly, there

has been no evidence of a cumulative effect of

alefacept on total lymphocyte count or lymphocyte

subset counts over two courses in the phase 3 IV

study (Fig. 6B) [21]. Fig. 7 shows the effect of five

courses of 7.5 mg of IV alefacept on CD4+ T cells

based on the results of an ongoing retreatment study2.

Mean reductions reached a plateau during course 3,

and reductions for courses 3 through 5 appeared

superimposable. At no time did mean CD4+ T-cell

counts drop below the lower limit of normal (LLN;

400 cells/mL).Because of the drug’s effects on T cells, the

product labeling recommends that CD4+ T-cell counts


be monitored weekly during alefacept therapy. Impor-

tantly, as a part of the clinical studies, safety and

tolerability assessments focused on the effect of ale-

facept on immune responses, including infection rates,

malignancies, and the development of antibodies.

Alefacept has not been associated with adverse events

indicative of generalized immunosuppression, and no

opportunistic infections or increased frequency of

malignancies have been reported (see ‘‘Safety and

tolerability’’ section). The selectivity of alefacept for

memory T cells is likely responsible for the lack of

effect on immune responses.

Relationship between memory T-cell reductions and

efficacy

The relationship between the selective targeting of

memory T cells by alefacept and its antipsoriatic

effect was proposed in the phase 2 study and vali-

dated in the phase 3 studies [12,21,22]. In these

studies, the area under the percentage change from

the baseline curve for blood lymphocyte counts over

the dosing interval (EAUC) was calculated for each

patient to relate the cumulative effect of alefacept on

memory T cells with antipsoriatic efficacy [21,22].

Patients were then divided into quartiles (Q) based on

EAUC (Q1 = lowest, Q4 = highest), and the percent-

ages of patients achieving a PASI-50, PASI-75, or

PGA of ‘‘clear’’ or ‘‘almost clear’’ at any time during

the treatment and follow-up periods, without the use

CD4+ Memory T Cells

Course 1 Course 2

Mea

n C

ou

nt

(cel

ls/µ

L)

Study Week

600

500

400

300

200

100

0 12 0 12

0 12 0 12

24 24

B.

CD4+ Naïve T Cells

Course 1 Course 2

Cohort 1, Alefacept (n=154)/Alefacept (n=154)

Cohort 2, Alefacept (n=142)/Placebo (n=139)

Cohort 3, Placebo (n=153)/Alefacept (n=151)

Mea

n C

ou

nt

(cel

ls/µ

L)

600

500

400

300

200

100

Study Week

24 24

Dosing Period Dosing Period

Dosing Period Dosing Period

Fig. 6 (continued ).


of other psoriasis systemic or phototherapies, were

expressed graphically.

There was a consistent relationship between the

magnitude of change in memory T-cell counts and

probability of response (Fig. 8) [21,22]. Regardless of

the definition of response (PASI-50, PASI-75, or

PGA of ‘‘clear’’ or ‘‘almost clear’’), a greater degree

of reduction in memory T-cell counts was generally

associated with a more favorable clinical outcome

[21,22]. The duration of response to alefacept also

was longer in patients who had more pronounced

reductions in memory T cells [21]. Time-course

analysis revealed that the peak effect of alefacept

on memory T cells occurred during treatment, where-

400

500

600

700

800

1100M

ean

Co

un

t (c

ells

/uL

)

Study Week

900

1000

Course 1 Course 2 Course 3 Course 4 Course 5

0 12 24 0 12 24 0 12 24 0 12 24 0 12 24

Dosing PeriodDosing Period Dosing Period Dosing Period Dosing Period

Fig. 7. Effects of repeat courses of 7.5-mg IV alefacept on circulating CD4+ T cells. Results shown are from an ongoing,

retreatment study. The number of patients at each time point in courses 1 to 4 ranges from 61 to 66. The number of patients

at each time point in course 5 ranges from 19 to 33. (Data on file, Biogen, Inc.)

0

20

40

60

80

100

Pat

ien

ts (

%)

Q2

Q1

Q4

Q3

n=84

Alefacept 10 mg +15 mg IM

40

n=85 n=85

5866

n=85

54

n=92

Alefacept 7.5 mg IV

n=92 n=92

62

n=91

51

33

75


(overall response rates) by EAUC of CD4+ memory T cells. Similar results were seen for CD8+ memory T cells (data not shown).

Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (From Gordon KB, Vaishnaw A,

O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of clinical improvement with reductions

of memory T-cell counts. Arch Dermatol 2003;139:1563–70; with permission; and Ortonne J-P, Lebwohl M, Griffiths CEM.

Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic

plaque psoriasis. Eur J Dermatol 2003;13(2):117–23; with permission.)


G.G. Krueger / Dermatol Cl

as the peak effect on PASI generally occurred well

after treatment cessation [21,22]. This finding further

suggests that reductions in memory T cells drive the

therapeutic response to alefacept.

The relationship between alefacept-induced T-cell

changes in psoriatic skin and clinical response was

also investigated. Chamian et al [23] reported data

that showed a significant correlation between reduc-

tions in lesional T cells and clinical improvement

with alefacept therapy. The selective targeting of

memory T cells by alefacept was 11 times greater

in skin lesions than in the peripheral circulation.

Although the reduction in T-cell counts in circu-

lation and skin clearly correlate with level and

duration of response, it is common to find patients

who seem to respond without much change in the

number of memory T cells in the circulation. The

same is true for those who do not respond. Clearly, if

a patient experiences significant improvement, there

is a decrease in T cells in skin. It would be beneficial

to know the reason for this discordance, because it

would allow the clinician to more accurately predict

response without performing a skin biopsy.

Pharmacodynamics in subpopulations

In both phase 3 studies of alefacept, analysis of

circulating total lymphocyte and CD4+ and CD8+

T-cell counts in those patients who received alefacept

plus concomitant immunosuppressants (methotrexate,

cyclosporine, prednisone, etanercept, leflunomide,

infliximab, or mycophenolate mofetil) did not reveal

any patterns that suggested an increased risk for

greater reductions in lymphocyte or lymphocyte sub-

set counts [24].

In the alefacept 15-mg IM group, changes in

circulating CD4+ and CD8+ T cells were determined

in patients who were refractory to or had contra-

indications to one or more other systemic psoriasis

therapies or phototherapy [19]. As mentioned previ-

ously, patients who reported no change or worsening

of disease while on such treatment were considered to

be refractory, and the most common contraindication

was a history of hypertension (21%). Analysis

showed that reductions in T cells were consistent

regardless of whether patients were refractory to or

had contraindications to one or more systemic thera-

pies or phototherapy—mean reductions at the time of

maximal effect ranged from 39% to 43% for CD4+ T

cells and from 47% to 53% for CD8+ T cells. These

results were comparable to those observed among

patients who were not refractory to and had no

contraindications to other systemic psoriasis therapies

or phototherapy.

Variability in circulating T cells

In the two phase 3 studies, there was a surprisingly

high degree of variability in circulating levels of

baseline T-cell counts [25]. For example, among

placebo-treated patients across both studies, baseline

CD4+ T-cell counts ranged from 325 to 2573 cells/mL(normal range, 404–1612 cells/mL) and baseline

CD8+ T-cell counts ranged from 110 to 1625 cells/

mL (normal range, 220–1129 cells/mL). In the alefa-

cept 10-mg IM study, the percentages of placebo-

treated patients who had at least one CD4+ T-cell

count below 400, 300, 200, and 100 cells/mL at any

time after the first dose were 8%, 2%, 0%, and 0%,

respectively. The corresponding percentages in the

alefacept 15-mg IM group were 28%, 9%, 2%, and

0%. For CD8+ T cells, 16%, 6%, less than 1%, and 0%

of patients in the placebo IM group and 39%, 23%,

7%, and 2% of patients in the alefacept 15-mg IM

group had counts below 200, 150, 100, and 50 cells/

mL, respectively. Most patients experienced a recovery

in T-cell counts during the treatment-free follow-up

period. At 12 weeks after the last IM dose, in the

10-mg group two (1%) placebo-treated patients had

CD4+ T-cell counts below the LLN, and 14 (9%) had

CD8+ T-cell counts below the LLN. At the same time

point, 11 (7%) patients treated with 15 mg of IM

alefacept had CD4+ T-cell counts below the LLN, and

32 (22%) had CD8+ T-cell counts below the LLN.

Results of the IV study were similar to those of the IM

study. Although these values were below the LLN,

they were not associated with adverse events and, as

noted previously, did not continue to decline with

further administration. These findings suggest that

variability in T-cell counts occurs in patients with

psoriasis regardless of therapy and that T-cell counts

generally recover to normal ranges following alefa-

cept therapy.

Quality of life

In addition to the obvious physical characteristics

of psoriasis, the disease causes significant impairment

in patients’ QOL. A large survey (>17,000 respon-

dents) conducted by the National Psoriasis Foundation

(NPF) found that patients often report difficulty

performing routine activities (eg, sleeping and exer-

cising), interacting with peers and family, making or

keeping friends, and getting a job [26]. Suicide is fre-

quently contemplated. Approximately 50% of patients

with severe psoriasis are not satisfied or only some-

what satisfied with their current treatment. More than

75% of patients with severe psoriasis are frustrated

with the lack of efficacy of their current treatment, and

87% report receiving treatment with topical agents,

which can be time-consuming to administer [26]. A

in 22 (2004) 407–426 415


survey of similar size was recently conducted in Eu-

rope by the European Federation of Psoriasis Patients

Organizations (EUROPSO) [27,28]. The findings of

EUROPSO paralleled those of the NPF.

Further complicating the management of psoriasis

is the lack of correlation between the patient’s per-

ception of their disease intensity and objective mea-

sures of disease severity (eg, BSA, PASI, and PGA),

which do not take into account the effect of psoriasis

on the patient’s QOL [29]. A recent pooled analysis

of baseline data from both phase 3 studies in the

alefacept clinical program yielded interesting results.

The primary QOL instrument used in these trials was

the Dermatology Life Quality Index (DLQI) [30]. At

baseline, the distribution of DLQI varied widely for

any given measure of BSA. That is, patients with

extensive BSA at baseline may have had high or low

DLQI. This was also true for patients with low BSA

at baseline who may have had high or low DLQI. In

addition, there was no correlation between baseline

PASI or PGA and baseline DLQI [29]. These data

underscore the need to address both the physical and

psychologic aspects of psoriasis.

QOL assessments have been included in the phase

2 and 3 studies of alefacept and the data have been

-8

-6

-4

-2

0

1

Mea

n C

han

ge

in D

LQ

I

2 WeeksAfter Last Dose

-4.4

-5.1

-7

-5

-3

-1

12 WeeksAfter Last Dose

2 WeeksAfter Last Dos

≥50% to <75% PASI ≥75%

-2.2 -2.1

-7.2

-2.9

*

*

Fig. 9. Mean change from baseline in DLQI by responder status

improvement in QOL. Results shown are from the phase 3 intram

bined for this analysis). *P < 0.001 versus nonresponders. (Repri

Clinical Study Group. Intramuscular alefacept improves health-rel

Dermatology 2003;206(4):307–15; with permission.)

published [31–33]. In the phase 3 studies, alefacept

significantly improved overall DLQI scores at 2 weeks

after treatment cessation compared with placebo, a

benefit that was largely preserved at 12 weeks after the

last dose [32,33]. Significant improvements over

placebo were also observed for the Dermatology

Quality of Life Scales and the Short Form–36 Health

Survey, a general health survey. The DLQI signifi-

cantly improved in patients who achieved a reduction

in PASI of 50% to less than 75% (Fig. 9); these pa-

tients also experienced visible clinical improvement.

It was not necessary for PASI to be reduced by 75% or

more or for the PGA to be clear or almost clear for

these benefits to be realized. Taken together, the

results of these three studies strongly suggest that

PASI-50 is clinically meaningful for both patients and

physicians. Other observations lend further support to

this conclusion [34]. First, the relationship between

PASI and severity of psoriasis is not linear. There is a

tendency for PASI to underestimate the actual im-

provement in psoriasis because of how the score is

calculated. Second, methotrexate, widely viewed as

an effective therapy for psoriasis, when given in an

aggressive dosing fashion in a small-scale 25-patient

trial, resulted in a PASI-75 in about one fourth of

Nonresponder

Responder

e12 Weeks

After Last Dose2 Weeks

After Last Dose12 Weeks

After Last Dose

PGA "Clear"/"Almost Clear" PASI

-6.6

-2.6

-7.1

-3.1 -2.8

-6.6*

**

at 2 weeks after the last dose. A negative change indicates

uscular study of alefacept (all treatment groups were com-

nted from Finlay AY, Salek MS, Haney J, for the Alefacept

ated quality of life in patients with chronic plaque psoriasis.

G.G. Krueger / Dermatol Cl

patients and a PASI-50 in about two thirds of patients

after 6 months of treatment [35]. Third, clinical

studies have shown that effective therapies for psoria-

sis can be consistently differentiated from placebo at

PASI-50. Fourth, patients who achieve PASI-75 often

choose to defer treatment until their PASI is below 50.

For these and other reasons, it seems that PASI-50

would serve as an effective endpoint when defining a

clinically meaningful response [34].

Safety and tolerability

The data presented in the following sections

demonstrate that alefacept is safe and well tolerated

in a broad spectrum of patients, including those on

concomitant immunosuppressant agents and those

who are refractory to or have contraindications to oth-

er systemic psoriasis therapies or phototherapy. The

incidence of serious adverse events, discontinuations,

infections, malignancies, and antialefacept antibodies

remain low over up to six alefacept courses. In addi-

tion, critical functions of the immune system are

maintained during alefacept therapy.

Table 1

Incidence of adverse events in the first course of the intravenous s

received concomitant immunosuppressants

Alefacept

Adverse event

Received (N = 21)

n (%)

Accidental injury 3 (14)

Pruritus 2 (10)

Allergic reaction 1 (5)

Anxiety 1 (5)

Arthritis 1 (5)

Contact dermatitis 1 (5)

Dizziness 1 (5)

Ear disorder 1 (5)

Gout 1 (5)

Headache 1 (5)

Hyperglycemia 1 (5)

Hypertension 1 (5)

Infectiona 1 (5)

Insomnia 1 (5)

Kidney calculus 1 (5)

Paresthesia 1 (5)

Pharyngitis 1 (5)

Rash 1 (5)

Respiratory disorder 1 (5)

This table lists all adverse events that were reported among alefac

suppressants. Patients may have experienced more than one advera Most episodes were common colds.

Data from Vaishnaw AK, Lee S. Concomitant use of alefacept an

at the 61st Annual Meeting of the American Academy of Dermato

Concomitant use of alefacept and immuno-

suppressants

As new, targeted immunotherapies are being de-

veloped and studied in patients with psoriasis, the

concomitant, sequential, or rotational use of these

agents with older, nonspecific immunosuppressants

is of interest. In the two phase 3 studies of alefacept,

the incidence of adverse events, serious adverse

events, and serious infections during the first course

of 7.5-mg alefacept in the IV study (cohorts 1 and

2 pooled) and 15-mg alefacept in the IM study were

analyzed according to concomitant use and prior use

(within 60 d before the first alefacept dose) of the

following immunosuppressants: methotrexate, cyclo-

sporine, prednisone, etanercept, leflunomide, inflix-

imab, and mycophenolate mofetil [24].

One or more immunosuppressant agents were used

concomitantly by 21 patients (6%) in the 7.5-mg

alefacept IV group and by 4 patients (2%) in the

15-mg alefacept IM group compared with 22 patients

(6%) in the placebo group (IM study and cohort 3 of

IV study pooled) [24]. There were no unusual patterns

of adverse events in the IV study (Table 1) or IM

in 22 (2004) 407–426 417

tudy among alefacept-treated patients who had and had not

Did not receive (N = 346)

n (%)

Placebo (N = 186)

n (%)

70 (20) 30 (16)

37 (11) 16 (9)

1 (<1) 1 (<1)

8 (2) 4 (2)

15 (4) 5 (3)

2 (<1) 3 (2)

16 (5) 6 (3)

2 (<1) 1 (<1)

0 1 (<1)

58 (17) 38 (20)

0 1 (<1)

10 (3) 6 (3)

33 (10) 20 (11)

2 (<1) 7 (4)

2 (<1) 2 (1)

5 (1) 0

51 (15) 23 (12)

3 (<1) 3 (2)

0 0

ept-treated patients who had received concomitant immuno-

se event.

d immunosuppressants in patients with psoriasis. Presented

logy. San Francisco, March 21–26, 2003.


study. The nature of the adverse events was consist-

ent between those patients who had and those who

had not received concomitant immunosuppressants.

Among the four patients in the 15-mg alefacept IM

group who had received concomitant immunosup-

pressants, one patient each reported arthritis, conjunc-

tivitis, diarrhea, eczema, edema, hypercholesteremia,

and insomnia.

Similar results were obtained when adverse events

were analyzed according to use of one or more

immunosuppressants within 60 days before the first

dose of alefacept [24]. A review of the safety data

collected during phase 3 studies of alefacept (admin-

istered by IM and IV injection) suggests that the

frequency and spectrum of adverse events or serious

infections is not altered by concomitant use or prior

use of immunosuppressants. An ongoing study using

combination therapy will address this question more

directly (see ‘‘Ongoing study of alefacept in clinical

practice’’ section for details).

Patients who were refractory to or who had

contraindications to other systemic therapies or

phototherapy

Data from both phase 3 studies of alefacept were

pooled to determined the adverse event profile in the

subset of patients who were considered refractory to or

who had contraindications, as defined previously, to

other systemic psoriasis therapies (cyclosporine,

methotrexate, and retinoids) or phototherapy (PUVA

0

2

4

6

8

10

Aleface

1 2 3

Pat

ien

ts (

%)

n=1359 n=826 n=415

0.50.8

4.1

3.1

1.8

4.9

Fig. 10. Incidence of serious adverse events and discontinuations b

therapy. Results shown are from all studies in the alefacept clinica

or UVB) [36]. Among the 714 patients who were

refractory to or had contraindications to one or more

systemic therapies or phototherapy, the only adverse

event to occur at an incidence of 5% or greater

incidence in the alefacept group compared with the

placebo group was pruritus (15% versus 10%).

Among the 431 patients who were refractory to or

had contraindications to two or more systemic thera-

pies or phototherapy, the following adverse events

were reported at an incidence of 5% or greater in the

alefacept group compared with the placebo group:

pruritus (15% alefacept versus 8% placebo), flu syn-

drome (13% versus 8%), rhinitis (12% versus 6%),

myalgia (6% versus 1%), and injection site pain (5%

versus 0%). Among the 206 patients who were refrac-

tory or had contraindications to three or more systemic

therapies or phototherapy, the following adverse

events occurred at an incidence of 5% or greater in

the alefacept group versus the placebo group: pruritus

(18% versus 11%), accidental injury (17% versus 8%),

and injection site pain (6% versus 0%). The safety

profile of alefacept in patients who were considered

refractory or had contraindications to one or more

other systemic psoriasis therapies or phototherapy was

similar to the safety profile observed in the overall

alefacept-treated patient population.

Multiple courses

Safety and tolerability data were obtained from all

studies evaluating alefacept as a treatment for psoria-

sis. These data were pooled, and the integrated results

pt Course

4 5 6

Discontinuations foradverse events

Serious adverse events

1.5

0.8 0.8

n=133 n=65 n=36

000

ecause of adverse events over multiple courses of alefacept

l program. (Data on file, Biogen, Inc.)

0

20

40

60

80

100

Pat

ien

ts (

%)

CD4+ count ≥250 cells/µL

CD4+ count <250 cells/µL

n=121

63

29 31

4438 39

47

26

44

0

43

n=1238 n=85 n=741 n=28 n=387 n=8 n=125 n=6 n=59 n=1 n=35

33

Alefacept Course

1 2 3 4 5 6

A.

0

20

40

60

80

100

Pat

ien

ts (

%)

CD8+ count ≥100 cells/µL

CD8+ count <100 cells/µL

n=178

40

2730

46

31

47 44

30

42

n=1181 n=155 n=671 n=78 n=337 n=35 n=98 n=20 n=45 n=10 n=26

353336

Alefacept Course1 2 3 4 5 6

B.

Fig. 11. Incidence of infections by circulating CD4+ (A) and CD8+ (B) T-cell counts over multiple courses of alefacept ther-

apy. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)


are presented here3. A total of 1359 patients received

at least a single course of alefacept, 826 received at

least two courses, 415 received at least three courses,

133 received at least four courses, 65 received at least

five courses, and 36 received at least six courses.

Adverse events

Alefacept was well tolerated over multiple

courses. Across all alefacept studies, there was no


increase in the incidence of serious adverse events or

discontinuations because of adverse events with re-

peated administration of up to six treatment courses

(Fig. 10). There was a tendency for rates of serious

adverse events and discontinuations to decrease with

continued courses of therapy. The percentage of

patients who experienced at least one serious adverse

event ranged from a high of 4.9% in course 1 to a low

of 0% in course 6. The most common serious adverse

events were accidental injury (0.4%, 0.6%, 0.2%, 0%,

0%, and 0% of patients in courses 1 through 6,

respectively) and cholelithiasis (0.2%, 0.5%, 0.2%,

Table 2

Incidence of serious infections by course of alefacept

Alefacept course

Infection

1 (N = 1359)

n (%)

2 (N = 826)

n (%)

3 (N = 415)

n (%)

4 (N = 133)

n (%)

5 (N = 65)

n (%)

6 (N = 36)

n (%)

Cellulitis 3 (0.2) 0 0 0 0 0

Pneumonia 0 2 (0.2) 1 (0.2) 0 0 0

Bacterial infection 2 (0.1) 0 0 0 0 0

Gastroenteritis 2 (0.1) 0 0 0 0 0

Abscess 1 (<0.1) 0 0 0 0 0

Appendicitis 0 0 1 (0.2) 0 0 0

Asthma 1 (<0.1) 0 0 0 0 0

Bronchitis 0 0 1 (0.2) 0 0 0

Burn infection 1 (<0.1) 0 0 0 0 0

Herpes simplex 0 1 (0.1) 0 0 0 0

Postprocedural site

wound infection

0 1 (0.1) 0 0 0 0

Wound infection 0 1 (0.1) 0 0 0 0

Total 10 (0.7) 5 (0.6) 3 (0.7) 0 0 0

Data on file, Biogen, Inc.


0%, 0%, and 0% of patients in courses 1 through 6,

respectively). Discontinuation rates because of adverse

events ranged from 1.8% in course 1 to 0% in courses

5 and 6. Headache (0.2% in course 1, 0% in other

courses), nausea (0.2% in course 1, 0% in other courses),

and herpes zoster (0.07%, 0%, 0.2%, 0.8%, 0%, and 0%

in courses 1 through 6, respectively) were the most

frequent adverse events that resulted in withdrawal.

Table 3

Incidence of malignancies by course of alefacept

Alefacept course

Malignancy

1 (N = 1359)

n (%)

2 (N = 826)

n (%)

Skin carcinoma 11 (0.8) 4 (0.5)

Skin melanoma 2 (0.1) 1 (0.1)

Lung carcinoma 0 1 (0.1)a

Prostatic carcinoma 1 (<0.1) 1 (0.1)

Adenocarcinoma of colon 0 0

Colonic polyps 0 0

Esophageal carcinoma 0 1 (0.1)

Lymphomac 0 1 (0.1)

Renal cell carcinoma 1 (<0.1) 0

Secondary neoplasm of brain 0 1 (0.1)a

Testicular cancer 1 (<0.1) 0

Total 16 (0.7) 9 (1.1)

Data on file, Biogen, Inc.a Same patient was diagnosed with both events.b Same patient was diagnosed with both events.c Two additional cases of lymphoma were diagnosed 5 and 6

Infections

Infections were analyzed by course and circulating

CD4+ (<250 cells/mL and �250 cells/mL) and CD8+

(<100 cells/mL and �100 cells/mL) T-cell counts

(Fig. 11). There was no evidence of an increased risk

of infection over multiple courses of alefacept, nor

was there an association between infections and CD4+

and CD8+ T-cell counts. Infections were generally

3 (N = 415)

n (%)

4 (N = 133)

n (%)

5 (N = 65)

n (%)

6 (N = 36)

n (%)

3 (0.7) 1 (0.8) 1 (1.5) 0

0 0 0 0

1 (0.2) 0 0 0

0 0 0 0

1 (0.2)b 0 0 0

1 (0.2)b 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

5 (1.2) 1 (0.8) 1 (1.5) 0

months after alefacept therapy (see text for details).

0

2

4

6

8

10

Pat

ien

ts (

%)

Postbaseline

Baseline

n=1291

0 0 0 0 0 0

1.5

0.8

2.4

n=1268 n=826 n=606 n=415 n=157 n=133n=77 n=65 n=40 n=36 n=14

0.30.7

1.3

Alefacept Course

1 2 3 4 5 6

Fig. 12. Incidence of antibodies to alefacept over multiple courses of therapy. All patients with available data were included in

the analysis. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)


mild and responsive to conventional therapy. The vast

majority of episodes were common colds. Serious

infections were experienced by 0.7%, 0.6%, 0.7%,

0%, 0%, and 0% of patients in courses 1 through 6,

respectively. These events are summarized in Table 2.

No cases of opportunistic or unusual infections, tu-

berculosis, or deaths related to infections were ob-

served in patients receiving alefacept.

Malignancies

The percentages of patients (n = 1359) who

developed malignancies were low and did not increase

over multiple courses of alefacept: these percentages

were 1.2%, 1.1%, 1.2%, 0.8%, 1.5%, and 0% in

courses 1 through 6, respectively. No relationship

between malignancies and circulating CD4+ or

CD8+ T-cell counts was observed. The specific

malignancies that were diagnosed are presented in

Table 3, the most common of which was skin carci-

noma (basal and squamous cell carcinomas). The

overall malignancy rate among alefacept-treated

patients was 25.6 per 1000 person-years of exposure4,

which is somewhat less than the corresponding rate in

the general psoriasis population (29.0 per 1000 per-

son-years) [37]. There were three cases of lymphoma

among alefacept-treated patients. A 68-year-old

woman with longstanding psoriasis and previous

exposure to methotrexate and PUVA developed fea-

tures consistent with sporadic B-cell non-Hodgkin’s

lymphoma, without an immunotherapy-related lesion.


She had received a total of 20 alefacept injections. A

53-year-old man was diagnosed with Hodgkin’s dis-

ease 6 months after his last dose of alefacept (34 total

doses). Before receiving alefacept, the patient had

been treated with methotrexate for 15 years. The other

case was a 62-year-old man who was diagnosed with

Hodgkin’s disease (stage IV) 5 months after his last

dose of alefacept (24 total doses). The patient had

previously received PUVA and UVB. Two of the three

patients had received significant prior immunother-

apy, which is known to be associated with an in-

creased risk of lymphoma [37,38]. Overall, total

lymphoma (Hodgkin’s and non-Hodgkin’s) occurred

at a rate of 0.53 per 1000 person-years of alefacept

exposure versus 1.6 per 1000 person-years in the

general psoriasis population [37]5.

Immunogenicity

Consistent with its composition as a fully human

fusion protein, the immunogenicity of alefacept was

low in all courses (Fig. 12). The percentage of

patients who tested positive for antialefacept anti-

bodies post baseline was highest during course 1

(2.4%) and lowest during courses 4 through 6 (0%).

In the few patients who developed antialefacept anti-

bodies after treatment initiation, antibody titers were

generally low (<1:40) and transient in most patients

and did not increase with sequential sampling and

treatment. Antibody titers were not associated with

immune hypersensitivity reactions.



Primary and secondary immune responses

A multicenter, randomized, open-label, parallel-

group study evaluated the effects of alefacept on

primary and secondary immune responses in patients

with chronic plaque psoriasis [39]. Patients were

randomized into two groups: alefacept (n = 23) and

control (n = 23). Antibody responses to the neo-

antigen bacteriophage fX174 and to the recall antigentetanus toxoid and diphtheria were evaluated. There

were no statistically significant differences between

the alefacept and control groups in antibody responses

to either antigen. Mean anti-fX174 titers were com-

parable in the two groups at all time points after the

first and second immunizations [39]. The observed

titers were comparable with those seen in healthy

volunteers after fX174 administration [40–44].

The IgG fraction of total anti-fX174 response at 2

weeks after the second immunization was 54% in the

alefacept group and 48% in the control group, indi-

cating that alefacept does not alter immunologic

memory [39]. No evaluable patient failed to show

an IgG anti-fX174 antibody response. Consistent

with an acquired immune response, antibody titers

rose rapidly after immunization with the recall anti-

gen, tetanus toxoid. The percentage of patients with a

twofold or greater increase in antitetanus titer at

3 weeks after immunization was similar in the alefa-

cept (89%) and control (91%) groups. Thus, a single

course of alefacept does not impair primary or sec-

ondary antibody responses to a neoantigen or memory

responses to a recall antigen.

Concomitant alefacept and ultraviolet B

The combination of alefacept and UVB has the

potential to provide synergistic efficacy with each

agent targeting T cells in a different way, one from

within and one from the surface. It has been hypoth-

esized that this combination might provide a faster

onset of action and longer duration of response than

observed with either agent alone.

The combination of alefacept and either narrow-

band (NB) or broadband (BB) UVB was evaluated in

an open-label study of patients with chronic plaque

psoriasis. Patients (N = f60) were enrolled at two

sites: one in France (NB UVB) [45] and one in the

United States (BB UVB) [46]. All patients received

15 mg of IM alefacept once weekly for 12 weeks.

Patients were randomized (1:1:1) to receive either no

UVB, UVB 3 times per week until clear or for up to 6

weeks, or UVB 3 times per week until clear or for up

to 12 weeks. An observation period of 12 weeks

followed the treatment period. The primary objective

was to determine the safety and tolerability of com-

bination therapy.

Results from both sites have been presented

[45,46]. Alefacept in combination with UVB was well

tolerated; adverse events were similar among patients

who received alefacept monotherapy and patients who

received combination therapy. No opportunistic infec-

tions were reported. Combination therapy seemed to

provide a more rapid onset of effect compared with

alefacept monotherapy. Complete results will be pub-

lished separately.

Ongoing study of alefacept in clinical practice

To understand the best way to manage existing

therapies during a course of alefacept, an international

study is being conducted to reflect what is projected to

be an approach that will be common to the usual

clinical setting [47]. Approximately 400 patients with

chronic plaque psoriasis will be enrolled in this open-

label study in which topical treatments, NB or BB

UVB (2–3 treatments/wk), systemic retinoids, and

prednisone will be permitted as concomitant therapies.

Methotrexate and cyclosporine will be tapered over

the first 4 and 12 weeks of alefacept therapy, respec-

tively. Patients must need systemic therapy, have

normal circulating CD4+ T-cell counts (�300 cells/

mm3 if on a stable dose of prednisone), and be naıve

to alefacept treatment. In each course, 15 mg of IM

alefacept will be administered once weekly for

12 weeks followed by 12 weeks of observation. Pa-

tients may receive up to three treatment courses.

The primary objective of this study is to evaluate

the safety of repeat courses of alefacept [47]. Other

prespecified objectives are to determine the efficacy

of initial and repeat courses of alefacept and the time

to retreatment with alefacept after the first two

courses. The results will provide valuable insight into

the management of other psoriasis therapies when

used concurrently with alefacept.

Alefacept in psoriatic arthritis

Although data are limited, some evidence suggests

that T cells may play a role in the pathogenesis of

psoriatic arthritis (PsA) [48–50]. Therefore, a pro-

spective, single-center, open-label pilot study was

conducted to determine the clinical effect and changes

in the synovium of patients with active PsA treated

with alefacept [51]. Patients (N = 11) had had chronic

plaque psoriasis for 1 year or more and active PsA,

defined as two or more swollen joints and two or more

tender joints. After a 28-day washout phase in which

current treatments were withdrawn, 7.5 mg of IV

alefacept was administered weekly for 12 weeks with

12 weeks of treatment-free observation. No concom-


itant treatment for PsA was allowed, with the ex-

ception of nonsteroidal anti-inflammatory drugs

(NSAIDs). Clinical assessments, which were per-

formed at baseline, after 4 and 12 weeks of treatment,

and at 16 weeks (ie, 4 wk after the last dose), included

a 30-joint count (28-joint count and both ankles) for

joint swelling and tenderness, physician and patient

assessment of disease activity, morning stiffness, pain

as assessed by a visual analog scale (VAS), serum

concentrations of C-reactive protein (CRP), and PASI.

Serial arthroscopic synovial biopsies of the same

index joint were performed under local anesthesia at

baseline and after 4 and 12 weeks of treatment (knee

joint, n = 7; wrist joint, n = 2; metacarpophalangeal

joint, n = 1; and ankle joint, n = 1).

Alefacept significantly improved the mean swol-

len and tender joint counts, disease activity score

(DAS), VAS, and CRP concentrations from baseline.

The mean PASI was lowered by 13% at 4 weeks,

23% at 12 weeks, and 28% at 16 weeks. Immuno-

histochemical analysis revealed significant decreases

from baseline in the mean number of macrophages in

the synovial sublining at 12 weeks (43% reduction),

CD4+ T cells at 4 and 12 weeks (42% and 59%

reductions, respectively), and CD8+ T cells at 4 and

12 weeks (13% and 60% reductions, respectively).

Patients who fulfilled the DAS response criteria at

12 weeks (n = 6) achieved a greater reduction in

the memory subset of T cells in both synovial tissue

and peripheral blood compared with nonresponders

(n = 5).

The improvement in clinical joint score and skin

psoriasis and changes in synovial tissue after treat-

ment with alefacept support the hypothesis that T-cell

activation plays an important role in PsA.

Alefacept in rheumatoid arthritis

T cells are believed to mediate the painful and

disabling inflammation of synovial tissues observed

in patients with RA [52]. Alefacept may prove to be a

valuable treatment option in RA because studies have

shown that it is the CD4+ memory subset of T cells

that predominate in synovium [52]. A 6-month,

randomized, double-blind, placebo-controlled, pilot

study was conducted to assess the safety, tolerability,

and efficacy trends of alefacept in patients with active

RA despite treatment with methotrexate [53]. IV

alefacept (3.75 mg or 7.5 mg) or placebo (n = 12/

group) was administered weekly for 12 weeks fol-

lowed by 12 weeks of observation. All patients

continued treatment with a stable dose of methotrex-

ate throughout the study. Additional disease-modify-

ing antirheumatic drugs were not allowed, but stable

doses of NSAIDs and corticosteroids (prednisone,

V10 mg/d) were permitted. Efficacy assessments

included swollen and tender joint counts and the

percentages of patients achieving American College

of Rheumatology (ACR) response scores of 20, 50,

and 70.

A total of 36 subjects with severe disease were

randomized into the three treatment arms [53]. Ale-

facept responses were superior to placebo with 58%

and 25% of subjects achieving ACR 20 at 6 months

in the 7.5-mg and 3.75-mg alefacept groups, respec-

tively, as compared with 17% in the placebo group.

ACR 50 and ACR 70 responses were 17% and 8%,

respectively, for each of the alefacept arms at 6

months. Without any further intervention, all subjects

in the 3.75-mg alefacept group who had achieved an

ACR 20 response at 14 weeks maintained this benefit

during the 12-week follow-up period. Alefacept se-

lectively reduced circulating CD4+ and CD8+ T cells,

with a return toward baseline levels during the

follow-up period. The author predicts that because

alefacept and methotrexate were well tolerated and

without identifiable safety concerns in this small

cohort of patients with RA, the combination will

have a similar profile in patients with psoriasis.

Summary

Alefacept is the first biologic agent to be approved

for the treatment of chronic plaque psoriasis. By

selectively targeting the memory T-cell population

involved in the pathogenesis of psoriasis, alefacept

provides durable clinical improvement without gen-

eralized immunosuppression. Moreover, alefacept is a

safe and effective treatment for psoriasis, regardless

of disease severity, prior treatment history, response

to prior therapy, or the presence of contraindications

to other systemic psoriasis therapies or phototherapy.

Patients who respond to alefacept benefit from ex-

tended periods free of disease and its treatments. As

experience with alefacept has grown, the favorable

safety and tolerability profile has been confirmed in

patients who have received up to six courses of ther-

apy. There has been no evidence of an increased risk

for infection or malignancy; no correlation between

rates of infection, malignancy, and circulating CD4+/

CD8+ T-cell counts; and low immunogenicity. Re-

search is ongoing to examine the use of alefacept in

PsA and RA and its use in combination with other

systemic psoriasis therapies and phototherapy.


Acknowledgments

The author expresses appreciation to colleagues

at Biogen for their willingness to provide key data

and interpretation and to Mike McNamara of Scien-

tific Connections for editorial support.

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http:\\www.eular.org

Dermatol Clin 22 (2004) 427–435

Current concepts and review of efalizumab in the treatment

of psoriasis

Craig L. Leonardi, MDa,b,*

aDepartment of Dermatology, St. Louis University School of Medicine, 1755 S Grand, St. Louis, MO 63104, USAbCentral Dermatology, 1034 South Brentwood Boulevard, Suite 600, St. Louis, MO 63117, USA

Psoriasis is commonly a disease of young adults cal advances in large-scale protein synthesis, has

with an average age of onset of 28 years. Those

individuals with the more severe forms of the disease

are thus faced with the requirement of decades of

therapy using the traditional systemic approaches.

The cumulative toxicities of these therapies, how-

ever, preclude their use in a chronic setting. To reduce

these treatment-related side effects, dermatologists

use various creative strategies in an attempt to control

psoriasis. For example, rotational treatment para-

digms are sometimes used, with the patient moving

from a highly effective to a less effective therapy

possessing a different side-effect profile. Alterna-

tively, combination therapy is sometimes used with

multiple agents at lower doses to reduce the risk of

toxicity. Last, intermittent treatments are also used,

with discontinuation of treatment and subsequent

recurrence of the disease [1]. Many of these patients

therefore have difficulty maintaining uninterrupted

control of their symptoms and thus experience a

significant impact of psoriasis on their lives. Further-

more, widespread dissatisfaction exists with the treat-

ments and with those who prescribe them. There is a

substantial unmet need for effective therapies that can

be safely administered on a long-term basis.

The pathophysiology of psoriasis has been dra-

matically reshaped by recent advances in cellular and

molecular immunology. Physicians now understand

the key role of T cells and their cytokine products in

the pathogenesis of this chronic, inflammatory dis-

ease. This new knowledge, coupled with technologi-


doi:10.1016/j.det.2004.03.015

* Central Dermatology, 1034 South Brentwood

Boulevard, Suite 600, St. Louis, MO 63117.


resulted in the ongoing development of more than

two dozen biologic therapies that target the key steps

in the inflammatory cascade. Efalizumab (Raptiva) is

one of the promising new targeted immunomodula-

tors designed to reduce inflammation in the body. It is

currently the only biologic agent approved by the US

Food and Drug Administration for continuous ad-

ministration to adult patients with moderate to severe

chronic plaque psoriasis.

Mechanism of efalizumab action and evidence of

immunobiologic activity

Efalizumab is a recombinant, humanized, mono-

clonal IgG1 antibody designed to down-regulate

inflammatory processes in the body (Fig. 1). Admin-

istered once weekly by subcutaneous injection, efali-

zumab binds to CD11a, the a subunit of leukocyte

function-associated antigen 1 (LFA-1). There, it dis-

rupts the interaction between LFA-1 and one of its

ligands, intercellular adhesion molecule 1 (ICAM-1).

ICAM-1 is a cell surface molecule that is expressed by

antigen-presenting cells (APCs) and is up-regulated

on both endothelial cells and keratinocytes within

psoriatic plaques [2]. Thus, efalizumab disrupts sev-

eral of the key T-cell–mediated steps involved in the

pathogenesis of psoriasis: it destabilizes the binding

of APCs and T cells, reducing the efficiency of initial

T-cell activation in lymph nodes; it decreases the

trafficking of T cells from the circulation into dermal

and epidermal tissues; and it interferes with the

secondary activation of memory-effector T cells

in the target tissues (Fig. 2). Finally, because CD11a

s reserved.

Fig. 1. Space-filling model of efalizumab. This full-length

IgG1 was originally developed in a murine system. Human

DNA sequences have replaced all but 3% of the original

murine sequences to reduce antigenicity.

C.L. Leonardi / Dermatol Clin 22 (2004) 427–435428

expression is unique to LFA-1, the effects of efalizu-

mab are believed to be confined only to those cells

expressing LFA-1.

Phase 1 and 2 trials have characterized the phar-

macodynamic profile of efalizumab and demonstrated

its clinical activity at the molecular level in patients

with psoriasis. Upon administration by either intra-

venous or subcutaneous routes, efalizumab rapidly

saturates cell surface CD11a on T cells and down-

regulates CD11a expression [3–7]. The effect is

quickly reversed, however, with CD11a levels re-

turning to normal 7 to 10 days following clearance of

efalizumab from the circulation (Fig. 3) [7].

Histologic changes also accompany CD11a satu-

ration and down-modulation. Reduced keratin 16 and

ICAM-1 expression suggest diminished keratinocyte

hyperproliferation and reduced cytokine-mediated

inflammation, respectively. Other findings include

thinning of the psoriatic epidermis, with a restoration

of normal phenotype, and a marked reduction in the

number of dermal and epidermal CD3+ T cells in

lesional skin.

A concomitant increase in the number of circulat-

ing CD3+ lymphocytes suggests that efalizumab

prevents T-cell trafficking from the circulation into

dermal and epidermal tissues. Clinically, a marked re-

duction of erythema, induration, and scaling is noted

early in treatment followed by reduction in the

involved body surface area [5,7].

Phase 3 clinical experience with efalizumab

Efalizumab therapy has been studied in more than

2700 patients. The results from a various large-scale

placebo-controlled and open-label phase 3 trials

demonstrate the rapid change and sustained efficacy

seen in patients with psoriasis. In blinded trials,

the primary endpoint was the percentage of patients

achieving a 75% reduction in their Psoriasis Area

and Severity Index (PASI-75) at 12 weeks as com-

pared with a placebo group. In addition, several

secondary endpoints were also assessed, including

PASI-50 response, Overall Lesion Severity (OLS),

Physicians’ Static Global Assessment, Dermatology

Life Quality Index (DLQI), an Itching scale, and the

Psoriasis Symptom Assessment (PSA) frequency and

severity subscales.

Short-term results

Efalizumab-treated patients experienced quick

onset of action. Following initiation of therapy at

1 mg/kg/week, a statistically significant reduction

in PASI was noted as early as 2 to 4 weeks [8–10].

These changes were most pronounced in the ery-

thema, induration, and scale components of the PASI.

In one trial, 22% of treated patients achieved

PASI-75 after 12 weeks of treatment as compared

with 5% of those who received placebo (P < 0.001)

[8]. At the same time point, 52% of treated patients

achieved a PASI-50 response. Overall, the mean im-

provement in PASI was 51% versus 17% (P < 0.001)

[8]. In a second trial, 27% of efalizumab-treated

patients achieved PASI-75 at 12 weeks as compared

with 4% receiving placebo (P < 0.001). As expected,

significant PASI-50 responses were also noted, with

59% versus 14% (P < 0.001) for the efalizumab and

placebo arms, respectively [10]. In a third blinded,

placebo-controlled trial, 39% versus 2.4% (P < 0.001)

of patients achieved PASI-75 at 12 weeks for treated

versus placebo groups, respectively. The PASI-50

responses seen in this trial were 61% versus 15%

of treated and placebo groups, respectively [11].

These results are summarized in Fig. 4. In addition

to PASI, all other physician-assessed measures of

disease severity achieved statistical significance by

week 12.

This efficacy noted by the investigators was also

paralleled by improvements in patient-reported out-

come measures. Patients periodically evaluated the

extent of their symptoms using an Itching scale and

the bipartite PSA scale, which incorporated symp-

tom frequency and severity subscales. At week 12,

•

•

•

•

MHC

B7 CD28

CD3

Activated APCImmunologic Synapse

Memory T Cell

LFA-1ICAM-1

CD11a

Antigen-Peptide

LFA-3CD4/CD8

TCR

CD2CD40LCD40

Costimulatory Molecules

LFA-1ICAM-1

T-Cell Reactivation, Proliferation, and Cytokine Production

T-CellActivation Signals

Costimulatory Signals

Cytokine production

Keratinocyte hyperproliferation

Inflammatory response

Effector-mediated killing response

A

Fig. 2. Mechanism of action. (A) In binding to CD11a, efalizumab disrupts the interaction of LFA-1 and ICAM-1, interfering

with the activation of T cells as a primary or secondary event. (B) ICAM is expressed by endothelial cells in sites of

inflammation. By disrupting the binding of LFA-1 to ICAM-1, efalizumab interferes with T-cell trafficking from the circula-

tion into the dermis and epidermis. As a consequence, blood lymphocyte counts are increased (but still normal) in efalizumab-

treated patients.

C.L. Leonardi / Dermatol Clin 22 (2004) 427–435 429

150

100

50

0

0 2 4 6 8

Week

Available CD11a binding sites during and after8 weeks of treatment with efalizumab

Per

cent

age

ofP

retr

eatm

ent L

evel

s

No TreatmentTreatment

10 12 14

Fig. 3. Efalizumab rapidly saturates CD11a binding sites on lymphocytes when administered intravenously or by subcutaneous

routes. On discontinuation of therapy, the number of binding sites quickly returns to pretreatment levels.


improvements were found in the Itching scale (38%

versus �0.2% for placebo, P < 0.001) andin the

frequency (48% versus 18% for placebo, P < 0.001)

and severity (47% versus 17% for placebo, P < 0.001)

of symptoms as assessed by the PSA subscales. The

functional and psychosocial impact of psoriatic symp-

toms on patients’ lives was captured using the DLQI

[14]. Overall DLQI scores at week 12 were signifi-

cantly improved as compared with placebo (47%

versus 14%, P < 0.001) [10]. These data demonstrate

70

Per

cent

of P

atie

nts

60

50

40

30

20

10

0Study 1

(n = 354)Study 2

(n = 556)

Fig. 4. Percentage of patients achieving PASI-75 or PASI-50 in efal

from three placebo-controlled trials are shown. Statistical significan

50 levels as compared with placebo.

that efalizumab improved patient functionality, pa-

tient well-being, and the symptoms most important to

patients with psoriasis, resulting in improved health-

related quality of life.

Intermediate-term results

One of the phase 3 trials showed that prolonging

efalizumab therapy from 12 to 24 weeks improved

Study 3(n = 332)

PASI-50

PASI-75

PASI-50

PASI-75

Efalizumab

Placebo

izumab-treated (1 mg/kg/wk) and placebo groups. The results

ce was achieved in all three trials at both PASI-75 and PASI-

70

*P < 0.001 vs placebo

Placebo(n=187)

Efalizumab1.0 mg/kg/wk

(n=369)

Efalizumab1.0 mg/kg/wk

(n=368)

60

50

40

30

20

10

0

24 Weeks

66.6%

43.8%

58.5%*

26.6%*

13.9%

4.3%

12 Weeks

PASI 75

PASI 50

Per

cent

age

of P

atie

nts

(%)

Fig. 5. Percentage of patients achieving PASI-75 at the primary endpoint (week 12) of a blinded, placebo-controlled trial and also

in an open-label treatment extension to 24 weeks. Significant numbers of patients improved in the 12- to 24-week time period.


response rates and maintained clinical responses.

Significant additional improvement was noted,

with 44% and 67% of patients achieving PASI-75

and PASI-50, respectively. These results are shown

in Fig. 5 [10]. As might be expected, the patient-

reported outcome measures were also maintained or

improved throughout this extended dosing period

[15–18].

Long-term results

An ongoing open-label phase 3 trial is examining

the efficacy and safety of patients treated with up to 3

years of continuous efalizumab therapy. To date, this

Main

MMonth 9Month 6Month 30

10

20

30

40

60

70

5041.3%

13.0%

22.4%

56.6% 57

51.7%

First 12 Weeks

24.5%

Per

cent

age

of P

atie

nts (n = 339)

Fig. 6. Percent of patients achieving PASI-75 and PASI-90 during

will last 36 months. The analysis is intent-to-treat with respect to

was carried.

is the longest ongoing trial evaluating the use of a

biologic therapy in patients with psoriasis.

Three hundred and thirty-nine patients entered the

trial and received efalizumab for 3 months. At the end

of this initial dosing period, 290 patients (82%)

achieved either a PASI-50 response or an OLS of

‘‘mild’’ or ‘‘clear’’ and were allowed to continue in

the maintenance phase of the trial for up to 3 years. A

preliminary analysis of this ongoing trial shows

excellent results: at 21 months, 55.9% of patients in

the maintenance period achieved PASI-75. Further-

more, 30% (more than half) of these patients are

PASI-90 responders (Fig. 6) [13]. The clinical re-

sponse of a long-term treatment patient and the

kinetics of his response are shown in Fig. 7. Collect-

tenance Period (ITT* n = 290)PASI 75

PASI 90

Month 21Month 18Month 15onth 12

.2%

25.9%

58.3% 56.2%

29.0%33.4%

55.9%

30.0%

21 months of continuous therapy. This study is ongoing and

entry into the maintenance period and the last observation

Before Treatment Day 84

PASI = 15BSA = 18%

PASI = 0BSA = 0%

A

16

14

12

10

8

6

4

2

0

20

18

1614

12

10

86

BS

A %

42

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

PASI Score

BSA %

21 22 23 24

PA

SI S

core

Month

B

Fig. 7. (A) Patient response to efalizumab therapy. *Tattoo has been covered to protect patient’s privacy. (B) Reduction in PASI

and body surface area (BSA) in response to continuous efalizumab therapy. By 24 months, the patient maintained complete

control of his psoriasis by weekly subcutaneous injections.


ively, these results demonstrate that efalizumab rap-

idly controls psoriasis symptoms and also seems to be

an effective long-term maintenance treatment.

Safety

With 2762 patients with psoriasis treated in 13

clinical trials, efalizumab represents the largest evi-

dence base in the psoriasis population for a biologic

therapy. To date, more than 2400 patients have re-

ceived efalizumab for at least 3 months, 904 for up to

6 months, and more than 225 for up to 1 year.

In general, efalizumab has been well tolerated.

Some patients experience acute flulike symptoms

when efalizumab therapy is initiated, however, in-

cluding headache, chills, fever, nausea, and myalgia.

During phase 3 trials, these events most commonly


occurred within 48 hours after administration of the

first two doses and were primarily mild to moderate

in severity and well tolerated when a conditioning

dose (0.7 mg/kg) was administered the first time. By

the third and all subsequent doses, the incidence of

these acute adverse events was similar to placebo [8].

In the trials, fewer than 1% of patients withdrew from

efalizumab treatment because of adverse events. The

adverse events that occurred at least 2% more fre-

quently in efalizumab versus placebo groups during the

first 12 weeks of treatment in randomized, placebo-

controlled, double-blind phase 3 trials are summarized

in Table 1.

Patients receiving long-term efalizumab therapy

did not exhibit any increased incidence of adverse

events over time nor did the safety profile change

over time [12,13,19]. To date, there has been no evi-

dence for cumulative toxicity or end-organ damage,

or increased risk of infection or malignancy with

prolonged dosing [13].

Serious adverse reactions occurred infrequently

and included serious infections requiring hospitaliza-

tion (0.3% of efalizumab patients versus 0.1% of

placebo patients), thrombocytopenia with platelet

counts lower then 52,000 (0.3% of patients), and

worsening of psoriasis requiring hospitalization

(0.7% of patients).

As part of the trial design, some patients abruptly

stopped therapy after 12 weeks of treatment. Al-

though most had a gradual recurrence of their disease,

13.8% experienced significant worsening of their

psoriasis and achieved the National Psoriasis Foun-

dation definition of ‘‘rebound’’ (PASI-125 as com-

pared with baseline or emergence of a new psoriasis

morphology within 12 wk on discontinuation of

treatment). An analysis of patients who experienced

Table 1

Adverse events in placebo-controlled study periods reported at a 2

Adverse event Placebo (N = 715)

Headache 159 (22%)

Infectiona 188 (26%)

Chills 32 (4%)

Nausea 51 (7%)

Generalized pain 38 (5%)

Myalgia 35 (5%)

Flu syndrome 29 (4%)

Fever 24 (3%)

Back pain 14 (2%)

Acne 4 (1%)

The most common adverse reactions associated with efalizumab

chills, fever, nausea, and myalgia within 2 days following the firsa Includes diagnosed infections and other nonspecific infection

Data from Raptiva (efalizumab) [package insert]. South San Franc

rebound showed that it was most likely to occur in

those who failed to achieve PASI-50 (ie, nonrespond-

ers). In addition, some patients randomized to receive

placebo also had worsening of their psoriasis and

achieved PASI-125.

Antibodies to efalizumab were predominantly

low-titer, detected in 6.3% (67 of 1063) patients

and clinically irrelevant [20]. To date, the presence

of anti-efalizumab antibodies has not been associated

with changes in efficacy, safety or efalizumab phar-

macodynamics [8].

The combined safety and efficacy profiles suggest

that efalizumab is appropriate for continuous treat-

ment and represents a significant advance not only for

patients with psoriasis but also for the dermatologists

attempting to treat them.

Practical concerns

Given as a once-weekly subcutaneous injection,

patients can self-administer efalizumab at home once

they are trained and have demonstrated competency

in reconstituting the drug, in loading the syringe, and

in administering the injection. Patients receive the

following: a 4-week supply containing four single-

use vials, each containing 125 mg of efalizumab as a

sterile lyophilized powder; preloaded single-use sy-

ringes containing 1.3 mL of sterile water; alcohol

swabs; instructions; and telephone support numbers,

if necessary. The experience from one trial showed

that patients rapidly learned this process and most

found self-administration ‘‘easy’’ or ‘‘very easy’’ [21].

When efalizumab therapy is initiated, a single

0.7-mg/kg subcutaneous conditioning dose is recom-

mended to diminish the incidence and severity of

% or higher rate in efalizumab than placebo groups

Efalizumab (1 mg/kg/wk) (N = 1213)

391 (32%)

350 (29%)

154 (13%)

128 (11%)

122 (10%)

102 (8%)

83 (7%)

80 (7%)

50 (4%)

45 (4%)

were a first-dose reaction complex that included headache,

t two doses.

s (most commonly upper respiratory tract infection).

isco, CA: Genentech, Inc.; 2003.


acute adverse events. This dose is followed 1 week

later by subcutaneous efalizumab (1 mg/kg/wk), with

no single dose to exceed 200 mg. Patients should be

instructed to rotate the injection sites between the

thigh, abdomen, buttocks, and upper arm with each

dose. Several studies have shown that efalizumab at

1 mg/kg/week is the optimal dose and that increasing

to 2 mg/kg/week or even 4 mg/kg/week is unlikely to

provide additional benefit.

Efalizumab is best used as a continuous therapy

for psoriasis. Because the effects of efalizumab on

T cells are reversible, recurrence of disease is ex-

pected on discontinuation. The rebound phenomenon

is easily avoided by transition to alternative treat-

ments in patients who must permanently stop therapy

or in those who fail to respond.

During therapy, patients should be monitored for

signs and symptoms of thrombocytopenia, and as-

sessment of platelet counts is recommended on ini-

tiating therapy and periodically while receiving

treatment. Efalizumab should be discontinued if

thrombocytopenia occurs.

Because efalizumab is a T-cell modulator, caution

should be exercised in patients with a history of re-

current or chronic infection, and treatment should

be temporarily stopped in patients with clinically

significant infections. Efalizumab should not be rou-

tinely combined with other immunosuppressive thera-

pies without close supervision. The most relevant

circumstance for dermatologists will involve transi-

tion on or off therapy. Additional studies are under-

way to evaluate various entry or exit strategies.

Because the role of efalizumab in the development

of malignancies is not clear, caution should be

exercised in high-risk patients, and treatment should

be discontinued in the event of malignancy. Excep-

tions to this situation might include development

of basal cell carcinoma or cutaneous squamous cell

carcinoma. Until more data have accrued, a conser-

vative approach is recommended.

The safety and efficacy of vaccines administered

to patients receiving efalizumab have not been fully

characterized. An early study assessing the develop-

ment of humoral immunity in response to inocula-

tion with a neoantigen suggested that efalizumab

might decrease immune responses on rechallenge.

Until more data exist, live or live-attenuated vaccines

should be avoided.

Summary

Efalizumab is a new therapeutic option that may

simplify psoriasis management for some patients. It

is approved as a single, once-weekly, subcutaneous

injection for continuous administration in adults with

moderate to severe chronic plaque psoriasis. Continu-

ous therapeutic use, without the need for rotation to

a new therapy or intermittent treatment discontinua-

tion, represents an advance in psoriasis management.

The results of multiple randomized, placebo-con-

trolled, double-blind phase 3 trials have demon-

strated consistent efficacy, and the safety database is

the largest to date of a biologic therapy approved for

psoriasis. In each trial, all efficacy endpoints reached

statistical significance relative to placebo. Efalizumab

is associated with a rapid onset of action, with im-

provement relative to placebo observed as early as 2 to

4 weeks after start of therapy. Patients achieve signif-

icant clinical benefit, as measured both by physician-

and patient-assessed outcomes, and this benefit is

maintained over the course of prolonged treatment

periods. Efalizumab seems to provide rapid, sustain-

able symptom control, which allows patients to return

to their normal activities of daily living.

Biologic therapies, such as efalizumab, are chang-

ing the treatment landscape by offering hope for

improved patient safety and uninterrupted control of

psoriasis. Efalizumab seems to be appropriate for a

wide range of patients, with convenient and well-

tolerated dosing schedules. The efficacy, safety, and

tolerability of prolonged efalizumab therapy demon-

strate the therapeutic value of this new agent in the

management of patients with moderate to severe

chronic plaque psoriasis.

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[1] Weinstein GD, White GM. An approach to the treat-

ment of moderate to severe psoriasis with rotational

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[2] Das PK, de Boer OJ, Visser A, Verhagen CE, Bos JD,

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[3] Bauer RJ, Dedrick RL, White ML, Murray MJ, Garo-

voy MR. Population pharmacokinetics and pharmaco-

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pharm 1999;27(4):397–420.

[4] Gottlieb A, Krueger JG, Bright R, Ling M, Lebwohl

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[5] Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R,

Walicke PA, Garovoy M. Psoriasis as a model for

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an anti-CD11a antibody. Arch Dermatol 2002;138(5):

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[6] Gottlieb AB, Miller B, Lowe N, Shapiro W, Hudson C,

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[7] Papp K, Bissonnette R, Krueger JG, Carey W, Gratton

D, Gulliver WP, et al. The treatment of moderate to

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[8] Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer

S, Tawfik NH, et al. A novel targeted T-cell modulator,

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349:2004–13.

[9] Gordon KB, Toth D, Papp KA, Hamilton TK, Walicke

P, Li N, et al. Efalizumab provides rapid clinical bene-

fit for patients with moderate to severe plaque psoria-

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Symposium. New York, June 17–22, 2003.

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[12] Menter A, Toth D, Glazer S, Walicke P, Li N, Garovoy

M, et al. Efficacy and safety of 24-week continuous

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American Association of Dermatology Academy. Chi-

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[13] Gottlieb AB, Gordon KB, Koo J, Lebwohl M, Walicke

P, Li N, et al. Long-term efalizumab treatment main-

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Dermatol Clin 22 (2004) 437–447

Psoriasis and its treatment with infliximab-mediated tumor

necrosis factor a blockade

Laura Winterfield, MDa, Alan Menter, MDa,b,c,*

aDepartment of Dermatology, University of Texas Southwestern Medical School, Dallas, TX, USAbBaylor University Medical Center, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA

cTexas Dermatology Associates, Dallas, TX, USA

Psoriasis is a chronic inflammatory skin condi- mately 15% of patients, joint pain presents before

tion, affecting approximately 2% of the US popula-

tion [1–3]. It is seen predominantly in whites ( > 80%

of cases) and occurs equally in men and women, with

a typical onset between the age of 20 and 30 years

[2]. Marked familial aggregation (30%) and a high

concordance rate in monozygotic twins (65%–72%)

indicate the role of a multifactorial genetic predispo-

sition in the emergence of psoriasis [4].

Psoriasis can be triggered in predisposed persons

by several factors, including bacterial infections, in-

flammatory insults, local trauma, psychologic stress,

drugs (eg, lithium, b-blockers, and antimalarial

agents), alcohol, and overexposure to the sun [5–8].

Skin involvement may range from minimal, with

small focal lesions on the elbows, knees, or scalp, to

extensive, with areas on the torso and extremities and,

in rarer instances, whole body involvement. The most

common plaque-type psoriatic lesions are usually

easily recognized by the presence of three cardinal

signs: acanthosis, erythema, and white or silvery

scales. Pruritus and nail dystrophy are frequently

associated. A subset of patients with psoriasis (up to

35%) develop or exhibit a progressive, inflammatory

arthritis (psoriatic arthritis [PsA]), marked by joint

swelling and pain; in most patients (�75%), psoriatic

skin lesions precede such arthritis, whereas in approxi-


doi:10.1016/j.det.2004.03.011

Support for this article was provided by an unrestricted

grant from Centocor, Malvern, Pennsylvania.

* Corresponding author. Baylor UniversityMedical Cen-

ter, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230.


(A. Menter).

obvious skin lesions [9].

Treatment options for psoriasis vary widely with

respect to mechanism of action, route of administra-

tion, efficacy, and adverse event risk. Minor skin

involvement usually responds well to topical therapy

(eg, corticosteroid-, vitamin D3-, or retinoid-contain-

ing products), and these formulations are associated

with a low risk of troublesome side effects. Such

treatments target local epidermal inflammation and

acanthosis caused by keratinocyte hyperproliferation.

In those patients with a larger area of involved skin

or more severe symptoms, traditional phototherapy,

ultraviolet B, and combined psoralen/long-wave

ultraviolet radiation (PUVA), or systemic therapy,

including oral retinoids, methotrexate, and cyclospor-

ine, is required. These approaches have been shown to

be highly effective in clearing psoriatic lesions [10,11]

but may be associated with side effects, such as

hepatotoxicity (methotrexate) and nephrotoxicity (cy-

closporine) [11,12], teratogenicity and skeletal hyper-

ostosis (oral retinoids) [13], and cancer (PUVA,

cyclosporine) [14,15], which limit their long-term use.

The safety limitations of conventional systemic

treatments, however, and a growing understanding of

the pathogenesis of psoriasis have stimulated intense

interest in inhibiting the immunologic processes that

contribute to the causes of psoriasis.

Tumor necrosis factor in the pathogenesis of

psoriasis

Psoriasis is an immune disease of activated T cells

and an exaggerated inflammatory response in the skin

s reserved.

L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447438

[16]. After passage through the skin’s endothelial

cells, activated T cells secrete type 1 (Th1) cytokines:

interferon l, interleukin 2 (IL-2), IL-6, IL-8, IL-12,

and tumor necrosis factor a (TNF-a) [17]. These

proinflammatory cytokines mediate several biologic

actions, which perpetuate and amplify the inflamma-

tory response, including induction of keratinocyte

proliferation and dermal vascular changes. Because

these cytokines ‘‘drive’’ skin inflammatory reactions

and other immune responses, an emerging therapeutic

strategy is selective deactivation of specific cyto-

kines. As a key contributor to the clinical features

of psoriasis, TNF-a is now considered an important

therapeutic target in drug development.

TNF-a exists as both transmembrane and soluble

proteins. The membrane-bound form of TNF-a is

cleaved by an enzyme to release a soluble circulating

form. Both forms of TNF-a are believed to be

biologically active. The soluble form may be more

potent, however [18]. TNF-a can be produced by

multiple cells of the body, including cells present in

the dermis and epidermis of patients with psoriasis,

such as activated T cells, keratinocytes, and Langer-

hans cells [19].

The concentrations of TNF-a and other inflam-

matory mediators in lesional skin from patients with

Table 1

Correlation between cellular actions of TNF-a and pathogenic me

Cellular action of TNF-a C

Stimulates synthesis of proinflammatory cytokines, such as

IL-1, IL-6, IL-8, and RANTES [74,75]

H

T

I

Activates NFkB, a nuclear transcription factor [74,75,77] D

Stimulates transcription of keratin-6 gene promoter [79] A

Retards progression of keratinocyte cell cycle [85] D

Induces SKALP/elafin gene in keratinocytes [81] E

n

r

Increases type 1 vasoactive intestinal peptide receptor

mRNA in keratinocytes [78]

P

s

Increases plasminogen activator inhibitor type 2, a serine

proteinase inhibitor [84]

P

Stimulates production of ICAM-1 and other adhesion

molecules [73,83]

F

Increases VEGF directly and increases production of

nitric oxide necessary for the induction of VEGF [76,86]

P

v

Decreases E-cadherin expression [82] F

o

i

Increases expression of CD44, a cell surface receptor

for hyaluronate [80]

P

Abbreviation: VEGF, vascular endothelial cell growth factor.

psoriasis are up-regulated [17,20]. Immunolabeling

of TNF-a and its receptors is increased when com-

pared with uninvolved skin. Furthermore, increases in

TNF-a production by monocytes in the blood of

patients with both active and inactive psoriasis cor-

relate with the clinical severity of the psoriasis [21].

Also, the distribution of TNF-a differs between

psoriatic and normal skin. In normal skin, TNF-a is

found mainly in the epidermal basal cell layers and

around eccrine ducts and sebaceous glands. In psori-

atic skin, TNF-a is present throughout all epidermal

layers and upper dermal blood vessels [22].

Through its pleiotropic actions, TNF-a is likely to

be an important stimulus for the events leading to

psoriasis, as summarized in Table 1. The presence of

TNF-a within the dermis recruits macrophages to the

area and induces secretion of other proinflammatory

cytokines and chemokines. The interaction of TNF-awith the vascular endothelium leads to the enhanced

expression of certain adhesion molecules and vascu-

lar endothelial growth factor, which encourages an-

giogenesis and facilitates migration of inflammatory

cells. Finally, the increased production of proinflam-

matory cytokines, which is at least partially triggered

by TNF-a, causes keratinocyte hyperproliferation.

These actions serve to amplify, propagate, and main-

chanisms of psoriasis

orrelation with psoriasis pathogenesis

yperproliferative epithelium; proliferation of keratinocytes;

-cell and neutrophil activation; chemotaxis; increases

CAM-1 mRNA

ecreases in the rate of apoptosis among keratinocytes

ctivates keratinocytes

ecreases the rate of apoptosis among keratinocytes

xpresses a proteinase inhibitor that the keratinocytes of

ormal skin do not express and that is involved in the

egulation of the cutaneous inflammatory process

romotes keratinocyte proliferation and stimulates

ynthesis of proinflammatory cytokines.

rotects cells from apoptosis

acilitates T-cell infiltration into the skin

romotes angiogenesis; with the creation of new blood

essels, T cells have increased access into the epidermis

acilitates Langerhans cell emigration and the initiation

f immune responses against antigens encountered

n epidermis

romotes migration of Langerhans cells from the epidermis

L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447 439

tain the abnormal inflammatory response that is

responsible for psoriasis and serve as the rationale

for use of TNF-a–blocking agents for the treatment

of this disease.

Characterization of infliximab

Infliximab (Remicade; Centocor, Malvern, Penn-

ysylvania) is a TNF-a–blocking agent approved for

treatment of Crohn’s disease and rheumatoid arthritis

(RA). It is a chimeric anti–TNF-a monoclonal anti-

body made by joining the human IgG1 constant

region to a murine-derived antigen-binding variable

region [23]. Infliximab binds with high affinity to

both soluble and transmembrane-bound forms of

TNF-a and, in this manner, inhibits the ability of

TNF-a to bind with its receptors and initiate the

intracellular signaling that leads to gene transcription

and subsequent biologic activity [24,25]. When pres-

ent at molar excess over TNF-a, three infliximab mol-

ecules can bind to each molecule of soluble TNF-a,thereby blocking all receptor binding sites on the

TNF. It does not bind with or inhibit the receptor-

mediated activity of TNF-b or any other known

antigen. The binding of infliximab to TNF-a is

sustained, so that likelihood of dissociation and

subsequent activity of TNF-a is low [26]. Because

of its inhibition of TNF-a activity, infliximab also

indirectly inhibits production of other proinflamma-

tory cytokines, and its combined actions are likely to

cause a reduction in proliferation of keratinocytes

[19,27]. Finally, in vitro evidence indicates that the

binding of infliximab to membrane-bound TNF-aresults in lysis of TNF-producing cells by means of

a complement- or antibody-dependent cell cyto-

toxicity mechanism. Reducing the population of such

Table 2

Randomized, placebo-controlled trials with infliximab

Study Population Treatment

IIS phase 2 [29] Mod to sev

plaque-type psoriasis

Infliximab, 5 mg/

Infliximab, 10 mg

Placebo (n = 11)

IMPACT [28] Active PsA Infliximab, 5 mg/

Placebo (n = 51)

SPIRIT [30] Mod to sev

plaque-type psoriasis

Infliximab, 3 mg/

Infliximab, 5 mg/

Placebo (n = 51)

Abbreviations: IIS, investigated-initiated study; mod, moderate; sea Open-label.b Blinded.

cells could have beneficial clinical effects, but this

finding has not yet been confirmed in vivo [25].

Clinical experience with infliximab

Randomized, controlled clinical trials

An expanding literature documents the efficacy

and safety of infliximab in the treatment of psoriasis.

Clinical experience with infliximab in psoriasis

ranges from randomized, placebo-controlled, dou-

ble-blind trials to open-label studies and case series.

Long-term follow-up studies and analyses of safety

are also beginning to appear, providing important

information about tolerability, safety, and durability

of the beneficial clinical effects seen with infliximab.

Three randomized, placebo-controlled trials of

infliximab that evaluate improvement in psoriasis

have been reported (Table 2) [28–30]. One was an

investigator-initiated study of infliximab in patients

with moderate to severe psoriasis (eg, �5% body

surface area [BSA]) [29]. This trial assigned patients

(N = 33) to receive either 5 mg/kg or 10 mg/kg of

intravenous (IV) infliximab or placebo on weeks 0, 2,

and 6 of the study, and these patients were evaluated

initially until week 10 (eg, the ‘‘induction’’ phase). At

baseline, randomized patients were clinically and

demographically similar across the groups, with a

mean age range of 35 to 51 years and mean Psoriasis

Area and Severity Index (PASI) scores of 20 to 26.

Beginning at week 2 of treatment and continuing

through week 10, decreases in psoriasis severity were

significantly greater with 5 mg/kg or 10 mg/kg of

infliximab than with placebo. At week 10, a reduction

of 75% or greater from the baseline PASI score (eg,

‘‘PASI-75’’ response) was seen in 82% and 73% of

Duration of double-blind

phase (wk)

Extension

phase (wk)

kg (n = 11)

/kg (n = 11)

10 10–26a

kg (n = 50) 16 16–32a

kg (n = 99)

kg (n = 99)

46 10–26b

v, severe.


patients given 5 mg/kg or 10 mg/kg doses of IV

infliximab, respectively, whereas only 18% of patients

treated with placebo reached this treatment goal.

The results of evaluation of psoriasis from a larger

investigator-initiated study, the Infliximab Multina-

tional Psoriatic Arthritis Controlled Trial (IMPACT),

support the results of the earlier study [29]. In

IMPACT, 102 patients with PsA who had failed

therapy with at least one traditional disease-modifying

antirheumatic drug (DMARD) were randomized to ei-

ther 5 mg/kg of infliximab or placebo, with infusions

administered at weeks 0, 2, 6, and 14. In addition to

significant improvements in joint signs and symp-

toms, based on American College of Rheumatology

response criteria, patients exhibited significant im-

provements in psoriatic skin involvement. Among

patients with a baseline PASI of 2.5 or greater, these

scores decreased from 8.4 to 1.6 at week 16 with

infliximab treatment [28]. By contrast, PASI scores

worsened for those patients receiving placebo (from

8.4 to 9.3). Approximately 67% of patients random-

ized to infliximab infusions exhibited a 75% decrease

in baseline PASI scores at week 16. Moreover, a

subset of patients (n = 69) who participated in the

IMPACT were receiving concomitant DMARD ther-

apy at baseline; among these patients, 56 received

concomitant methotrexate throughout the 16-week

study period. PASI scores remained largely un-

changed from baseline levels in those patients receiv-

ing methotrexate paired with placebo, indicating that

methotrexate alone did not exert a positive effect on

PASI scores.

The Study of Psoriasis with Infliximab Induction

Therapy (SPIRIT) trial [30] is to be fully reported at

the 62nd annual meeting of the American Academy of

Dermatology, but preliminary analysis noted rapid,

dose-related improvements in psoriatic symptoms.

The SPIRIT trial was a phase 2 multicenter, double-

blind, randomized, placebo-controlled study in pa-

tients (N = 249) with plaque psoriasis affecting 10%

or more of their BSA; individuals were randomized in

a 1:2:2 ratio to either placebo (n = 51), 3 mg/kg of

infliximab (n = 99), or 5 mg/kg of infliximab (n = 99)

infusions and treated at weeks 0, 2, and 6. Concomi-

tant psoriasis therapy was prohibited with the excep-

tion of tar or salicylic acid–containing shampoos

during the study period. PASI assessments, quality-

of-life questionnaires, and physician global ratings

were scheduled every 2 weeks through week 10.

Sustained efficacy of infliximab

Results from extension phases in all three ran-

domized trials of infliximab have been reported and

provide evidence of sustained efficacy (see Table 2).

In the earlier investigator-initiated study, investigators

followed up patients for an additional 16 weeks. At

week 26, 33% and 67% of patients who received

5 mg/kg or 10 mg/kg, respectively, maintained a 75%

improvement in PASI. Individuals were given single

infusions of infliximab if a loss of response occurred

(eg, <50% reduction in baseline PASI score) [31]. At

week 26, 9 (41%) of 22 patients who had received

infliximab during the double-blind phase exhibited a

loss of response and required one or two additional

infliximab infusions. This retreatment largely im-

proved PASI scores but not to the extent seen with

a full induction regimen.

The 34-week (weeks 16–50) open-label extension

of the IMPACT in patients with PsA showed that

intermittent retreatment with infliximab effectively

maintained skin and joint improvements [28]. In-

fusions of 5 mg/kg infliximab (at weeks 16, 18, 22,

30, 38, and 46) were administered to patients who had

initially received either placebo or infliximab during

double-blind infliximab treatment. Twelve (86%) of

14 patients who exhibited a PASI-75 response at

week 16 sustained that level of improvement at week

50. The mean reduction in baseline PASI score was

81% at week 50. Moreover, patients who were

initially given placebo and then switched to inflixi-

mab exhibited skin and joint responses of a similar

magnitude to those who had received infliximab

during the blinded phase of the study.

The SPIRIT trial provided data during weeks 14

to 26 for 198 patients who received no further in-

fliximab treatment after the initial three infusions at

weeks 0, 2, and 6 [32]. At week 26, 14% and 30% in

the 3-mg/kg and 5-mg/kg groups, respectively, main-

tained a 75% improvement in PASI.

Collectively, the results of the extension phases of

the randomized studies demonstrated that the benefit

of infliximab induction treatment persists over time

and is dose dependent, but is variable for individual

subjects. Moreover, the data suggest that infrequent

maintenance dosing may sustain clinically meaning-

ful therapeutic responses for most patients.

Uncontrolled, open-label trials

Six uncontrolled trials of infliximab in patients

with psoriasis or PsA have been reported (Table 3)

[33–38]. These noncomparative trials examined re-

sponse to infliximab therapy among small groups of

patients (N = 6 to 16) with severe psoriasis or PsA

refractory to other systemic therapies. Patients in these

studies had undergone one or more courses of treat-

ment with PUVA or DMARDs, such as methotrexate,

Table 3

Noncomparative trials with infliximab

First author Population N Treatmenta Duration

Antoni [33] All with PsA 10 Infliximab, 5 mg/kg induction and

then intermittently

12 mo

Salvarani [37] All with PsA 16 Infliximab, 3 mg/kg, at 0, 2, 6, 14, 22,

and 30 wk

30 wk

Cauza [34] All with PsA 9 Infliximab, 3 mg/kg, at 0, 2, 6, 14,

and 22 wks

22 wk

Ogilvie [36] All with PsA 6 Infliximab, 5 mg/kg, at 0, 2, and 6 wk 10 wk

Chan [35] 5 with psoriasis; 2 with PsA 7 Infliximab, 5 mg/kg, intermittently 15 mo

Schopf [38] All with psoriasis 8 Infliximab, 5 mg/kg, at 0, 2, and 6 wk 10 wk

a Patients continued stable doses of other antiarthritis/psoriasis drugs.


but continued to exhibit PASI scores indicating sub-

stantial skin involvement. Across these studies, inflix-

imab was administered as an ‘‘induction’’ regimen of

either 3 mg/kg or 5 mg/kg at weeks 0, 2, and 6, and

thereafter on an individualized basis or, in the case of

longer-term studies, on an intermittent schedule. Fur-

thermore, patients were usually maintained on a stable

dose of the pre-existing treatment regimen.

The magnitude and timing of improvements in

psoriatic skin lesions seen in these noncomparative

trials were largely comparable to those observed in the

controlled trials. For example, Antoni et al [33] treated

10 patients with PsA with a 5-mg/kg infliximab

induction regimen and reported an average decrease

of 71% in PASI score at week 10. Likewise, Schopf

et al [38] found that a 5-mg/kg infliximab induction

regimen in eight patients resulted in a mean decrease

of 89% in PASI at week 10. At week 14, 8 weeks

following the last infliximab infusion, PASI scores

were decreased by an average of 66% from baseline.

Maintenance treatment over longer periods seems

to preserve initial treatment response. For instance,

after 44 weeks of intermittent infliximab treatment

(every 8 wk), 8 of the 10 patients in the study

reported by Antoni et al [33] exhibited PASI scores

that decreased by an average of 71.3%. Similarly, in

the largest uncontrolled trial, 16 patients with severe

treatment-refractory PsA, treated with 3-mg/kg in-

fliximab infusions at three consecutive 8-week inter-

vals following an initial induction regimen, continued

to show a robust treatment response. At week 30, PASI

scores were decreased by an average of 86% from

baseline [37]. Quality-of-life instruments showed that

the improvement in skin involvement seen with long-

term infliximab treatment can also have a significant

positive effect on patients’ personal and health-related

quality of life. Among patients repeatedly hospitalized

for severe, recalcitrant psoriasis, those who received

repeated intermittent infusions no longer required

hospitalization and exhibited significant improve-

ments in quality of life, marked by the ability to return

to full-time employment [35].

Thus, the results from these uncontrolled studies

support those of the randomized trials, showing that

infliximab is highly effective for the rapid improve-

ment of severe psoriasis and PsA; furthermore, they

suggest that prudent intermittent treatment seems to be

critical for maintaining clinically relevant responses.

Case series

The first report of the efficacy of infliximab in

treating psoriasis described the case of a 57-year-old

woman who had refractory inflammatory bowel dis-

ease treated with infliximab. Infliximab infusion

dramatically improved the patient’s psoriasis [39].

Since this observation, a growing number of case

reports documenting the use of infliximab for psoria-

sis and PsA have appeared in the literature. They

describe the treatment of patients (a total of 20 cases)

who had longstanding, recalcitrant, or severe disease,

affecting more than 50% of their BSA, including the

face, hands, feet, and scalp [40–49]. In several

instances, patients presented relatively uncommon

types of psoriasis, including pustular, palmoplantar,

and erythrodermic forms [41,43,47,49]. In some

cases, patients had undergone prior treatment with

most available topical, phototherapy, and systemic

approaches, with skin lesions remaining refractory to

therapy. As might be expected, many of these patients

reported impaired quality of life, psychosocial diffi-

culties, and depression [42,49].

In nearly all patients, infliximab treatment con-

sisted of infusions of 3 to 10 mg/kg at weeks 0, 2, and

6, with intermittent maintenance treatments thereafter.

Patients were maintained on pre-existing treatment

regimens, often involving several agents, including

methotrexate, cyclosporin and topical therapies, and


nonsteroidal anti-inflammatory drugs for manage-

ment of pain in patients with PsA. With the addition

of infliximab to their treatment regimen, most

patients (16 of 20) exhibited dramatic improvements

in skin involvement. After 4 weeks of treatment

among patients who responded well to infliximab

treatment, lesions were described as reduced in area

and severity, with improvements characterized by a

significant reduction in redness and thickness, and

healing of individual fissures. In some patients, PsA-

related clinical symptoms, such as joint swelling and

tenderness, also improved.

Safety of infliximab

More than 432,000 patients worldwide have re-

ceived single or multiple doses of infliximab. Inflixi-

mab has been approved for use in moderate to severe

or fistulizing Crohn’s disease, refractory to conven-

tional therapies, and for combined use with metho-

trexate in RA, refractory to methotrexate alone.

Therefore, infliximab’s 10-year safety experience

comprises predominantly patients with these condi-

tions. Interpolating the adverse event profile of inflixi-

mab for patients with psoriasis from the safety

database for patients with Crohn’s disease and RA

may skew the analysis. Crohn’s disease and RA are

chronic, debilitating systemic diseases associated

with comorbidities for which patients may also be

receiving other immunosuppressive therapies. Ac-

cordingly, the safety experience in these conditions

may be less favorable than would be anticipated in

patients receiving monotherapy with infliximab for

moderate to severe psoriasis. Alternately, additional

safety issues may be identified with expanded studies

in a new patient population, such as in those with

psoriasis alone.

Safety and tolerability of infliximab in rheumatoid

arthritis and Crohn’s disease

Overall, infliximab has been well tolerated in

controlled clinical trials involving patients with RA

and Crohn’s disease. An integrated safety database

is available that comprises nine open-label and pla-

cebo-controlled clinical trials involving 453 patients

(Crohn’s disease, RA, and ulcerative colitis) who

received at least one dose of infliximab [50]. The

most frequent adverse events reported in 10% or more

of infliximab-treated patients included headache, nau-

sea, and upper respiratory tract infection (URI). Less

frequently reported adverse events included abdomi-

nal pain, pharyngitis, fever, vomiting, coughing, rash,

pain, rhinitis, sinusitis, urinary tract infection, fatigue,

and pruritus. Infection was seen in 21% of patients

given infliximab compared with 11% in those given

placebo. Serious adverse events associated with in-

fliximab have been infrequent. Seven (1.5%) of

453 patients developed a lymphoproliferative disorder

while undergoing infliximab therapy.

A broader analysis, including 913 patients with

RA or Crohn’s disease exposed to infliximab, showed

that the rate of malignancy with infliximab was low

and similar to rates expected in the general population

based on the National Institutes of Health SEER

database [50] Although safety statistics like these

are encouraging, the long-term data still remain in-

sufficient to answer the question of an increased risk

for lymphoproliferative disorders and other malignan-

cies [51]. Continued surveillance of all infliximab-

treated patients is ongoing in an effort to conclusively

define this issue.

In the overall safety database analysis, infusion

reactions, defined as any adverse event occurring

during the infusion period or the 2-hour postinfusion

observation period, were more common among inflixi-

mab-treated patients compared with those receiving

placebo (16% and 6%, respectively) [50]. Among

1207 infliximab infusions, 5% (58 of 1207) were

associated most commonly with nonspecific symp-

toms. Of these reactions, only four (0.03%) were

considered serious; they were characterized by car-

diopulmonary symptoms, such as chest pain, palpita-

tions, hyper- or hypotension, and dyspnea [50]. In

another report [52] documenting the frequency of

infusion reactions to infliximab in 165 consecutive

patients with Crohn’s disease, the overall incidence of

infusion reactions was 6.1% (29 of 479) of infusions,

affecting 9.7% (16 of 165) of patients. Mild, moder-

ate, or severe acute reactions occurred in 3.1% (15 of

479), 1.2% (6 of 479), and 1.0% (5 of 479) of

infliximab infusions, respectively. Typically, symp-

toms improved substantially or resolved completely

after infusion rate adjustments alone or the addition of

treatment with acetaminophen and antihistamines.

Less commonly, steroids or epinephrine was admin-

istered. Pretreatment with these agents may also limit

the reactions.

Safety and tolerability of infliximab in psoriasis

The safety experience for infliximab in patients

with psoriasis is considerably smaller than that in the

integrated analysis of safety in patients with Crohn’s

disease and RA in clinical studies. In the investigator-

initiated study reported by Chaudhari et al [29],

headache was the only adverse event that occurred

more often with infliximab than with placebo. Infu-

sion reactions were seen during the 16-week post-

induction study phase in 4 (14%) of 29 patients treated


with infliximab; these were all considered mild and

transient [31]. Unlike the pattern of adverse events

seen in the integrated analysis of infliximab safety

data [50], the frequency of infection (including cellu-

litis in the placebo group and dental abscess, com-

munity-acquired pneumonia and otitis externa in the

infliximab group) was similar between the placebo

and infliximab groups (infliximab, n = 7; placebo,

n = 6) [29]. This variance may be related to differ-

ences in the patient populations, with respect to

morbidity and history of immunosuppressant use or

the small patient numbers. In the SPIRIT trial, the

most frequent adverse events in infliximab-treated

patients were headache, pruritus, and URI [32]. The

most frequently reported infections were URIs, sinus-

itis, and pharyngitis, the latter two occurring more

frequently in the infliximab-treated groups compared

with placebo. This finding may have been in part

because of the shorter follow-up period in the placebo

group. Similarly, in the IMPACT, the most frequent

adverse events in infliximab-treated patients were

URI, headache, nausea, sinusitis, and rash [53]. One

patient developed an infection of the knee [28]. No

opportunistic infections were reported in any of these

three studies.

Reactivation of latent tuberculosis

Most people infected with Mycobacterium tuber-

culosis contain the initial infection and develop latent

tuberculosis (TB). This state is characterized by evi-

dence of an immune response against the bacterium

(a positive tuberculin skin test [TST]), but no signs of

active infection, including the absence of symptoms

or chest radiograph evidence of disease [54]. The

incidence of a positive TST without signs of active

infection is approximately 1% in non-Latino individ-

uals born in the United States, but may be higher in

other ethnic groups [55]. Serious cases of reactivation

of latent TB (both disseminated and nondisseminated

presentations) have been reported with all TNF-ainhibitors [56–59]. Through February 2003, there

were 537,000 patient years of exposure to infliximab

in the United States and 109 cases of TB reported in

infliximab-treated individuals. Thus, before starting

TNF-a inhibitor therapy, patients should be screened

for latent TB infection with a TST.

Congestive heart failure

Experimental evidence has suggested that TNF-amay be implicated in the pathogenesis of heart failure

[60]. Three large-scale clinical trials of TNF-a inhibi-

tors in patients with advanced congestive heart fail-

ure (CHF)—one 150-patient study of infliximab [61]

and two etanercept (a fusion protein directed against

TNF) trials involving a total of 2048 participants

[62]—were prematurely halted for lack of benefit or

adverse outcomes, prompting a warning from the US

Food and Drug Administration about the safety of

these therapies for at-risk patients with RA. In the

trial evaluating infliximab, the combined risk of death

from any cause or hospitalization for heart failure was

increased in the patients randomized to 10 mg/kg of

infliximab relative to placebo (P = 0.043). A similar

picture emerged from the two etanercept trials, which

showed that the effects of the fusion protein were not

different from placebo (P = 0.17 and P = 0.34,

respectively). In support of the observations from

these trials were reports to the MedWatch program

on 47 patients who developed new or worsening CHF

during TNF antagonist therapy. After TNF antagonist

therapy, 38 patients developed new-onset CHF and

9 patients experienced heart failure exacerbation [63].

In contrast to the findings from these three trials

and the MedWatch data, however, an abstract pre-

sented at the 2003 Annual Scientific Meeting of the

American College of Rheumatology indicated that

anti-TNF therapy conferred a cardioprotective effect

in patients with RA [64]. The report examined medi-

cal records of 13,171 patients with RA from the

National Data Bank for Rheumatic Disease over a

period of 2 years and found that among those treated

with anti-TNF therapies, the prevalence rate of CHF

was significantly reduced.

Demyelinating conditions

As TNF-a antagonists have become increasingly

used, there have been several reports of demyelinat-

ing and other central nervous system events in

patients receiving TNF antagonists [65]. Although

the causal relationship between these demyelinating

events and currently available TNF-a antagonists

remains unclear, it seems prudent to avoid use of

TNF-a antagonists in patients with a history of

demyelinating disease.

Formation of anti-infliximab antibodies

All biologic TNF-a inhibitors (eg, infliximab, eta-

nercept, and adalimumab) are ‘‘foreign’’ proteins and

therefore potentially immunogenic [66]. Antibody

data are highly dependent on the sensitivity and

specificity of the assay method used, however, so

comparison of the incidence of antibodies to inflixi-

mab with the incidence of antibodies to other products

may be misleading. Although the clinical relevance of

antibodies to the anti–TNF-a inhibitors is difficult to

define, it is possible that immune responses that


develop following treatment with foreign proteins

may limit the efficacy of such treatments and increase

the incidence of adverse events [67].

It has been shown that the development of anti-

bodies to infliximab (ATI) can be reduced by several

approaches, including appropriate dose selection, use

of concomitant immunosuppressive agents, and ad-

ministration of regular maintenance doses. The effect

of dose on antibody formation and concomitant im-

munosuppressive therapy was demonstrated in a

phase 2 RA study evaluating an infliximab induction

regimen of 1 mg/kg, 3 mg/kg, or 10 mg/kg, with and

without methotrexate [68]. With infliximab monother-

apy, 53%, 21%, and 7% of patients with RA exhibited

ATI when treated with 1 mg/kg, 3 mg/kg, and 10 mg/

kg of infliximab, respectively. Antibody titers were

reduced at each dose level with concomitant metho-

trexate to 15%, 7%, and 0%, respectively. The data for

treatment in the absence of immunosuppressant agents

are similar to the results presented for the develop-

ment of ATI in the SPIRIT trial. Following induction

dosing at weeks 0, 2, and 6, 27.5% of patients with

psoriasis receiving 3 mg/kg and 19.5% of patients

receiving 5 mg/kg of infliximab were antibody posi-

tive by week 26 [69]. Furthermore, the titer of ATI

was generally low, with 37 of 38 subjects positive

for antibodies presenting with titers less than or equal

to 1:40.

Regular maintenance dosing with infliximab has

been associated with a reduced incidence of antibody

formation in clinical studies. In a trial in patients with

active Crohn’s disease [70], individuals who received

a single infusion of infliximab showed a 28% inci-

dence of ATI compared with an 8% rate in those

receiving induction and regular maintenance in-

fusions of infliximab. Also, the frequency of ATI in

patients with RA who were administered induction

and maintenance doses of infliximab was 9%, similar

to the rate in patients with Crohn’s disease who re-

ceived maintenance infusions [71]. Additional studies

are ongoing to determine the incidence of ATI in

patients with psoriasis receiving long-term main-

tenance and intermittent treatment.

ATI may influence the frequency of infusion re-

actions [70]. A higher incidence of these events was

seen in Crohn’s disease and RA trials in patients with

ATI compared with those who were antibody nega-

tive or inconclusive for antibodies [70,72]. Most

infusion reactions were mild to moderate in nature,

and there was no correlation with the presence of ATI

and serious infusion reactions in the Crohn’s disease

and RA studies.

The potential for loss of response in conjunction

with ATI is a concern, but regular maintenance

treatment with infliximab seems to sustain response

even in the presence of ATI. For example, in patients

with Crohn’s disease who were administered mainte-

nance treatment, the proportion of subjects achieving

a clinical response after 1 year was similar in anti-

body-positive and antibody-negative subjects [70].

When infliximab is administered intermittently, how-

ever, there is evidence from a cohort of 125 consecu-

tive patients with Crohn’s disease who were treated

‘‘as needed’’ with infliximab that indicates efficacy

may decrease in patients who develop sufficient

concentrations of ATI [72]. Specifically, 36 of

53 patients initially responded well to 5 mg/kg of

infliximab, but among those who developed ATI

(n = 19), 11 (58%) exhibited a loss of response to

infliximab treatment. Moreover, none of the patients

in the trial who exhibited a continued response to

infliximab (n = 21) were ATI positive.

Summary

Evidence that the proinflammatory cytokine

TNF-a plays a major role in the development and

maintenance of psoriasis is the rationale for the use of

anti–TNF-a therapies. Infliximab is a chimeric hu-

man-murine antibody that selectively blocks the ac-

tivity of TNF-a. Randomized, controlled clinical

trials, open-label investigations, and case reports have

shown that infliximab therapy leads to rapid, sub-

stantial improvements in psoriasis lesions that are

among the highest seen with use of the systemic

agents to date. Significant improvement in psoriatic

joint involvement also has been reported. Impor-

tantly, the burden of organ toxicity with biologic

therapy is lower, with no clear indication to date of

hepatotoxicity, nephrotoxicity, skeletal changes, or

teratogenicity that may result from traditional sys-

temic therapies. As with other biologic agents, be-

cause of the relatively short-term (5–10 y) safety

data, it is impossible to be certain at this time about

the increased malignancy risk. Potential concerns

and questions related to the immunosuppressive and

immunogenic properties of infliximab, including in-

creased risk of infection, infusion reactions, and

waning therapeutic response in the psoriasis popula-

tion, are currently being fully examined and charac-

terized in phase 3 trials. The ongoing studies of

infliximab in patients with moderate to severe psoria-

sis will yield a more sophisticated understanding of

the benefits and risks associated with this treatment

option and ultimately determine the role of this

biologic agent in the psoriasis armamentarium.


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Dermatol Clin 22 (2004) 449–459

The treatment of psoriasis and psoriatic arthritis with

etanercept: practical considerations on monotherapy,

combination therapy, and safety

Paul S. Yamauchi, MD, PhDa,b,*, Vivian Gindi, MDa,b,Nicholas J. Lowe, MD, FRCPa,b

aClinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USAbDivision of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA

Etanercept is a recombinant fusion protein that is cally driven by overproduction of an inflammatory

currently approved by the Food and Drug Adminis-

tration (FDA) for the treatment of rheumatoid arthri-

tis, polyarticular-course juvenile rheumatoid arthritis,

ankylosing spondylitis, psoriatic arthritis, and in

April 2004, approved for the treatment of moderate

to severe plaque psoriasis. Etanercept is manufac-

tured by Amgen under the trade name Enbrel. Eta-

nercept is manufactured by Amgen under the trade

name Enbrel.

Etanercept was first used in human clinical studies

in 1992, and in 1995 the rheumatoid arthritis studies

were initiated. In 1998, etanercept was FDA-

approved for the treatment of rheumatoid arthritis.

Four years later, etanercept became the first FDA-

approved drug for the treatment of psoriatic arthritis.

Of all the biologic agents that are in use or potentially

will be used for the treatment of psoriasis and

psoriatic arthritis, etanercept has the longest track

record for safety data and current evidence supports

the efficacy of etanercept in the treatment of psoriasis

[1,2].

Up to 42% of patients with psoriasis develop

psoriatic arthritis [3]. Both diseases are immunologi-


doi:10.1016/j.det.2003.12.002

* Corresponding author. Clinical Research Specialists,

2001 Santa Monica Boulevard, Suite 490W, Santa Monica,

CA 90404.


(P.S. Yamauchi).

cytokine called tumor necrosis factor-a (TNF-a)[4,5]. Etanercept is a disease-modifying drug by

acting as a soluble TNF-a receptor that competitively

binds to TNF-a. Once bound to etanercept, TNF-ais prevented from binding to cell surface receptors

on target cells and its proinflammatory effects are

thereby blocked.

Role of tumor necrosis factor-A in psoriasis and

psoriatic arthritis

Tumor necrosis factor-a is a proinflammatory

cytokine with a molecular weight of approximately

17 kd. TNF-a is expressed in psoriatic disease mainly

by activated macrophages and monocytes but is also

produced by other cell types found within psoriatic

plaques including dendritic cells, Langerhans’ cells,

and T cells. TNF-a exerts a wide range of biologic

activities that include antiviral properties, growth

regulation of different cell types, and immunomodu-

lation of several signal transduction cascades.

Mechanism of action

One major mechanism of action of TNF-a is the

induction of other inflammatory cytokines, such as

interleukins-1, -2, -6, and -8; granulocyte-macro-

phage colony-stimulating factor; and interferon-g [4].

s reserved.

P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459450

Other inflammatory molecules induced by TNF-a,such as prostaglandin and leukotriene synthesis, are

well known to incite bone resorption and cartilage

degradation in arthritis [5,6]. In addition, TNF-astimulates collagenase and matrix metalloproteinase

production by neutrophils and fibroblasts that lead

to tissue and joint damage [5,7].

Tumor necrosis factor-a also stimulates T-cell ad-

hesion to the endothelium through the up-regulation

of adhesion molecules on the surface of endothelial

cells. One report demonstrated the TNF-a–depen-dent up-regulation of intercellular adhesion molecule

type 1, E-selectin, and vascular cell adhesion mole-

cule type 1 on endothelial cells [8]. The induction of

T-cell trafficking into the dermis through adhesion

molecule binding in the vasculature is an important

signaling event in the pathogenesis of psoriasis

There are two major receptor variants for TNF-a:the p55 and p75 receptors. These high-affinity recep-

tors are bound to the surface of the cells, such as

macrophages, lymphocytes, keratinocytes, and endo-

thelial cells, and are composed of the extracellular

binding site for TNF-a, the transmembrane domain,

and the cytoplasmic tail, which is responsible for sig-

nal transduction through the activation of NFkB [9].

In addition, there are soluble receptors for TNF-athat are not membrane-bound that seem to act as

competitive inhibitors for TNF-a binding to cell sur-

face receptors. The activity and levels of these solu-

ble receptors are not sufficient enough, however, to

inhibit the inflammatory cascade caused by TNF-ain disease states, such as psoriasis and psoriatic arthri-

tis [10,11]. Levels of TNF-a receptors are up-regu-

lated in epidermal dendritic cells and keratinocytes

following treatment with TNF-a [12].

Several studies have demonstrated that TNF-a is

implicated in the pathogenesis of psoriasis and pso-

riatic arthritis. TNF-a levels have been shown to be

Fig. 1. Structure o

increased in psoriatic plaques and in the synovial

fluid of patients with active psoriatic arthritis [13,14].

TNF-a concentrations are also increased in the serum

of patients with psoriasis and in suction blisters

induced in psoriatic patients [15]. Furthermore, levels

of TNF-a have been shown to correlate with disease

severity (ie, increasing during worsening of the pso-

riasis and decreasing after effective therapy) [15–18].

Acute-phase reactants, which are elevated in inflam-

matory arthritides, correlate with the expression of

TNF-a in the serum and synovial fluid [19].

Structure and function of etanercept

Because there is significant correlation between

disease activity of psoriasis and psoriatic arthritis and

TNF-a levels, direct antagonism of TNF-a is a

logical treatment modality. Etanercept is a recombi-

nant molecule comprised of the extracellular binding

domain of the TNF-a p75 receptor fused to the Fc

portion of IgG1 molecule (Fig. 1). The molecular

weight of etanercept is 150 kd consisting of 934

amino acids and is almost 10 times larger than

insulin. Etanercept is a fully human dimeric fusion

protein produced by Chinese hamster ovary cells and

functions as a TNF inhibitor by binding to and

inactivating both free and membrane-bound TNF-athereby preventing interactions with its cell surface

receptors. Studies have demonstrated that etanercept

does not induce complement mediated TNF-a cell

lysis in vitro and has very low immunogenicity. The

Fc portion of IgG1 serves to stabilize etanercept and

prolong the median half-life, which is 4.8 days. The

dimeric form of etanercept allows binding to two

TNF-a molecules at an affinity 50 to 1000 times

greater than the naturally occurring soluble mono-

f etanercept.

P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459 451

meric form of the TNF-a receptor [20]. This accounts

for the greater inhibitor activity of etanercept than the

natural soluble receptor [21].

Indications, dosage, and usage of etanercept

Etanercept is FDA-approved for the treatment

of rheumatoid arthritis, polyarticular-course juve-

nile rheumatoid arthritis, ankylosing spondylitis,

and psoriatic arthritis, and more recently, moderate

to severe psoriasis.

The dosage of etanercept for adults is 50 mg per

week continuously for rheumatoid arthritis, anky-

losing spondylitis, and psoriatic arthritis. For the

treatment of psoriasis, the initial dosage of etanercept

is 50 mg twice weekly for 12 weeks followed by step-

down dosing to 50 mg weekly continuously. For

pediatric patients with juvenile rheumatoid arthritis

(4 to 17 years), the dosage is 0.8 mg/kg/wk (50 mg

maximum per week). The drug is self-administered

by the patient subcutaneously.

Etanercept is supplied as a sterile, preservative-

free, lyophilized powder for subcutaneous injection

after reconstitution with 1 mL of supplied bacterio-

static water. Each vial contains 25 mg of etanercept

plus stabilizers including 10 mg sucrose, 40 mg man-

nitol, and 1.2 mg tromethamine. At the time of this

writing, etanercept will be available as 50 mg doses

per vial. Etanercept is stored in the refrigerator and

should not be frozen. Reconstituted etanercept is

stable for up to 14 days in the refrigerator. The sup-

plied syringe does not contain any latex.

The frequency of dosing is once or twice a week

depending on the indication. Because etanercept is

supplied as 25-mg doses per vial, for the 50-mg

weekly dosing, patients are instructed to administer

two shots the same day and can be given at the same

time. Alternatively, etanercept can be administered

25 mg twice a week, spaced every three to four days.

For psoriasis, the initial dose is 50 mg twice weekly

for the first 12 weeks and patients administer etaner-

cept as two 25-mg injections twice weekly every three

to four days (four injections per week). The dosage is

then stepped down to 50 mg weekly continuously

(two injections per week). With the advent of the

50-mg vial, the number of injections will be reduced

to half (two shots per week for 12 weeks and then one

shot per week for psoriasis). Pediatric patients can

administer etanercept once a week at 0.8 mg/kg or in

divided doses twice a week at 0.4 mg/kg. The most

common locations for subcutaneous injections are the

abdomen, thighs, and upper arms. To minimize injec-

tion site reactions, patients are instructed to place their

injections at least an inch apart from the prior injection

site or to inject at contralateral sites.

Clinical efficacy in psoriatic arthritis

The safety and efficacy of etanercept were as-

sessed in a phase III randomized, double-blinded,

placebo-controlled study for 24 weeks in 205 patients

with active psoriatic arthritis. Patients were random-

ized equally to receive either etanercept, 25 mg, twice

weekly or placebo twice weekly. Patients with psori-

atic arthritis were between 18 and 70 years of age and

had greater than or equal to three swollen joints and

greater than or equal to three tender joints with one or

more of the following joint diseases: distal interpha-

langeal involvement, polyarticular arthritis, arthritis

mutilans, asymmetric psoriatic arthritis, or ankylosing

spondylitis. These patients also had plaque psoriasis

with a qualifying lesion of greater than or equal to

2 cm in diameter. Patients who were on methotrex-

ate therapy for more than 2 months could continue

the methotrexate if the dose was less than 25 mg

per week.

The primary end point in the study for psoriatic

arthritis was the American College of Rheumatology–

20 definition of improvement as set forth by the FDA.

These guidelines include a 20% improvement in both

tender and swollen joints plus 20% improvement in

three of the following: patient’s pain assessment,

patient’s assessment of disability, physician’s global

assessment, patient’s global assessment, or C-reactive

protein or erythrocyte sedimentation rate.

In those patients with psoriatic arthritis who

received etanercept, the clinical responses were evi-

dent 4 weeks into treatment and were maintained

through the 24 weeks of treatment. At 12 weeks, 59%

of the patients who received etanercept achieved the

American College of Rheumatology–20 response

compared with 15% in the placebo group. The

responses were similar to patients who were or were

not receiving concomitant methotrexate therapy. At

week 12, 62% of patients who received concomitant

etanercept plus methotrexate attained the American

College of Rheumatology–20 response compared

with 58% in the group who received etanercept alone.

In addition, the skin lesions of psoriasis were also

improved with etanercept in this trial, relative to

placebo, as measured by percentages of patients

achieving improvements in the Psoriasis Area and

Severity Index (PASI). Responses increased over

time, and at 24 weeks the proportions of patients


achieving a 50% or 75% improvement in the PASI

were 47% and 23%, respectively, in the etanercept

group compared with 18% and 3% in the placebo

group, respectively.

Mease et al [2] showed that twice weekly subcu-

taneous injections of etanercept (25 mg) for 12 weeks

resulted in substantial remission of both psoriasis and

psoriatic arthritis. Eighty-seven percent of patients

with psoriatic arthritis had a reduction in their arthri-

tis as measured by the psoriatic arthritis response

criteria versus 23% of placebo patients. The Ameri-

can College of Rheumatology–20 was achieved by

73% of etanercept-treated patients compared with

13% of placebo-treated patients. In addition, 26%

of the etanercept-treated patients achieved a 75%

improvement in the PASI compared with none in

the placebo-treated group. The median PASI im-

provement was 46% in etanercept-treated patients

versus 9% in placebo-treated patients.

Radiographic response

In the phase III psoriatic arthritis study, radio-

graphic changes were also assessed. Radiographs of

the hands and wrists were obtained at baseline and at

months 6 and 12. A modified total sharp score that

included the distal interphalangeal joints was used to

measure the degree of pencil-and-cup deformity, joint

space changes, gross osteolysis, and ankylosis. More

patients in the placebo group exhibited larger magni-

tudes of radiographic worsening compared with the

etanercept-treated group. At the end of 1 year, eta-

nercept inhibited radiographic progression of joint

space narrowing and erosions compared with placebo,

which led to progressive worsening [22].

Clinical efficacy in psoriasis

The phase II and III trials of etanercept as mono-

therapy treatment for chronic plaque psoriasis have

demonstrated significant clearance of psoriatic pla-

ques. The phase II trial was a 24-week, multicentered,

double-blinded, placebo-controlled study in which

112 patients with moderate to severe psoriasis (more

than 10% of their body surface area) who had re-

ceived prior systemic treatment were enrolled. Pa-

tients were randomized to receive 25 mg etanercept

twice a week (N = 55) or placebo (N = 57). At weeks

12 and 24, 30% and 56% of patients who received

etanercept achieved a 75% improvement in the PASI

score, respectively, versus 2% and 5% of the placebo

group at the same time intervals.

The onset of action of etanercept is of moderate

rapidity. After 4 weeks of therapy, there was about an

overall 28% improvement in the PASI score. Almost

40% of the patients attained a PASI 50 improvement

by week 4.

In addition, the Dermatology Life Quality Index

(DLQI) was measured in the phase II trial. The

DLQI is a reliable 10-question survey completed by

the patient that analyzes the impact various skin dis-

eases, such as psoriasis, have on a patient’s quality of

life [23]. Physical and social elements including pain,

itching, occupation and school performance, leisurely

activities, and relationships are measured by the

DLQI. The improvement in the DLQI scores corre-

lated well temporally with the improvement in

PASI scores.

There were two phase III trials conducted for the

treatment of psoriasis with etanercept: the Global

phase III trial and the United States phase III trial

[1]. The Global phase III trial was a 6-month, double-

blinded, multi-centered, placebo controlled study in

which patients were randomized to receive either pla-

cebo (N = 204), etanercept 50 mg weekly (N = 204),

or etanercept 50 mg twice-weekly (N = 203) for

3 months. Thereafter, all patients were crossed-over

to receive etanercept at 50-mg weekly for the next

3 months. The data was adjusted for the intent-to-treat

analysis. At 3 months, 46% of the patients attained a

PASI 75 improvement in the 50-mg twice-weekly

dose compared to 3% in the placebo group. When

the dosage of etanercept at 50 mg twice weekly for

3 months was stepped down to 50 mg weekly for

3 additional months, the improvement was sustained

with 50% of the patients attaining a PASI 75 im-

provement at 6 months.

The phase III trial conducted in the United States

was a double-blinded, multi-centered, placebo-

controlled study divided into 2 parts. In the first

part, patients were randomized to receive placebo

(N = 168), etanercept at 25 mg weekly (N = 169),

50 mg weekly (N = 167), or 50 mg twice weekly

(N = 168) for 6 months. In the placebo group, after

receiving placebo for 3 months, the patients were

crossed over to receive etanercept at 50 mg per week.

The data was adjusted for the intent-to-treat analysis.

At 3 months, 49% of the patients attained a PASI

75 improvement in the 50-mg twice-weekly dose

compared to 4% in the placebo group, 34% at the

50-mg weekly dose, and 14% in the 25-mg weekly

dose. There was continued improvement with longer,

continuous treatment. At 6 months, 59% of the

patients attained the PASI 75 improvement in the

50-mg twice-weekly dose, 44% in the 50-mg weekly

dose, and 25% in the 25-mg weekly dose. Patients in


the original placebo group who were crossed over to

receive etanercept at 50-mg weekly at month

3 exhibited improvement of their psoriasis with

33% of them achieving the PASI 75 improvement

— a response rate consistent with that in the 50-mg

once-a-week dose at 3 months (34%).

In the second part of the United States phase III

trial, the abrupt discontinuation and retreatment with

etanercept were evaluated. For all patients who

attained a PASI 75 or greater improvement at any

dose (N = 409), when etanercept was abruptly dis-

continued, the median time to loss of response

(defined as loss of half the of the PASI improvement)

was 85 days. In addition, in the 409 patients observed

during the discontinuation period, there was no con-

version of morphology (pustular psoriasis, erythro-

dermic psoriasis, or unusual morphology), no serious

adverse events or hospitalizations due to withdrawal,

and no study discontinuation due to adverse events.

Only one patient (25 mg once per week of etanercept)

out of the 409 evaluated during the withdrawal phase

had an episode of rebound. When patients were

retreated with etanercept following loss of response,

the PASI 75 response rates after 3 months of re-

treatment with etanercept were similar to PASI 75 re-

sponse rates seen after the initial 3 months of

treatment with etanercept. No significant tachyphi-

laxis with etanercept was evident with repeated treat-

ments. In addition, retreatment with etanercept was

not associated with increased antigenicity or forma-

tion of neutralizing antibodies.

The onset of action with etanercept was rapid in

the phase III trials. The improvement in the PASI

scores was statistically significant over placebo for all

three doses as early as 2 weeks. Higher dosages of

etanercept resulted in faster clearance of the psoriasis.

The DLQI was also assessed in the phase III trial and

improvements in the DLQI correlated well temporally

with the improvement in the PASI scores at all doses

used in the study. Finally, etanercept was well toler-

ated at all dosages with no increased adverse events

evident at the 50-mg twice-weekly dose.

The results of the Global and United States

phase III trials underscore several important points.

There is a dose-dependent response rate with eta-

nercept as evidenced by higher dosages of etaner-

cept exhibiting faster response rates and higher

efficacy. At 6 months, efficacy with step-down dosing

from 50 mg twice weekly to 50 mg weekly was

similar to 50-mg twice-weekly dosing continuously.

Etanercept was not associated with rebound follow-

ing abrupt discontinuation, and retreatment with eta-

nercept resulted in comparable reestablishment of

clinical response. Finally, there was no increased in-

cidence of adverse events evident with higher doses

of etanercept.

Safety: frequently asked questions

Between May 1, 1993, and December 31, 2001,

over 121,000 patients have received etanercept in

controlled clinical trials and in clinical practice. Of

all the biologic agents that are currently in use or

potentially will be used for the treatment of psoriasis

and psoriatic arthritis, etanercept has the longest track

record for safety data.

Injection site reactions

In clinical trials, the adverse event that occurred

more frequently in patients treated with etanercept

over the placebo group was transient injection site

reactions. These injection site reactions typically

occurred 2 to 3 weeks into treatment and consisted

of erythema, pain, itching, or swelling. The mean

duration of the reaction was approximately 3 to 5 days.

A biopsy of an injection site reaction revealed a peri-

vascular lymphohistiocytic reaction in the dermis but

there was no evidence of a panniculitis (author’s per-

sonal observations). Topical steroids, oral antihista-

mines, and compresses are typically used to alleviate

injection site reactions. In the clinical trials, injection

site reactions did not become severe enough to war-

rant discontinuation of etanercept.

Does etanercept increase risk of malignancies?

The long-term safety data in clinical trials show

the incidence of malignancies was not increased in

the etanercept-treated group when compared with the

expected number from the National Cancer Insti-

tute’s database [24]. The expected number of ma-

lignancies was 42 and the observed incidence was

41. There were no predominant types of malig-

nancies observed and a total of five lymphomas

were reported. In postmarketing surveillance

(N = 127,379), the observed number of malignan-

cies was 277 and the expected incidence was 1020.

In addition, a study has demonstrated that lym-

phoma rates are low but increased in patients with

psoriasis [25]. Patients with psoriasis had a 2.95

relative rate of developing lymphoma compared with

those without psoriasis. As a TNF-a inhibitor, how-

ever, there is always the possibility that etanercept

can affect the immune system’s response to cancer

and specific concerns and risks versus benefits should


be discussed with the patient, especially if there is a

history of malignancy.

Does etanercept increase the risk of serious

infections?

The rates of infection that required hospitalization

or parenteral antibiotic therapy were 0.04 per pt-year

in the etanercept-treated group in clinical trials [24].

This rate is very similar to the total population,

which was 0.03 to 0.09 per pt-year. In postmarketing

surveillance, the reported rate is 0.007 per pt-year.

There have been rare cases of serious infections and

sepsis, which included fatalities when patients were on

etanercept. Patients who are on concurrent immuno-

suppressants, or patients who have serious underlying

medical conditions, such as diabetes, that make them

predisposed to infections may be at increased risk of

infection when administered etanercept and caution

should be exercised when considering etanercept.

Should etanercept be discontinued if an infection

develops?

There are no specific guidelines regarding the

discontinuation of etanercept in patients who develop

an infection and patient situations should be assessed

individually. Patients who develop a new infection

while on etanercept therapy should be closely moni-

tored. In the authors’ opinion, etanercept should not

be administered to patients with sepsis or active

infections, including chronic or localized infections.

Until the infection subsides, etanercept should be

discontinued temporarily.

Is laboratory testing required for patients on

etanercept?

There is no specific laboratory or blood testing

that is required to monitor treatment with etanercept.

No correlation exists with organ toxicity, such as

hepatotoxicity or nephrotoxicity, with etanercept.

There have been rare cases of pancytopenia reported

with the usage of etanercept, however, but a cause

and effect relationship has not been reported. It is up

to the treating physician’s discretion to determine if

laboratory testing is indicated.

Is tuberculin testing required before initiation of

etanercept therapy?

The current guideline is that no specific tuberculin

testing is required before treatment with etanercept.

This is in contrast to other TNF-a antagonists, such as

infliximab and adalimubab, in which tuberculosis

screening is required before initiation of therapy be-

cause of the incidence of complement mediated lysis

of macrophages present in tuberculous granulomas,

which could release mycobacteria systemically and

activate tuberculosis. The incidence of tuberculosis in

121,000 patients who have received etanercept be-

tween May 1, 1992, and December 13, 2001, was

0.02% (N = 20), which was similar to the background

incidence of tuberculosis in the general population.

There has not been a temporal association between the

development of tuberculosis and etanercept therapy. It

is up to the physician’s discretion whether to initiate

purified protein derivative testing for etanercept ther-

apy. Given this regard, however, the use of purified

protein derivative testing might be advisable for

patients undergoing nonselective systemic therapy,

such as methotrexate or cyclosporine.

Can etanercept be administered to patients who test

positive for tuberculosis?

There are no specific recommendations regarding

the use of etanercept in patients with previous posi-

tive testing for tuberculosis. In the clinical trials, there

was no incidence of reactivation of tuberculosis in

patients who were purified protein derivative–posi-

tive. Treatment with etanercept should not be started

in patients with active infections, including chronic

and localized infections. If a patient is purified pro-

tein derivative–positive and the chest radiograph is

negative for radiographic evidence of active tubercu-

losis, then preventative therapy with isoniazid should

be instituted before treatment with etanercept.

Does etanercept cause demyelination disorders?

In postmarketing surveillance, there have been

rare incidences of demyelinating disorders and exacer-

bation of pre-existing multiple sclerosis occurring in

patients treated with etanercept [26]. Cases of trans-

verse myelitis, optic neuritis, and new onset or

exacerbation of seizure disorders have been observed

with etanercept. The causal relationship between

these central nervous disorders and etanercept

remains unclear. Caution should be exercised when

considering etanercept in patients with a history or

family history of multiple sclerosis.

Can etanercept be administered to patients with

congestive heart failure?

There were two large clinical trials that evaluated

the use of etanercept in the treatment of heart failure.


These trials were terminated because of lack of

efficacy. The results of one study suggested higher

mortality in patients treated with etanercept com-

pared with placebo but the second trial did not

corroborate these observations.

There have been reports of worsening conges-

tive heart failure and rare instances of new onset

of congestive heart failure without identifiable

precipitating factors in patients treated with eta-

nercept [27]. Caution should be exercised when

using etanercept in patients who have a history of

heart failure.

Does etanercept increase the risk of autoimmunity?

In two trials, the percentage of patients evaluated

for antinuclear antibodies who developed a positive

antinuclear antibodies titer (titer � 1:40) was higher

in patients treated with etanercept (11%) than in

placebo-treated patients (5%) [28,29]. The percent-

age of patients who developed new positive anti–

double stranded DNA antibodies was higher in the

etanercept-treated group (15%) compared with pla-

cebo (4%) [28,29]. There have been rare cases of

drug-induced systemic lupus erythematosus asso-

ciated with etanercept therapy [30].

Can etanercept be given during pregnancy or

breastfeeding?

Etanercept is rated pregnancy category B by the

FDA. No formal studies have been conducted in

pregnant women who have received etanercept. It is

not known if etanercept is excreted in human milk or

absorbed systemically after ingestion. Because many

drugs and immunoglobulins are excreted in human

milk and because of the potential for serious adverse

reactions in nursing infants, a decision should be

made whether to discontinue nursing or to discontin-

ue the drug.

Can immunizations be given during etanercept

treatment?

Most psoriatic patients receiving etanercept were

able to mount effective B-cell immune responses.

Patients on therapy with etanercept may receive con-

current vaccinations, except for live vaccines. There

are no data available on the secondary transmission

of infection by live vaccines in patients receiv-

ing etanercept.

Practical considerations on usage of etanercept

Most psoriatic patients are able to self-administer

etanercept when offered to them. If self-administra-

tion by the patient is not achievable, then a family

member or friend can administer the drug at home.

The nursing staff easily can learn how to teach pa-

tients the technique in administering etanercept. In

addition, specialty pharmacies are now available that

can demonstrate to the patient how to self-inject

etanercept. Because etanercept can be given once a

week, it may be possible for the uncommon patient to

come in weekly to the clinic for injections if home

administration is not achievable. If the patient is truly

needle phobic, then etanercept and other injectable

agents are obviously not possible and other treatment

modalities for psoriasis and psoriatic arthritis must

be used.

Monotherapy dosing of etanercept

Most patients with moderate to severe plaque

psoriasis often exhibit improvement with mono-

therapy step-down dosing of etanercept. Initial clear-

ance of psoriatic plaques can be seen as early as

2 weeks at 50 mg twice weekly. The symptoms of

psoriatic arthritis respond quicker than skin lesions.

Frequently, patients notice a decrease in morning

stiffness, pain, and swelling in their joints as soon

as 2 weeks. It is not uncommon for a patient to state

that the arthritis ‘‘feels better’’ after one injection.

Etanercept is an ideal agent as first-line therapy in the

treatment of psoriasis or psoriatic arthritis because of

its high efficacy, excellent safety profile, and conve-

nience. Once a patient has started a good treatment

regime with etanercept, follow-up visits are con-

ducted every 3 to 4 months.

The maintenance dosage of etanercept for clear-

ance of psoriasis is 50 mg weekly. Some psoriatic

patients can maintain clearance of their psoriasis at

decreased doses of etanercept, such as 25 mg per

week, or even at longer intervals, such as every

10 to 14 days. Other patients develop remission of

their psoriasis for an extended period of time when

etanercept is discontinued. Should the psoriasis re-

lapse at the lower dosages or upon discontinuation,

retreatment with 50 mg weekly of etanercept is

instituted without loss of efficacy as seen in the

clinical trials with retreatment. Etanercept is not

associated with rebound or change or morphology

upon abrupt discontinuation of etanercept. In a mi-

nority of patients, the psoriasis may worsen even at

50-mg weekly dosing etanercept. This can be precipi-

tated by known factors, which worsen psoriasis such

Table 1

Summary of six psoriatic patients treated with etanercept and combination therapy

Patient Age (y) Previous treatment Arthritis

Initial combination therapy

with etanercept

PASI score

before etanercept

After

etanercept Arthritis response

1 (M) 57 UVB, cyclosporine, acitretin, etretinate,

methotrexate, 6-thioguanine

None Methotrexate, 20 mg po weekly 29 10 —

2 (M) 51 UVB, PUVA, methotrexate, cyclosporine Present Cyclosporine, 200 mg po qd 27 14 Improved, major

3 (M) 52 Acitretin, hydroxyurea None Acitretin, 25 mg po qod 28 10 —

Hydroxyurea, 1.5 g po qd

4 (M) 33 PUVA, calcipotriene cream and ointment Present Calcipotriene cream and ointment bid 22 10 Improved, moderate

5 (M) 45 Cyclosporine, acitretin, methotrexate Present Methotrexate, 15 mg po weekly 24 12 Improved, major

6 (F) 55 Methotrexate, acitretin, UVB None Acitretin, 25 mg po qod UVB weekly 14 7 —

P.S.Yamauchiet

al/Derm

atolClin

22(2004)449–459

456


as stress or streptococcal throat infections. In these

instances where the psoriasis flares at maintenance

dosages, the dose of etanercept can be increased to

50 mg twice weekly until the psoriasis improves.

Then the dosage can be stepped down to 50 mg

weekly for maintenance control.

In contrast to psoriasis, it is recommended that

patients with psoriatic arthritis be maintained at the

conventional dose of 50 mg per week. Etanercept has

been shown to inhibit radiographic progression of

joint destruction. Any stoppage of etanercept or

lowering the dose may potentially cause further

osteolysis and joint space narrowing. If a patient is

diagnosed with psoriatric arthritis and has moderate

to severe psoriasis, step-down dosing is recommended

to gain quick control of the psoriatric plaques.

Combination therapy with etanercept

Iyer et al [31] reported six cases of patients with

severe recalcitrant psoriasis that was partially resist-

ant to other ongoing systemic agents or phototherapy

whose disease activity showed marked improvement

with the addition of etanercept to the treatment

regime. Three of the patients also had severe psoriatic

arthritis. Table 1 illustrates the improvement in the

disease activity for each of the six patients following

the addition of etanercept to their treatment regime.

When etanercept was combined with other agents,

each of the patient’s psoriasis and those with psori-

atic arthritis became more responsive to treatment

and allowed lower doses of other systemic agents to

be used to limit their side effects. For example,

patient 2 demonstrated a response to cyclosporine,

but the dosage was limited by the development of

medication-related hypertension.

In addition, no additional toxicity was found with

etanercept when added to such agents as methotrex-

ate, hydroxyurea, acitretin, or cyclosporine. None of

these patients developed any serious or opportunis-

tic infections. Addition of etanercept did not poten-

tiate any type of organ toxicity, myelosuppression,

metabolic or lipid abnormalities, hypertension, or

malignancies. No drug interactions with etanercept

were evident.

These case reports underscore two important

points. First, etanercept can be added safely to some

other systemic and topical agents to augment efficacy

and develop more potent combination regimens in

severe recalcitrant cases of psoriasis, at least over a

short-term crisis period. Second, etanercept can play

a role in diminishing the short- and long-term tox-

icities of other systemic medications by allowing

lower doses of these agents to be used while main-

taining disease control. Etanercept is an excellent

choice that can be used in combination therapy for

the treatment of psoriasis.

Etanercept offers a good method to wean and

transition psoriatic patients off of systemic agents.

One prevalent problem with these systemic agents,

such as cyclosporine and methotrexate, is the occur-

rence of rebound and flare-ups on abrupt cessation.

For example, a patient with psoriasis who has attained

good clearance with cyclosporine at 5 mg/kg most

likely rebounds with sudden discontinuation. The

addition of etanercept at 50 mg per week prevents

this from occurring. Because the onset of action for

etanercept is typically evident in about 4 weeks, the

dose of cyclosporine should be held constant for that

period of time. After 4 weeks, the dosage of cyclo-

sporine can slowly be lowered by 50 to 100 mg every

2 to 4 weeks while maintaining the etanercept.

Laboratory monitoring and blood pressure checks

should be performed while on cyclosporine. With

methotrexate, the dosage can be lowered by 2.5 mg

every 2 to 4 weeks after instituting therapy with

etanercept for 4 weeks. There are no specific guide-

lines for transitioning off of systemic agents while on

etanercept but these are some of the methods that the

authors have used.

Summary

It is quite evident the pathogenesis of psoriasis is

modulated by immune-mediated mechanisms that

invoke activated T cells and inflammatory cytokines,

such as TNF-a. Current immunosuppressive systemic

treatments may be effective in controlling psoriasis to

a certain degree but have significant drawbacks, such

as toxicity and relapse of the disease on discontinua-

tion. The advantages of biologic agents are their

greater selectivity in targeting specific pathways in

the inflammatory cascade of psoriasis with a much

higher safety profile. With specific antagonism di-

rected against TNF-a, etanercept has demonstrated

remarkable efficacy in the treatment of psoriasis and

psoriatic arthritis.

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Dermatol Clin 22 (2004) 461–465

Current concepts and review of pimecrolimus in the

treatment of psoriasis

Klaus Wolff, MD, FRCP

Department of Dermatology, University of Vienna, Vienna General Hospital, Waehringer Guertel 18–20, Vienna A-1090, Austria

The ascomycine macrolactam derivative pimecro- systemic treatment of patients with psoriasis. A

limus is a novel inflammatory cytokine-release inhib-

itor [1 – 6] that has a high degree of cytokine

selectivity. The first ascomycine derivative to show

efficacy in a disease was SDZ 281-240, which a

proof-of-concept study showed cleared psoriasis as

effectively as the high-potency corticosteroid clobe-

tasol-17-proprionate when applied topically under

occlusive conditions [7]. Pimecrolimus has been

shown to suppress atopic dermatitis [8,9] and contact

dermatitis [10] when applied topically and psoriasis

when delivered topically under occlusion [11]. A

large-scale experience with pimecrolimus cream has

now accumulated in atopic dermatitis where multi-

center studies proved high efficacy and safety. Studies

in more than 2000 patients confirm that topical

pimecrolimus is suitable for short-and long-term treat-

ment of atopic dermatitis in adults, children, and in-

fants older than 3months [7]. After topical application,

the levels of pimecrolimus in blood remain consis-

tently low and no clinically relevant, drug-related,

systemic adverse events have been reported [12].

When given systemically in animal models with

inflammatory skin disease, pimecrolimus exhibits

high anti-inflammatory activity [1] and a low poten-

tial for systemic immunosuppression [7]. Pimecroli-

mus therefore has been considered for use in the


doi:10.1016/j.det.2004.03.013

Part of this work was supported by a grant from Novartis

AG, Basel, Switzerland. The author has served as a

consultant to Novartis Research Institute, Vienna, Austria;

however, he has no direct financial interest in this subject

matter, neither with Novartis nor with any companies

making competing products.


randomized, double-blind, placebo-controlled proof-

of-concept phase 1/2 study has confirmed the efficacy,

safety, and tolerability of this drug as an oral treat-

ment in psoriasis [13]. Although pimecrolimus is not

yet approved as a systemic drug, the experience

available to date suggests that it might be a novel,

highly effective systemic drug for psoriasis and other

inflammatory skin diseases.

Preclinical profile

Pimecrolimus is a calcineurin inhibitor that selec-

tively targets T cells and mast cell activation in vitro.

It blocks the release of helper T-cell (Th1 and Th2)

cytokines [14] and inhibits the induction of corecep-

tors involved in the accessory cell-dependent acti-

vation of inflammation-mediating T cells [15]. In

addition, it prevents the production of cytokines and

the release of proinflammatory mediators from mast

cells [14,16,17]. In animal models, pimecrolimus is

highly active against skin inflammation after systemic

application. In contrast to cyclosporin and tacrolimus,

pimecrolimus has only a low potential to impair

systemic immune responses [1,6,18,19]. In rats, oral

pimecrolimus is superior to cyclosporin by a factor of

4 and superior to tacrolimus by a factor of more than

2 in the down-regulation of allergic contact dermati-

tis; in mice, oral pimecrolimus is superior to cyclo-

psorin and equal to tacrolimus in inhibiting allergic

contact dermatitis [19]. Although in these animal

models pimecrolimus is highly effective in suppress-

ing the inflammatory response in the elicitation phase

of allergic contact dermatitis, it has no effect on the

s reserved.

K. Wolff / Dermatol Clin 22 (2004) 461–465462

induction phase, which is in contrast to oral cyclo-

sporin or tacrolimus [18]. Also, although the inhibi-

tion of the primary immune response with tacrolimus

and cyclosporin is associated with a decrease in

lymph node weight and cellularity, this effect is not

observed with pimecrolimus [18,19].

Also in contrast to cyclosporin and tacrolimus,

pimecrolimus has a low immunosuppressive effect in

animal models when given systemically. For instance,

the potential of pimecrolimus to suppress a graft-

versus-host reaction is 8 and 66 times less than

tacrolimus and cyclosporin, respectively. This finding

also holds for allogeneic kidney transplantation and

antibody production models [1,6,19].

In summary, it seems that pimecrolimus has a

different profile than other calcineurin inhibitors such

as tacrolimus and cyclosporin. It is equal to or even

more potent than tacrolimus and cyclosporin in

suppressing cutaneous inflammatory responses; in

addition, it interferes only with the elicitation phase

and not with the initiation phase of an immune

response and is far less effective in suppressing a

systemic immune response than tacrolimus or cyclo-

sporin. These findings suggest that oral treatment

with pimecrolimus in humans with inflammatory skin

disease should leave systemic immune surveillance

intact as a natural defense system.

Fig. 1. The clinical efficacy of pimecrolimus is shown for a patient r

Oral pimecrolimus in patients with psoriasis

Clinical efficacy

Pimecrolimus is highly effective in suppressing

psoriasis. In a randomized, double-blind, placebo-

controlled, multiple-rising-dose study, it was shown

that pimecrolimus was highly effective in down-

regulating psoriatic disease activity [13]. Although

there was no change in Psoriasis Area and Severity

Index (PASI) scores in patients taking the placebo or

in patients receiving low doses of pimecrolimus daily

(5 mg, 10 mg, and 20 mg, respectively), there was

clear efficacy in patients receiving 40 mg (20 mg

twice daily) and 60 mg (30 mg twice daily) of

pimecrolimus per day. This improvement involved a

reduction of scaling, erythema, and infiltration of

lesions (Fig. 1), and led to a significant reduction of

patients’ PASI score to an almost complete clearing

of lesions after 4 weeks of treatment. This response

was clearly dose-dependent (Fig. 2). The mean re-

duction of PASI (change from baseline at day 28) was

60% for the 40-mg/day and 75% for the 60-mg/day

patient groups [13]. These results now have been

confirmed by a multicenter study, which reported on

143 patients with moderate to severe chronic plaque

psoriasis and extending over 12 weeks of treatment;

eceiving 30 mg twice daily on day 0 (left) and day 28 (right).

Fig. 2. The clinical efficacy of pimecrolimus as assessed by percentage of PASI change from baseline for the different dose

levels. (From Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Creig G, et al. Pimecrolimus identifies a common

genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002;119:

876–87; with permission.)

K. Wolff / Dermatol Clin 22 (2004) 461–465 463

the median change in PASI from baseline showed a

clear dose-dependent effect and again was greatest

for the 40-mg/day and 60-mg/day groups [20]. At

12 weeks, the median reduction in PASI was 80%

and 58% in the 60-mg and 40-mg groups, respec-

tively, and 43% of patients were clear or almost clear

of disease following 12 weeks of treatment with

60-mg/day dosages [20].

Follow-up and recurrences

In the original study [13], follow-up evaluation

showed recurrence of psoriasis after 8 weeks but no

rebound. In the two highest-dose (40-mg and 60-mg)

patient groups in the multicenter study [20], more

than half of the patients had not experienced disease

relapse 10 weeks after stopping treatment.

Pharmacokinetics

Pharmacokinetics of pimecrolimus reveal rapid

absorption, attainment of steady state after 5 to 10

days, and a linear dose dependency at steady state

[13]. Both Cmax and AUC0–24 increased broadly in

proportion to the dose. Steady state was reached after

days 5 to 10 at daily administrations of 30 mg of

pimecrolimus twice daily, and Cmax and AUC0–24

reached 54.5 ng/mL and 589.9 ng h/mL at steady

state, respectively [13].

Pharmacogenomics

Gene expression analysis identified a common

genomic profile for pimecrolimus in blood cells of

patients with psoriasis [13]. Blood samples subjected

to a gene expression analysis using gene chips for

the survey of more than 7000 genes permitted the

identification of a common genomic profile of pime-

crolimus consisting of approximately 150 genes.

Pimecrolimus strongly down-regulated the expres-

sion of genes associated with the macrolactam target

pathway, cellular activation and proliferation, antigen

presentation and genes related to cellular metabolism,

signal transduction, transcription factors, and inflam-

matory mediators. Genes related to lymphocyte re-

cruitment, chemotaxis, and cellular migration were

also down-regulated, but no significant changes in

T-lymphocyte markers could be detected at the RNA

expression level, suggesting an absence of a systemic

T-cell suppressive effect of the drug. There was also

no change of expression for transforming growth

factor b1–3 and for interleukin 1 (IL-1), IL-2, IL-8,

and IL-10. None of the expression changes in genes

that showed change were clearly related to side

effects or toxicity, and genes associated with apopto-

sis, stress, and enzymatic induction did not change

expression [13].

Tolerability

Pimecrolimus is well tolerated and lacks notable

clinical and laboratory side effects. In the previously

described study [13], there were no clinically notable

and significant changes in physical examination,

blood pressure, heart rate, and ECG throughout the

study. The only consistent side effect recorded was a

transient feeling of warmth on the upper chest occur-

ring about 40 minutes after ingestion of the drug and

K. Wolff / Dermatol Clin 22 (2004) 461–465464

lasting approximately 90 minutes. It did not occur

every time after drug intake, and in 75% of all

patients it did not occur more than 3 times during

28 days of treatment. Furthermore, the sensation of

warmth was not a matter of concern for the patients.

Hematology and blood chemistry analyses re-

vealed no significant changes throughout the study,

and there were no notable changes of kidney func-

tion, such as glomerular filtration rate or renal plasma

flow, and glucose tolerance tests were normal [13].

Tolerability of pimecrolimus has been confirmed in a

multicenter study comprising 243 adult patients with

psoriasis and atopic dermatitis over a treatment period

of 12 weeks [21]. The only adverse effect that

showed a clear dose–effect relationship was the

transient mild to moderate feeling of warmth de-

scribed previously. Headache and common gastro-

intestinal symptoms, such as nausea and dyspepsia,

were the most commonly observed adverse effects,

but these were not significantly increased as com-

pared with placebo-treated patients; this finding was

also true for skin and systemic infections. These data

indicate that pimecrolimus has an excellent safety

profile in short-term treatment (4 wk and 12 wk,

respectively) of patients and is also in line with the

pharmacogenomic profile of pimecrolimus examined

in the original study on this drug [13].

Immunology

Pimecrolimus leaves immunologic parameters

unaffected. Intradermal testing for delayed hypersen-

sitivity reactions to recall antigens showed no signif-

icant changes from pre-to post-treatment testing for

the pimecrolimus-and placebo-treated patients [13].

Flow cytometry analysis of blood lymphocyte sub-

populations revealed no significant differences be-

tween treatment groups and patients taking placebo.

In addition, no consistent or significant changes or

patterns were seen in the proliferation of lymphocytes

or in the patterns of cytokine release before and after

4 weeks of treatment [13]. The absent suppressive

effect on circulating lymphocytes is of considerable

importance because, as discussed later, pimecrolimus

down-regulates T cells in the skin.

Histopathology

Histopathologically and immunopathologically,

pimecrolimus reverses the psoriatic phenotype to

normal [13]. After 4 weeks of treatment, pimecroli-

mus induces an almost complete reversion of psoria-

tic epidermal hyperplasia and a marked reduction of

the inflammatory infiltrate. In addition, it induces the

expression of proliferation-associated keratin-16 and

the proliferating Ki-67+ keratinocytes. Staining pat-

terns of involucrin and filaggrin reverted from that

typical for psoriasis to near that of normal epidermis,

and keratinocyte activation was significantly reduced

or abolished. In contrast to pimecrolimus’ absence of

effect on circulating lymphocytes [13], there was a

significant reduction of CD3+, CD4+, and CD8+

dermal lymphocytes and of CD3+ and CD4+ epider-

mal lymphocytes; importantly, there was no signifi-

cant change in the CD1a+ subpopulation in the

epidermis and dermis, indicating that pimecrolimus

leaves Langerhans cells unchanged [13].

Summary

Although pimecrolimus is approved as a topical

treatment for atopic dermatitis in the United States,

the European Union, and most other Western coun-

tries, it is not yet approved for use as a systemic drug

because phase 2 studies are still ongoing. Nonethe-

less, evidence accumulated to date indicates the

following: it has a genomic profile of broad anti-

inflammatory activity without evidence of toxicity as

evaluated in blood cells, it exhibits excellent clinical

tolerability after 4 and 12 weeks of oral treatment,

and it is highly effective in a concentration-dependent

manner in patients with moderate to severe plaque

psoriasis. The impressive clinical efficacy of pime-

crolimus compares favorably with that of established

systemic treatments for psoriasis, such as psoralen

with ultraviolet A (PUVA), retinoic acid PUVA com-

binations, and cyclosporin [13]. No impairment of

organ function, as assessed by clinical and laboratory

examinations, and no systemic immune suppression

have been noted in the studies performed thus far. In

addition, no viral infections and increase of skin

infections were seen throughout the time patients

were observed [13,21]. These findings harmonize

with the observed gene profiling of the drug, which

showed down-regulation of genes responsible for the

target pathway, inflammation, activation, prolifera-

tion, chemotaxis, and migration of leukocytes but

did not reveal changes in gene expression that might

be linked to treatment-related immune suppression

and toxicity [13]. The findings also seem to verify the

observation in animal models in which pimecrolimus

had high skin-selective, anti-inflammatory activity

and a very low potential for effective systemic im-

mune responses [6].

The efficacy of pimecrolimus in psoriasis and its

short-term safety are encouraging, but it will have to

be determined whether the safety profile of this novel

K. Wolff / Dermatol Clin 22 (2004) 461–465 465

drug continues to be as favorable when it is admin-

istered over longer periods of time. Multicenter trials

are underway to answer these and other questions. The

experience available with this drug to date is unique,

however, and supports the notion that pimecrolimus

may also be effective for other T-cell–mediated skin

diseases. The efficacy of oral pimecrolimus already

has been shown in atopic dermatitis [22].

References

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[3] Neckermann G, Bavandi A, Meingassner JG. Atopic

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[4] Paul C, Graeber M, Stuetz A. Ascomycins, promising

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Surg 2001;20:233–41.

[7] Rappersberger K, Meingassner JG, Fialla R, Foedinger

D, Sterniczky B, Rauch S, et al. Clearing of psoriasis

by a novel immunosuppressive macrolide. J Invest

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[8] Van Leent EJM, Graber M, Thurston M, Wagenaar A,

Spuls PI, Bos J. Effectiveness of the ascomycin macro-

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tis. Arch Dermatol 1998;134:805–9.

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[10] Queille-Roussel C, Graeber M, Thurston M, Lacha-

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Contact Dermatitis 2000;42:149–50.

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Wagenaar A, Weidinger G, et al. The novel ascomycin

derivative SDZ ASM 981 is effective for psoriasis

when used topically under occlusion. Br J Dermatol

1998;139:992–6.

[12] Van Leent EJM, Ebelin ME, Burtin P, Spuls PI, Bos

JD. Low systemic concentrations of SDZ ASM 981

after topical treatment of extensive atopic dermatitis

lesions. Eur Acad Dermatol Venereol 1998;11:S133–4.

[13] Rappersberger K, Komar M, Ebelin ME, Scott G, Bur-

tin P, Creig G, et al. Pimecrolimus identifies a common

genomic anti-inflammatory profile, is clinically highly

effective in psoriasis and is well tolerated. J Invest

Dermatol 2002;119:876–87.

[14] Grassberger M, Baumruker T, Enz A, Hiestand P,

Hultsch T, Kalthoff F, et al. A novel anti-inflammatory

drug, SDZ ASM 981, for the treatment of skin dis-

eases: in vitro pharmacology. Br J Dermatol 1999;

141:264–73.

[15] Kalthoff FS, Chung J, Grassberger M, Stuetz A. SDZ

ASM 981 potently inhibits the induction of coreceptors

involved in the accessory cell-dependent activation of

inflammation-mediating T cells [abstract]. J Invest Der-

matol 2001;117:440.

[16] Hultsch T, Muller KD, Meingassner JG, Grassberger

M, Schopf RE, Knop J. Ascomycin macrolactam

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cytokines in RBL 2H3 mast cells in an immunophilin-

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Grassberger M, et al. The ascomycin macrolactam

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Immunol 2001;108: 275–80.

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M, Schuurman H, Tanner M, et al. SDZ ASM 981 is

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Dermatol Clin 22 (2004) 467–476

Retinoid therapy for psoriasis

Paul S. Yamauchi, MD, PhDa,b, Dalia Rizk, MDa, Nicholas J. Lowe, MDa,b,*

aClinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USAbDivision of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA

The systemic retinoids possess a remarkable range and is no longer available. The use of topical tazar-

of activities and clinical applications. They are an im-

portant form of therapy for patients with more severe

and resistant types of psoriasis. In general, with plaque

psoriasis, systemic retinoids are used most effectively

in combination with other forms of therapy, such as

phototherapy or other systemic agents. With general-

ized pustular psoriasis, they are effective as mono-

therapy and are frequently helpful for the control of

exfoliative psoriasis.

The Food and Drug and Administration (FDA) in

the United States has approved four derivatives of

systemic retinoids. Isotretinoin, whose main indica-

tion is for cystic acne, has been found to be ineffective

for plaque-type psoriasis as monotherapy treatment

[1]. Clinical responses, however, were observed with

isotretinoin for pustular psoriasis [1] and in conjunc-

tion with phototherapy for psoriasis [2,3]. Bexarotene

is approved for the treatment of cutaneous T-cell

lymphoma. One report showed that bexarotene at

0.5 to 2 mg/kg/d reduced lesions in patients with

moderate to severe psoriasis [4].

Topical retinoids for the treatment of psoriasis was

introduced in the United States in 1997 for the treat-

ment of plaque-type psoriasis. The only FDA-ap-

proved topical retinoid for psoriasis is tazarotene gel

and cream. Topical tazarotene has remained one of

the mainstay treatments for psoriasis.

This article focuses on the treatment of psoriasis

with acitretin, the only systemic retinoid approved for

psoriasis, and also briefly discusses its predecessor,

etretinate, which was replaced by acitretin in 1997


doi:10.1016/S0733-8635(03)00126-8

* Corresponding author. Clinical Research Specialists,

2001 Santa Monica Boulevard, Suite 490W, Santa Monica,

CA 90404.

E-mail address: [email protected] (N.J. Lowe).

otene is also discussed in detail. Combination therapy

of retinoids, both topical and systemic, with photo-

therapy and other therapeutic agents is described. In

addition, new retinoid analogues that are currently

undergoing clinical investigation at the time of prep-

aration of this article are mentioned. Finally, potential

toxicities and adverse effects associated with reti-

noids are discussed.

Chemistry and pharmacology

Fig. 1 shows the chemical structures of acitretin

and etretinate. Acitretin is the principle active metab-

olite of the prodrug, etretinate. They are very similar

to each other except that etretinate is the ethylester

form of acitretin. Because of this modification, how-

ever, under physiologic conditions etretinate is in an

uncharged state and is 50 times more lipophilic than

acitretin, which carries a negative charge [5]. Conse-

quently, etretinate is accumulated in adipose tissue

because of its high lipophilicity as opposed to acitre-

tin, which is not stored in fat. This is the main phar-

macokinetic reason why acitretin has a much shorter

half-life (approximately 50 hours) than etretinate

(approximately 120 days). In light of the highly tera-

togenic effects associated with systemic retinoids (dis-

cussed later) and because of its long half-life and

detection in the serum up to 2 years after discontinu-

ing treatment, etretinate was withdrawn from the

market in 1997 following the introduction of acitretin.

Studies have demonstrated that the concurrent

ingestion of ethanol with acitretin results in the trans-

esterification conversion of acitretin to etretinate [6,7].

Furthermore, higher alcohol consumption was linked

to higher etretinate concentrations. This is clinically

significant because the ingestion of alcohol extends the

s reserved.

Fig. 1. Chemical structures of etretinate (A) and acitretin (B).


half-life of acitretin to the same as that of etretinate

because of the enzymatic conversion. There are no data

documenting the spontaneous formation of acitretin

to etretinate in the absence of alcohol consumption.

It is also important to instruct patients that sys-

temic retinoids, including acitretin, have higher ab-

sorption and improved bioavailability when ingested

with food [8].

Fig. 2 illustrates the structure of tazarotene. Min-

imal systemic absorption of tazarotene occurs because

of rapid metabolism in the skin to the active metab-

olite, tazarotenic acid, which is systemically absorbed

and further metabolized. Tazarotenic acid is hydro-

philic and is rapidly metabolized causing no apparent

accumulation within body tissues. More than 99% of

tazarotenic acid is bound to plasma proteins. The

metabolism of tazarotene to tazarotenic acid occurs

through esterase hydrolysis in skin. On conversion,

tazarotenic acid exhibits a half-life of approximately

18 hours in both normal and psoriatic patients.

Mechanism of action

The exact molecular mechanism by which reti-

noids are able to exert their effects on psoriasis is

unknown. It has been demonstrated that acitretin

modulates the cellular differentiation of the epider-

mis, which results in deceased scaling, erythema, and

thickness of the plaques. There is also histologic

evidence that acitretin decreases the thickness of the

stratum corneum and the inflammation in the epider-

mis and dermis that is associated with psoriasis.

Tazarotene has multiple effects on keratinocyte

differentiation and proliferation, and inflammation

processes that contribute to psoriasis. In animal mod-

els, topical tazarotene blocks induction of ornithine

Fig. 2. Chemical structure of tazarotene.

decarboxylase activity, which is associated with cell

proliferation and expression. In vitro skin models and

cell cultures have demonstrated tazarotene suppresses

expression of MRP8, a marker of inflammation pres-

ent in high levels in the epidermis of psoriasis patients

and inhibits the formation of hyperkeratotic plaques.

Tazarotene also induces the expression of tazarotene-

induced gene 3, a suppressor gene that may inhibit

epidermal hyperproliferation in treated plaques.

There are two classes of nuclear retinoid recep-

tors that have been identified: the retinoic acid recep-

tor and retinoid X receptor. The retinoic acid receptors

and retinoid X receptors are each composed of three

different subtypes, labeled a, b, and g [9]. Nuclear

retinoid receptors exist as dimers, and retinoic acid

receptors are known to form heterodimers with reti-

noid X receptors [10]. Acitretin has been shown to

activate all three subtypes of retinoic acid receptor,

despite the absence of measurable binding to any of

the subtypes [10]. Tazarotenic acid selectively binds

to retinoic acid receptors and exhibits little affinity for

retinoid X receptors [11]. The function of these

retinoic acid receptor– retinoid X receptor hetero-

dimers is unknown in the skin. Such data indicate

that further studies are necessary to understand the

interaction of acitretin with nuclear receptors.

Monotherapy with systemic retinoids

Several studies have confirmed the efficacy of

acitretin treatment for different types of psoriasis

[12–19]. Pustular forms of psoriasis are more re-

sponsive to systemic retinoid monotherapy than

plaque-type psoriasis, which responds more slowly.

With plaque-type psoriasis, it is possible to enhance

the response to therapy by combining retinoids with

other treatments.

Pustular psoriasis

When acitretin is used as monotherapy for gen-

eralized pustular psoriasis, the initial dose is 25 to

50 mg per day, but higher doses may be required

in some patients. A rapid resolution of generalized

pustular psoriasis is achieved usually within 10 days


of initiating acitretin, which is probably the drug of

first choice for the treatment of this condition.

One advantage with acitretin for pustular psoriasis

over methotrexate is the absence of acute effects on

the peripheral blood count. Methotrexate may occa-

sionally produce acute leukopenia in patients with

generalized pustular psoriasis, which can lead to a

major toxicity risk in these patients. Pustular psoria-

sis leads to rapid proliferation of monocytes in the

S-phase of the cell cycle. Methotrexate, which blocks

DNA synthesis in these cells, may lead to failure of

maturation of cells beyond mitosis that leads to mye-

losuppression [20]. This phenomena is not clinically

evident with acitretin,

After the clearance of pustulation, the psoriasis

can continue to be controlled by reducing the dose of

acitretin (eg, decreasing acitretin at 25 mg per day to

25 mg every other day or to 10 mg per day). Some

patients, however, relapse and develop plaque-type

psoriasis. In such patients, alternative forms of ther-

apy, such as phototherapy, can gradually be instituted

in combination with acitretin. When the psoriasis

improves, the retinoid then can be tapered down.

In women of childbearing age, acitretin should

probably be avoided whenever possible, even for

pustular psoriasis. If acitretin is required, strict birth

control practices must be adhered to and alcohol must

be avoided. In such situations, oral isotretinoin with

its shorter half-life of 10 to 20 hours may be used

as an alternative to control the pustulation. Starting

doses range from 1 to 1.5 mg/kg/d. If necessary,

phototherapy may be initiated to control the psoriasis.

Another situation in which acitretin is effective is

in the treatment of palmoplantar pustular psoriasis,

particularly where there is significant hyperkeratosis

or severe pustulation. Isotretinoin may be used as an

alternative in women who are fertile. Retinoid ther-

apy reduces the degree of hyperkeratosis and pustu-

lation. If monotherapy with acitretin is not achieving

the desired results, then combination with psoralen

plus UVA (PUVA) phototherapy is extremely useful.

Alternatively, hydroxyurea at 500 mg twice a day in

conjunction with acitretin is another way of control-

ling palmoplantar pustular psoriasis.

Exfoliative erythrodermic psoriasis

In exfoliative erythrodermic psoriasis, acitretin is

useful at starting doses of 25 to 50 mg per day. It

is advantageous to use emollients liberally along

with the application of mild topical corticosteroids

(eg, triamcinolone acetonide [0.025% cream or oint-

ment]) under occlusion to achieve more rapid resolu-

tion of psoriasis.

Rarely, patients with severe exfoliative erythro-

dermic psoriasis may need to use a combination of

acitretin with methotrexate. This combination should

only be used rarely and, when it is, only with careful

monitoring of the peripheral blood count and liver

function tests.

Another option for the treatment of exfoliative

psoriasis is to use methotrexate or cyclosporine

therapy to achieve a rapid improvement after which

the methotrexate or cyclosporine dosage is reduced

and low doses of acitretin (10 to 25 mg per day)

are introduced.

Combination therapy for moderate to severe

plaque psoriasis

In patients with severe plaque psoriasis, especially

if the condition is extensive with hyperkeratosis, the

use of a retinoid plus other forms of treatment, par-

ticularly phototherapy, has been shown to be highly

effective. The dose of the retinoid or the amount of

alternative therapy required when used separately can

be reduced if used in combination with each other.

Acitretin and psoralen plus UVA phototherapy

For combination therapy, the optimum dose for

acitretin is 0.3 mg/kg/d, either 2 weeks before starting

phototherapy or at the same time. The increases in

ultraviolet radiation should be more gradual and

cautious than in patients not taking systemic retinoids

because of an increased risk of ultraviolet radiation-

induced erythema. This is not a true photosensitivity,

but probably represents increased epidermal trans-

mission of the ultraviolet radiation because of altered

optical properties of the stratum corneum caused by

the retinoid.

The concomitant use of PUVA with acitretin has

been studied by several investigators [21–27]. Most

patients receiving the combination improve more

quickly than with PUVA or acitretin alone. In addi-

tion, the total number of ultraviolet radiation exposures

can be reduced. Following clearance of psoriasis,

various maintenance regimens may be used. Acitretin

administered in low maintenance doses can be effec-

tive, or acitretin therapy can be stopped and mainte-

nance therapy is undertaken solely with PUVA.

In a double-blinded comparative study, patients

with severe, widespread psoriasis were randomized to

receive either PUVA alone or PUVA in combination

with acitretin [21]. Eighty percent of patients with

PUVA alone demonstrated marked or complete clear-

ing of psoriasis, whereas 96% of patients who re-


ceived adjunctive therapy with PUVA plus acitretin

exhibited the same degree of improvement. The mean

cumulative UVA dose given to patients who received

combination therapy was 42% less than that required

for patients who received PUVA alone.

When patients with psoriasis were initially treated

with acitretin at 50 mg per day for 2 weeks followed

by decreasing the amount to 25 mg per day in

conjunction with PUVA for up to 10 weeks, there

was a 40.5% reduction in the total cumulative UVA

dose, a decrease of the overall duration of treatment

by almost 18 days, and a reduction in the number of

PUVA treatments by nearly six sessions, when com-

pared with treatment with PUVA alone [22].

Bath PUVA together with acitretin is another

option for treatment of patents with pustular, plaque-

type, or erythrodermic psoriasis [24]. After 4 weeks of

treatment, patients had greater than a 90% response

rate with no relapse after 3 months.

The safety of PUVA is now of concern because of

the risk of melanoma and nonmelanoma skin cancer.

Whether or not acitretin alters this risk is unknown at

this stage.

Acitretin and UVB phototherapy

Acitretin plus UVB therapy is another combina-

tion form of therapy to treat psoriasis and has been

investigated [28–30]. This option can be used for

those patients who are intolerant of side effects

associated with oral psoralens, such as gastrointesti-

nal toxicity.

Treatment with UVB combined with acitretin at

50 mg per day or placebo resulted in greater clearance

with fewer treatments and smaller amounts of UVB

radiation when acitretin was used compared with

placebo [29]. A 74% improvement in the psoriasis

score was noted in patients treated with acitretin plus

UVB compared with 35% with UVB only. In addi-

tion, in the same study, when only acitretin was used,

there was a 42% reduction in psoriasis. There was a

decrease in the total number of hours of exposure

time to UVB therapy by approximately 6 hours when

acitretin was used to attain clearance compared with

light treatment alone. Another study demonstrated

that when patients with psoriasis were initially treated

with 35 mg per day of acitretin during the first

4 weeks of therapy followed by concomitant therapy

with UVB radiation plus 25 mg per day of acitretin

and compared with the placebo group, there was a

79% decrease in the psoriasis severity index in the

acitretin and UVB group and 35% reduction in the

UVB-only group [28]. In addition, the medium cu-

mulative dose to achieve 75% clinical improvement

was 41.5% lower when acitretin was combined.

Finally, the number of treatments to attain 80% to

100% clearance of psoriatic plaques was decreased

by 5.6 sessions with UVB plus acitretin versus UVB

only [30]. The total UVB dose and minimal erythema

dose was reduced by approximately 20%.

In summary, reasons for combining PUVA or

UVB with systemic retinoids include the following:

1. Better clearance

2. Decreased cumulative ultraviolet doses

3. The number of treatments and duration of PUVA

therapy is reduced

4. The possibility of reduction or cessation of acit-

retin therapy before the occurrence of side ef-

fects, such as hyperlipidemia or alopecia

Combination therapy with other agents

Combination therapy of acitretin with other mo-

dalities other than light therapy can be used to control

psoriasis. Concomitant treatment with acitretin and

topical calcipotriene may help reduce psoriatic pla-

ques better than with either alone [31,32]. In addition,

acitretin at 25 mg per day together with hydroxyurea,

500 mg twice daily, has been effective for some pa-

tients with chronic plaque psoriasis and pustular

psoriasis. When using combination therapy with aci-

tretin and hydroxyurea, the complete blood count

should be carefully monitored.

Combination therapy with immunomodulatory agents

New-generation drugs are being developed that

selectively target key cytokines and receptor mole-

cules on T cells and antigen-presenting cells that

are involved in the pathogenesis of psoriasis. These

immunomodulators are in the form of monoclonal

antibodies or fusion proteins that are administered

as injections either subcutaneously, intramuscularly,

or intravenously.

One biologic agent that is currently on the market

and is FDA-approved for rheumatoid arthritis and

psoriatic arthritis is etanercept. Etanercept is currently

undergoing clinical trials as monotherapy treatment

for psoriasis. Etanercept is a fusion protein that acts as

a soluble tumor necrosis factor and competitively

binds to tumor necrosis factor thereby preventing

tumor necrosis factor from binding to cell surface

receptors on target cells. Because tumor necrosis

factor is involved in the pathogenesis of psoriasis,

through such inhibition, etanercept serves as an anti-

inflammatory agent that is beneficial in the treatment

Fig. 3. Patient with recalcitrant plaque-type psoriasis (A) before and (B) after treatment with 25 mg acitretin each day plus

etanercept, 25 mg twice a week subcutaneously for 8 weeks.


of psoriasis. A recent report demonstrated that com-

bination therapy with etanercept together with various

systemic agents, such as cyclosporine, methotrexate,

acitretin, or hydroxyurea, in patients with severe

recalcitrant psoriasis resulted in marked improvement

and reduction in the PASI score [33]. More impor-

tantly, no added toxicity was seen in these patients

when etanercept was combined with a systemic agent.

Fig. 3 shows a patient with refractory psoriasis who

responded well to combination therapy with 25 mg

per day of acitretin plus twice-weekly 25-mg subcu-

taneous injections of etanercept.

Combination treatment with systemic agents and

immunomodulators underscores the significance of

treating psoriasis in the future. With the advent of

new biologic agents and the existing systemics, this

new approach to combination therapy may provide an

impetus in controlling psoriasis that previously was

difficult to treat.

Other systemic retinoids

Oral tazarotene

An oral form of tazarotene (a topical retinoid

approved for plaque psoriasis and acne) has recently

been developed that is currently not available on the

market during the preparation of this article. Tazar-

otene is converted to its active metabolite, tazarotenic

acid, which has a short elimination half-life of 7 to

12 hours (Allergan, unpublished data).

In a dose escalation study, 181 patients with mod-

erate to severe plaque psoriasis received daily doses

of oral tazarotene (0.4 to 6.3 mg) or placebo (Lowe

et al, submitted for publication). Optimal efficacy

was seen with the 4.2-mg dose. At this dosage, the

body surface area involvement was reduced by 17%

at week 12 and 82% of patients were satisfied or very

satisfied with oral tazarotene. Fig. 4 shows a patient

who had good clearance of psoriatic plaques with oral

tazarotene at 4.2 mg per day by week 12.

The only significant adverse effect noted was chei-

litis at doses of 2.8 mg or higher. There were no other

dose-related adverse events, such as increased liver

function enzymes, hyperlipidemia, or changes in the

hematologic profile. The shorter half-life of oral taza-

rotene may potentially be a useful alternative for sys-

temic retinoid treatment in women of childbearing

age with psoriasis.

Toxicities and adverse reactions associated with

systemic retinoids

Teratogenicity

All systemic retinoids are highly teratogenic with

a pregnancy category of X rated by the FDA. Major

human fetal abnormalities associated with retinoids

include meningomyelocele, meningoencephalocele,

multiple bony malformations, facial dysmorphia, low-

set ears, high palate, decreased cranial volume alter-

ations, and cardiovascular malformations.

Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks.


In light of its teratogenicity, acitretin must not

be used by women who are pregnant or who intend

to become pregnant during therapy or at any time

for at least 3 years following discontinuation of

therapy. In addition, acitretin must not be used by

women who may not use reliable contraception while

taking acitretin or for at least 3 years following

cessation of treatment. In addition, the current guide-

line states that ethanol must not be ingested by female

patients either during treatment with acitretin or for

2 months after discontinuing acitretin to avoid con-

version into etretinate, which carries a much longer

elimination half-life. This is caused by the trans-

esterification of acitretin to etretinate by ethanol as

previously discussed.

Mucocutaneous toxicity

Mucocutaneous toxicity occurs with all of the

systemic retinoids [34]. The common mucocutaneous

side-effects in order of frequency are cheilitis, skin

peeling, alopecia, xerosis, rhinitis, nail dystrophy,

epistaxis, sticky skin, retinoid dermatitis, and xeroph-

thalmia. Hair loss may occur a few weeks after

initiation of treatment and ceases 6 to 8 weeks after

discontinuation of therapy. In rare cases, chronic hair

loss has occurred. Patients frequently find these

symptoms extremely difficult to accept. Rapid reduc-

tion in retinoid therapy is desirable to reduce the

impact on patients of these toxicity problems. Some

studies have suggested that 800 IU of vitamin E daily

may reduce some of the mucocutaneous effects of

systemic retinoids [35].

Arthralgias and myalgias

Some patients develop muscle pain and myalgias

with or without an elevation of creatine phospho-

kinase. In general, it is wise for patients to avoid

excessive muscle exercising, particularly excessive

weight lifting and contact sports, because these forms

of activity may increase such risks. Arthralgias occur

in a small percentage of patients and disappear on

discontinuation of therapy.

Pseudotumor cerebri

Acitretin and other systemic retinoids have been

associated with cases of pseudotumor cerebri (benign

intracranial hypertension). Such symptoms and signs

include papilledema, severe headaches, nausea and

vomiting, and visual disturbances. If pseudotumor

cerebri is suspected, ophthalmologic evaluation for

papilledema should be conducted and if present, the

retinoid should be discontinued immediately. Oral

retinoids should not be taken with tetracycline or

tetracycline derivatives because of increased risk of

pseudotumor cerebri.

Ophthalmologic effects

Ocular toxicity does not seem to be a major prob-

lem with acitretin, although rare cases of disturbances

of color vision have been recorded. Most of the ocu-

lar symptoms have been mucocutaneous in nature,

such as dry eyes, irritation of eyes, and loss of brow

and lashes. Other side effects, such as blurred vision,

cataracts, decreased night vision, and diplopia, are

much less common.

Skeletal toxicity

There is some concern that long-term high-dose

acitretin therapy is associated with changes that re-

semble diffuse idiopathic skeletal hyperostosis, which

include anterior spinal ligamentous calcification and

the formation of osteophytes and bony bridges. Disk

space narrowing is not evident in diffuse idiopathic


skeletal hyperostosis. There seems to be a cumulative

threshold dose of 25 to 30 g etretinate below which

skeletal toxicity is not seen radiographically.

Psychiatric effects

There are no recorded incidents of suicide or

depression linked to patients on systemic retinoid

therapy for the treatment of psoriasis. There is clearly

a background of depression with some psoriasis

patients but this has not been noted to be aggra-

vated by acitretin (Lowe NJ, unpublished observa-

tions, 2002).

Hyperlipidemia

Hyperlipidemia occurs in approximately 25% to

50% of patients. Occasionally, severe levels reaching

five to eight times the normal value occur, but usually

levels are increased two to three times the normal. The

incidence of pancreatitis or eruptive xanthomas with

increased triglyceride levels is uncommon. In addi-

tion, levels of high-density lipoproteins decrease with

oral retinoids. These abnormal levels are reversible on

cessation of therapy. Patients with an increased tend-

ency to develop hypertriglyceridemia include those

with diabetes mellitus, obesity, increased alcohol in-

take, or a familial history of these conditions. There

are a number of ways to manage hyperlipidemia

including low-fat diets, reduced alcohol intake, physi-

cal activity, the use of polyunsaturated fish-oil supple-

ments, and prescribing lipid-lowering drugs.

Hepatotoxicity

All the systemic retinoids have the potential for

liver toxicity. Elevations of aspartate transaminase

(serum glutamic-oxaloacetic transaminase), alanine

transaminase (serum glutamate pyruvate transami-

nase), g-glutamyltransferase (GGTP), low-density li-

poproteins, and alkaline phosphatase have occurred

in 33% of patients treated with acitretin. During the

clinical trials in the United States for acitretin, 3.8%

of patients had sufficient elevation of liver function

tests that they were discontinued from further treat-

ment. If hepatotoxicity is suspected with acitretin, the

drug should be discontinued and a liver work-up

should be conducted.

Frequency of follow-up

Blood investigations should include a full blood

count; a complete metabolic panel including liver

enzymes; renal function tests; creatine phosphoki-

nase; and a lipid panel including triglycerides, cho-

lesterol, and high-density lipoproteins. In all women

of childbearing age, a monthly pregnancy test must

be conducted. These investigations should be per-

formed initially every 2 weeks while on clearance

doses, reducing to monthly or 2-monthly assessments

depending on the maintenance dose required. There is

presently no requirement for liver biopsy.

Guidelines for the use of systemic retinoids in

psoriasis

The following guidelines apply for the use of sys-

temic retinoids in psoriasis:

1. Acitretin can be prescribed for male patients or

postmenopausal female patients. It is up to the

clinician’s discretion to prescribe acitretin in

women of childbearing age keeping in mind the

strict guidelines associated with acitretin’s

teratogenicity. If there is any suggestion that a

woman desires pregnancy, or suspicion that

adequate birth control methods will not be

practiced, or abstinence from alcohol cannot be

avoided, then acitretin should not be prescribed

to that woman.

2. Careful pretreatment and screening should be

performed to exclude the possibility of hyper-

lipidemia and hepatotoxicity. Risk factors

for hyperlipidemia (diabetes mellitus, obesity)

should be looked for and a history of alco-

hol use and hepatitis should be screened in

every patient.

3. Retinoids should be considered as monother-

apy in generalized pustular psoriasis.

4. Combination therapy of acitretin with PUVA or

UVB is advised in patients with severe plaque

psoriasis and localized palmoplantar psoriasis,

including local pustular psoriasis of the palms

and soles.

5. Combination therapy of acitretin with hy-

droxyurea may be beneficial in some patients

with plaque or pustular psoriasis. In addition,

combination therapy with the retinoids and

the new immunomodulatory biologic agents

may play pivotal roles in the future treatment

of psoriasis.

6. New retinoids, such as oral tazarotene, seem to

have a good safety profile. Longer-term studies

and combination studies with this drug are ea-

gerly awaited.


Topical tazarotene

There are four formulations for topical tazarotene:

(1) 0.05% gel, (2) 0.1% gel, (3) 0.05% cream, and

(4) 0.1% cream. All four vehicles and strengths can

be used for plaque psoriasis. In general, gels and the

more concentrated strengths tend to have a higher in-

cidence of irritation, pruritus, erythema, stinging, and

desquamation. These side effects are most apparent on

initial applications but alleviate with continuous usage.

In two multicentered, double-blinded, random-

ized, placebo-controlled studies involving 660 pa-

tients, tazarotene gels 0.05% and 0.1% applied once

a day for 3 months were found to be efficacious and

safe for the treatment of plaque psoriasis. The most

profound effect with tazarotene gel was the improve-

ment of plaque elevation [36].

Results of two multicenter studies showed that

topical therapy once daily with tazarotene in a cream

formulation at concentrations of 0.05% or 0.1% was

effective in the treatment of plaque psoriasis [37]. A

total of 1303 patients participated in these random-

ized, double-blinded, placebo-controlled trails in

which tazarotene creams 0.1% and 0.05% or vehi-

cle were applied daily to all psoriatic lesions for

12 weeks followed by a 12-week posttreatment pe-

riod. Tazarotene creams 0.05% and 0.1% were sig-

nificantly more effective than vehicle in terms of

clinical success rates and in reducing the severity of

the clinical signs of plaque psoriasis. Tazarotene

cream 0.1% was generally more effective, although

slightly less well tolerated, than the 0.05% cream.

Both tazarotene concentrations showed good mainte-

nance of therapeutic effect during a 12-week post-

treatment period. Tazarotene creams 0.05% and 0.1%

for the treatment of psoriasis were found to be safe

with acceptable tolerability.

To counteract potential irritation from tazarotene,

topical corticosteroids may be combined to the

lesions. A study showed that application of tazarotene

in the evening and a mid- to high-potency topical

corticosteroids in the morning achieved significantly

greater reductions in scaling, erythema, and overall

lesional severity, and a decreased incidence of adverse

events [38]. Combination therapy by alternating tazar-

otene and high-potency steroids each day significantly

increased the treatment success rate and lowered

incidence of treatment-related adverse effects [39].

Short contact with tazarotene minimizes the local

irritation on the skin. For patients who are beginning

therapy with tazarotene, initial application times of

15 minutes in the evenings and then washing off the

tazarotene decreases the incidence of stinging, burn-

ing, and erythema. As the patient becomes accus-

tomed and more tolerant to tazarotene, application

times are prolonged incrementally until patients can

leave it on overnight.

Combination treatment using tazarotene with ul-

traviolet therapy has become very popular for the

treatment of plaque psoriasis [40–43].The efficacy of

tazarotene reported in clinical trials suggests that this

drug may help to improve the efficacy of photo-

therapy, and perhaps reduce the ultraviolet light

exposure required without introducing additional,

clinically significant problems. Broad or narrow band

UVB plus tazarotene combination achieves greater

reductions in the elevation and scaling of difficult-to-

treat psoriatic plaques than UVB phototherapy alone.

The tazarotene combination therapy also achieved

initial treatment success in less than half the time

needed with phototherapy alone. Combining UVB

phototherapy with tazarotene treatment seems to offer

a valuable therapeutic option that is more efficacious

and faster than UVB phototherapy alone.

Summary

Both systemic and topical retinoids provide an

excellent alternative for the treatment of psoriasis.

Retinoids are generally used as combination therapy

with other treatment modalities, such as phototherapy

or other topical or systemic agents, and can be com-

bined with the newer biologic agents, such as eta-

nercept. Newer retinoids are being developed to treat

psoriasis with the hope of a less toxic side effect

profile. For now, retinoids remain a mainstay for the

treatment of psoriasis.

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Dermatol Clin 22 (2004) 477–486

Psoriatic arthritis: prevalence, diagnosis, and review of

therapy for the dermatologist

Eric M. Ruderman, MD*, Siddharth Tambar, MD

Department of Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw 2300,

Chicago, IL 60611, USA

Psoriatic arthritis (PsA) is an inflammatory arthri- and Wright [4] have described five different clinical

tis that is commonly associated with psoriasis. Char-

acteristic symptoms of any inflammatory arthritis

include pain and stiffness in affected joints, morning

stiffness lasting longer than 30 minutes, and stiffness

that is accentuated by prolonged rest and relieved

with activity.

Prevalence and presentation of disease

Although psoriasis affects 1% to 3% of the United

States population, it has been reported that 7% to

31% of patients with psoriasis also have PsA [1].

The wide range may relate to the variability in the

populations studied, from community-based cohorts

to referral clinics or hospitalized patients. There is an

equal gender distribution, onset of joint complaints is

typically in the 30s to 50s, and whites have a greater

incidence as compared with African Americans and

Asians. In the United States, the incidence of new

cases is approximately 6 per 100,000, and the preva-

lence is 100 per 100,000 [2,3].

Although previously believed to be a less severe

variant of rheumatoid arthritis (RA), PsA is now

considered a distinct disease process as first described

by Moll and Wright [4]. When compared with RA,

patients with PsA tend to have less tender joints and

less prominent joint effusions. Significant joint de-

struction and pain, however, are still possible. Moll


doi:10.1016/S0733-8635(03)00127-X



(E.M. Ruderman).

patterns of joint involvement:

1. Asymmetric oligoarthritis, where fewer than

five joints are affected in an asymmetric

distribution.

2. Symmetric polyarthritis, in which more than

five joints in a symmetric pattern are in-

volved. This pattern is almost indistinguishable

from RA.

3. Distal arthritis, characterized by distal interpha-

langeal joint involvement.

4. Arthritis mutilans, a destructive arthritis that re-

sults in severe deformities.

5. Spondyloarthropathy, disease affecting the spine

(spondylitis), sacrum-sacroiliac joints (sacro-

iliitis), and hip-shoulder joints with or without

peripheral arthritis.

Studies done since Moll and Wright [4] published

their classification scheme have not found the same

distribution in all patient populations [5]. Further-

more, some patients present with more than one

pattern, and many undergo a change in the pattern

of their arthritis during follow-up [6,7]. One proposed

disease classification is limited to just three patterns:

(1) asymmetric oligoarthritis, (2) symmetric polyar-

thritis, and (3) spondyloarthropathy. Other series

have suggested that nearly all patients fit into the

second pattern [8,9]. Another group has suggested

that the disease is best divided into just two subsets:

peripheral arthritis, and axial (spinal) disease with or

without peripheral arthritis [7]. Oligoarthritis has

been considered the most common initial presenta-

tion, although recent series have questioned this

s reserved.

Box 2. Radiographic features of PsA

Peripheral

Asymmetric distributionDistal interphalyngeal joint

involvementPeriostitisPreservation of bone densityBony ankylosisPencil-in-cup deformities

E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486478

presumption [7,10]. Although rare, isolated distal

interphalangeal (DIP) synovitis and arthritis mutilans

are considered the most specific joint findings in PsA.

The pattern of severity of the joint disease is not

related to the pattern or severity of the skin disease.

In the majoriy of patients, however, skin findings

develop years before the arthritis [11]. At present,

most information on disease patterns is observational.

Current efforts to develop better outcomes measure-

ments in PsA may ultimately produce characteriza-

tions of disease patterns that are more clearly related

to pathogenesis or response to specific therapies.

Axial

Sacroiliitis (may be asymmetrical)Vertebral syndesmophytesIntervertebral ankylosisParavertebral ossification

Diagnosis

Psoriatic arthritis is considered a seronegative

spondyloarthropathy, a group of diseases that in-

cludes ankylosing spondylitis, reactive arthritis or

Reiter’s syndrome, and the arthritis associated with

inflammatory bowel disease. These diseases share a

predilection for asymmetric peripheral arthritis and

axial or spinal involvement. As with other spondy-

loarthropathies, musculoskeletal manifestations of

PsA may also include inflammation at the site of

attachment of tendons and ligaments (enthesitis),

especially at the Achilles tendon insertion and the

insertion of the plantar fascia into the calcaneus.

Dactylitis, also described as a sausage digit, may also

be seen. These digits develop swelling and tenderness

of the entire finger or toe because of inflammation of

the tendons along with the involved joints. Inflam-

matory eye involvement has been observed in up to

one third of patients with PsA [11].

The diagnosis of PsA is based on the clinical

presentation of joint complaints, a history of psoria-

sis, radiographic changes, and a possible family

history of psoriasis. The presence of other arthritis

conditions makes the diagnosis of PsA difficult at

times; a diagnosis of PsA requires the exclusion of

other possible causes of joint symptoms (Box 1).

Confounders include the coexistence of gout and

Box 1. Differential diagnosis of PsA

OsteoarthritisGoutRheumatoid arthritisReactive arthritisAnkylosing spondylitisInflammatory bowel disease–related

arthritis

osteoarthritis in some patients. Gouty arthritis is

commonly seen in association with psoriasis, pre-

sumably related to the hyperuricemia resulting from

rapid skin cell turnover [12]. Osteoarthritis is a

common disease, and in women DIP involvement

with Heberden’s nodes may be mistaken for the DIP

synovitis seen in PsA. The presence of soft tissue

swelling and erythema around the joint may help

to distinguish PsA changes from osteoarthritis.

Finally, RA or another arthritic condition may be

present in a patient who also happens to have

unrelated skin psoriasis.

There are no specific laboratory studies used in

making the diagnosis of PsA. An elevated erythrocyte

sedimentation rate, C-reactive protein, or leukocyto-

sis is seen in one third of patients, consistent with a

nonspecific inflammatory state [13].Thecommon find-

ing of normal acute-phase reactants may help to dis-

tinguish PsA from RA. Although PsA is classically

considered a rheumatoid factor–negative disease,

both antinuclear antibodies and rheumatoid factor

may be present in 10% of patients [5].

There are common and distinct radiographic

changes in PsA (Box 2). In one study, radiographic

damage was found in two thirds of patients at initial

presentation [14]. Bone changes in PsA may be dis-

tinct from the findings in other inflammatory ar-

thropathies, and may include a combination of

erosion and new bone formation in distal joints.

Distinctive radiographic features of PsA include

asymmetric oligoarticular distribution, relative ab-

sence of periarticular osteopenia, involvement of

E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486 479

the DIP joints, and involvement of the sacroiliac

joints [15]. Other changes include joint space loss

with or without ankylosis; destruction of isolated

joints; fluffy periostitis; and lysis of the terminal

phalanges (acro-osteolysis). Pencil-in-cup appearance

of phalanges is also described, and is a combination

of tapering of the middle phalanx and bony pro-

liferation at the base of the distal phalanx. In contrast

to RA, bone density in PsA is usually preserved [16].

Findings in the axial skeleton include para-

vertebral ossification, vertebral syndesmophytes,

asymmetric sacroiliitis, apophyseal sclerosis, and

calcification of the interspinous or anterior ligaments

[15]. Cervical spine findings include intervertebral

disk-space narrowing and ankylosis; both atlantoaxial

fusion and subluxation may be found in the upper

cervical spine. Temporomandibular joint involve-

ment, with condylar erosions and condylar osteolysis,

may occur [17].

MRI may be more sensitive than plain radio-

graphs in documenting the articular, periarticular,

and soft tissue inflammation in PsA [18]. MRI seems

to be especially useful in demonstrating entheseal

changes, such as inflammation and new bone forma-

tion, and may be useful in differentiating an early

spondyloarthropathy from early RA [19,20].

Damage and disability

Opinions differ as to the extent of joint dam-

age and subsequent disability in PsA. Some popula-

tion studies suggest a disease with a relatively

benign course. An evaluation of psoriasis in Olmsted

County, Minnesota, from 1982 through 1991 identi-

fied 66 cases of PsA among 1056 confirmed cases of

psoriasis [3]. During the 10-year follow-up period,

only 3% and 8% of the patients developed erosive

changes on foot and hand radiographs, respectively

[3]. Only 25 patients developed extra-articular mani-

festations of disease, including enthesitis, inflamma-

tory eye disease, and urethritis. A population study in

Finland showed a similar incidence rate of PsA, but

found that 46% of the patients developed erosive

joint disease [21]. The difference may relate to an

ascertainment bias in the Finnish study that limited its

cohort to patients receiving medication for their PsA.

Cohort analyses of referral populations also sug-

gest that PsA is frequently associated with a signifi-

cant amount of erosive arthritis [10,14]. In a study

of 220 patients with PsA seen at a Canadian re-

ferral center, Gladman et al [14] found that 67% of

the patients had erosive disease. The presence of

DIP joint involvement and symmetrical polyarthri-

tis were associated with the most advanced radio-

logic changes in this study. Similarly, Torre Alonso

et al [10] reported on a Spanish cohort of 180 pa-

tients with PsA, 57% of whom had erosive disease

on radiographs.

Although PsA has traditionally been viewed as a

disease with a benign prognosis, radiographic evi-

dence, such as that described previously, indicates

that the disease is more progressive and destructive

than previously thought. In a comparison of radio-

graphic changes in PsA and RA, there was no

significant difference in the severity of damage seen

in hands and feet [22]. Furthermore, both groups had

similar numbers of joints affected by significant

radiologic damage. Although the highest rate of

peripheral joint involvement in PsA seems to be

within 12 months of disease onset, the disease has

been shown to be progressive in terms of the number

of joints affected and the damage to those joints [23].

It has been suggested that possible indicators of poor

prognosis include younger age at onset, extensive

skin involvement, and certain HLA antigens [24].

Although the degree of skin involvement and HLA

type do not demonstrate a consistent impact between

studies, the most reliable factor in determining a poor

prognosis is polyarticular onset of disease. In fact, in

a recent prospective study the only independent risk

factor predictive of erosive and deforming disease

over time was a polyarticular onset of disease [25].

Disability and reduced quality of life in psoriatic

arthritis may be caused by factors other than joint

damage alone. In a recent study comparing 47 pa-

tients with RA and PsA of equivalent duration, the

patients with RA seemed to have greater disease

severity, as suggested both by radiographic damage

and the medication they were taking [26]. Function

and quality of life scores were similar for both

groups, however, leading the authors to suggest that

this finding may have resulted from the additional

burden of skin disease in the PsA patients [26]. In a

separate study, PsA patients reported more limitations

because of emotional problems than a comparison

group of RA patients [27]. This finding is consistent

with the psychosocial disability that has been

reported in connection with psoriasis [28].

In most patients (70%), arthritis symptoms de-

velop years after skin changes present. In 10% to

15%, arthritis precedes psoriasis, yet a significant

family history of psoriasis may help in making the

diagnosis. In 15% of patients the initial presentation

includes arthritis and psoriasis together [11,14]. The

correlation between skin disease and arthritis is

limited; only 35% of patients with PsA note a re-

lationship between the severity of their skin disease


and joint activity [14]. With respect to predictors of

future arthritis in patients with isolated psoriasis, nail

involvement is the only clinical feature that identifies

patients with psoriasis who are likely to develop

arthritis [15]. In fact, nail involvement is found in

80% of patients with PsA [29]. Moreover, the only

significant relationship shown between severity of

arthritis and psoriasis has been DIP joint activity and

nail involvement [30].

Disease pathogenesis

The pathogenesis of PsA is unknown, but genetic,

environmental, and immunologic factors all seem

to influence disease susceptibility. Forty percent of

patients with psoriasis or PsA have a first-degree rela-

tive with disease [29]. Individual HLA antigens, found

on the short arm of chromosome 6, have been asso-

ciated with PsA, and may be involved in antigen pre-

sentation, or they may be in linkage disequilibrium

with another disease susceptibility gene. HLA anti-

gens B13, B17, B38, B39, B27, Cw*0602, DR4, and

DR7 have been implicated [29,31,32]. HLA-B7 and

HLA-B27 are found more commonly in patients with

PsA compared with patients with isolated skin pso-

riasis [29]. HLA-B27 itself is actually more common

in the other seronegative spondyloarthropathies, how-

ever, and is only found in approximately 40% of

patients with PsA. HLA-DR4, which is strongly

associated with RA, is also associated with the poly-

articular form of PsA [29]. HLA-B39, -B27, and

-DQw3 have been reported to be associated with

disease progression [33]. Genetic inheritance of genes

other than HLA antigens also may be important. A

separate gene locus on chromosome 16 has also been

associated with PsA, with inheritance from the father

being more strongly associated with developing the

condition when compared with inheritance from the

mother of the same allele [34].

Just as with the inflammatory response seen in

psoriatic skin lesions, immunologic factors have been

implicated within the joint spaces in PsA. T cells

found in plasma and synovium are predominantly

CD8+ cells and are activated, expressing HLA-DR

molecules and interleukin (IL)-2 receptors [35].

These activated cells also secrete multiple proinflam-

matory cytokines and within the synovium there are

elevated levels of tumor necrosis factor (TNF)-a,IL-1, IL-2, and the anti-inflammatory cytokine

IL-10 [36]. The overall milieu results in proliferation

and activation of synovial and epidermal fibroblasts.

At the same time there are increased numbers of

osteoclast precursors, resulting in osteoclastogenesis

and bony erosions [37].

Environmental factors are also believed to play a

role in pathogenesis of PsA. An infectious etiology

has been proposed. Elevated levels of IgG antibody to

the C-terminal of Streptococcus pyogenes M protein

have been found compared with patients with only

skin psoriasis, RA, and controls [38]. Exacerbations

of both psoriasis and PsA have been reported in the

context of HIV infection; however, the viral role in

this situation is not clear [39]. Trauma may also be

involved, similar to the Koebner phenomenon in

which patients may develop psoriasis at site of pre-

vious trauma. Some patients with PsA have reported

a history of trauma before the onset of their dis-

ease [40].

Treatment

Treatment of PsA has generally been similar to

treatment of other types of inflammatory arthritis,

including RA. Physical therapy and other nonmedical

treatments may be useful. Nonsteroidal anti-inflam-

matory drugs have been shown to be effective in PsA

[41,42]. Some authors have raised concern that non-

steroidal anti-inflammatory drugs may exacerbate the

associated skin disease [43,44]. Corticosteroids are

also used, although again there is some concern over

exacerbation of skin disease, particularly after with-

drawal of relatively short courses, and concern that

corticosteroids may cause the skin disease to become

resistant to other therapies [2,44]. Other authors have

suggested that the use of corticosteroids may be an

important risk for the development of PsA in a patient

with psoriasis [45].

Historically, the management of PsA unresponsive

to anti-inflammatory therapy has borrowed from the

disease-modifying antirheumatic drugs commonly

used to treat RA. Injectable gold salts, although

infrequently used at the present time, were one of

the earliest second-line therapies for RA, and clinical

benefit from the use of these agents in PsA has been

reported [46–48]. Similar to the experience in RA,

auranofin, the oral form of gold, seems to be less

effective than the parenteral forms, although it may

be better tolerated [48,49]. Hydroxychloroquine and

other antimalarials have been reported to be effective

in PsA in uncontrolled series, although hydroxy-

chloroquine has been reported to exacerbate skin

disease in some cases [50].

A meta-analysis of 12 clinical trials of various

medications for PsA found statistical benefit relative

to placebo only for intravenous methotrexate, sulfa-

Box 4. American College of Rheumatologyresponse criteria

Both

20% improvement in tender-jointcount

20% improvement in swollen-jointcount

Plus 20% improvement in three of five ofthe following criteria

Patient pain assessment (100 mm vi-sual analog scale)

Patient global assessment (100 mm vi-sual analog scale)

Physician global assessment (100 mmvisual analog scale)

Patient self-assessed function (HealthAssessment Questionnaire or similarinstrument)

Acute-phase reactant value (erythro-cyte sedimentation rate or C-reac-tive protein)


salazine, azathioprine, and etretinate, although study-

related issues limited the interpretation of the results

of the last two [51]. The authors noted a significant

placebo response in all 12 trials, and suggested that

this limits the ability of uncontrolled trials to guide

treatment decisions in PsA.

Despite the issue of placebo response, anecdotal

reports and open series may provide a clue to the

value of a particular therapy by using a variety of

measurements of disease activity. Controlled clinical

trials, however, require predetermined end points,

generally including defined response criteria. The Pso-

riatic Arthritis Response Criteria (PsARC) (Box 3),

developed for use in clinical trials of sulfasalazine, in-

cludes measurements of tender and swollen joints,

and patient and physician assessments of disease

activity [52]. The American College of Rheuma-

tology (ACR) response criteria includes these same

measurements, and adds the elements of pain, func-

tional assessment, and acute-phase reactant levels

(Box 4) [53]. An ACR-20 response indicates 20%

improvement in these measurements of disease activ-

ity. ACR-50 and ACR-70 responses, respectively,

indicate 50% and 70% improvement. Although the

ACR response criteria have been used to evaluate

treatment response in PsA, some have raised concern

that these response criteria may be less reliable in this

disease because of the generally lower sedimentation

rates and lower joint counts. Efforts are currently

underway to develop and validate disease-specific

response criteria in PsA.

Sulfasalazine, originally developed some 50 years

ago for use in treating RA, has been demonstrated

in controlled trials to be effective in PsA. Using the

PsARC, sulfasalazine, 2 g/d, was shown to be statis-

tically more effective than placebo in a multicenter

Box 3. Psoriatic arthritis response criteria

Improvement in at least two of fourcriteria, one of which must be tender- orswollen-joint score

Physician global assessment (� 1 uniton a scale of 0 to 5)

Patient global assessment (� 1 unit ona scale of 0 to 5)

Tender-joint score (� 30%)Swollen-joint score (� 30%)

PlusNo worsening in any criterion

trial in 221 patients [52]. In this same group of pa-

tients, the drug was shown to be more effective for

the management of peripheral arthritis than for axial

disease [54]. In a separate placebo-controlled study of

sulfasalazine, 3 g/d, in 351 patients with spondyloar-

thropathies, the drug was found to be particularly

effective in the subset of patients with PsA [55].

Cyclosporine, frequently used in the treatment of

psoriasis, has been evaluated in the treatment of PsA,

although there are no published double-blind studies

with this agent. Early series described the use of

relatively high doses of cyclosporine, up to 6 mg/kg/d

[56,57]. More recent studies have used lower doses to

reduce toxicity [58,59]. In a prospective, open study

of cyclosporine for psoriasis and PsA, the drug was

clearly more effective for skin disease than for joint

symptoms [58]. A 50% reduction in skin involvement

was achieved within 5 to 6 weeks of initiation of

therapy, whereas a 50% reduction in joint symptoms

took 24 weeks. A prospective, open 1-year compari-

son of cyclosporine and methotrexate for the treat-

ment of PsA demonstrated improvement in multiple

measurements of joint disease activity for both

compounds [60]. Cyclosporine was initially dosed

at 3 mg/kg/d in this trial, then raised as necessary to a

maximum of 5 mg/kg/d; the comparable dose range


for methotrexate was 7.5 to 15 mg/wk. In a 24-week

prospective, open study, cyclosporine, 3 mg/kg/d,

was statistically more effective than sulfasalazine,

2 g/d, in reducing pain, the primary end point [59].

Methotrexate, another drug frequently used to

treat psoriasis, was reported to be effective as a par-

enteral therapy for PsA as early as 1964 [61]. A

retrospective analysis of 59 patients treated for up to

11 years with weekly low-dose methotrexate (initially

15 mg/wk) reported response in 43 patients that was

unrelated to the initial severity of disease [62]. The

only placebo-controlled, blinded study of low-dose,

oral methotrexate for the treatment of PsA was

published in 1984, and included 37 patients with

active arthritis that could not be treated successfully

with aspirin or nonsteroidal anti-inflammatory drugs

[63]. Although a variety of arthritis assessments were

evaluated, including grip strength, morning stiffness,

and joint counts, the only variable that statistically

improved compared with placebo was the physician

global assessment [63].

Etretinate, also used to treat psoriatic skin disease,

has been investigated as a therapy for PsA [64,65].

One open-label trial treated 40 patients for up to

24 weeks with etretinate, 50 mg/d, reducing the dose

to 25 mg daily when necessary because of side effects

[65]. Significant improvements were seen in all

measurements of PsA disease activity. Thirty-nine

of the 40 patients had mucocutaneous side effects,

however, including nine in whom these side effects

resulted in discontinuation of therapy. Such toxicity

has limited the acceptance of etretinate as a therapy

for PsA.

Finally, leflunomide, the most recently introduced

antimetabolite for the treatment of RA, has been ex-

amined in PsA [66,67]. This drug, a pyrimidine

synthesis inhibitor, is believed to work by selectively

reducing activated inflammatory cells, particularly

T cells, in inflamed joints. A placebo-controlled study

demonstrated a modest response rate of 58% in the

leflunomide group compared with 38.5% in the

placebo group (again highlighting the placebo re-

sponse in this disease) [67]. There was also a statis-

tically significant improvement in skin lesions in

the leflunomide group. The discontinuation rate was

quite high for both groups in this 24-week study.

In addition to potential differences in efficacy,

there are potential differences in toxicity that must

be evaluated before applying RA therapy to PsA.

This is highlighted in a recently published review that

examined and compared disease-modifying antirheu-

matic drugs treatment courses in disease-modifying

antirheumatic drugs in 104 patients with PsA and

102 patients with RA [68]. Agents used included

parenteral gold, methotrexate, and sulfasalazine.

Patients were treated longer for RA with both gold

and methotrexate (35 versus 12 months and 72 versus

12 months, respectively), whereas the treatment

course for sulfasalazine in PsA was slightly longer

(17 versus 12 months). Although the results did not

show a difference in efficacy for the three drugs in

these two diseases, toxicity was seen more frequently

among the PsA patients. Rash and hematologic dis-

orders were the most common toxicities leading to

discontinuation of therapy in PsA patients treated

with gold, whereas elevated serum transaminases,

hematologic disorders, and infections were the most

common reasons in the methotrexate-treated patients.

The authors comment that these differences in toxic-

ity may limit the applicability of RA therapies to

patients with PsA [68].

Biologic response modifiers

The perceived imbalance between efficacy and

toxicity may be one of the factors that have limited

the widespread use of second-line agents in PsA. Bio-

logic response modifiers may hold the key to revers-

ing this imbalance. Recent studies have demonstrated

both clinical and radiographic improvement in RA

with compounds that block the biologic activity of

TNF-a [69–72]. Experimental evidence has sug-

gested that TNF-a also may play an important role

in the pathogenesis of PsA [36,73]. These findings,

coupled with the clinical experience in RA, have led

to trials of TNF-a antagonists in PsA.

Infliximab, a chimeric monoclonal antibody di-

rected against TNF-a, has been studied as a therapy

for PsA in several small open-label treatment studies

[74–76], and in a larger placebo-controlled trial [77].

A placebo-controlled study of infliximab in 40 pa-

tients with spondyloarthropathies included 13 with

PsA [78]. Regimens studied with this intravenously

administered agent have included loading doses at 0,

2, and 6 weeks, followed by repeated doses every

8 weeks. Doses have ranged from the 3 mg/kg dose

commonly used as the initial dose in RA to 5 mg/kg,

the dose used for the treatment of Crohn’s disease and

ankylosing spondylitis [74,76,78].

Results in all of these studies have been encour-

aging. More than half of the patients in two of the

open-label trials achieved an ACR-70 response after

the loading doses and maintained this response with

ongoing treatment [75,76]. In the spondyloar-

thropathy trial, the primary end points of patient

and physician assessment on a visual analog scale

improved significantly in the treatment group, where-


as the placebo group remained unchanged [78].

Results were seen as early as 2 weeks, and main-

tained through 12 weeks in this short study.

A recently reported double-blind, placebo-con-

trolled trial of infliximab in PsA included 102 patients

with active disease (more than five actively inflamed

joints) [77]. Patients were randomized to receive

5 mg/kg of infliximab or placebo at 0, 2, and 6 weeks,

and then every 8 weeks thereafter. Background ther-

apy with second-line agents, including methotrexate,

was allowed, as was therapy with nonsteroidal anti-

inflammatory drugs and less than 10 mg of pred-

nisone, but the doses were to remain stable. At

16 weeks, the percentage of patients achieving an

ACR-20, -50, and -70 was 69%, 49%, and 29%,

respectively. Only 8% of the placebo-treated patients

achieved an ACR-20, and none reached a higher level

of response. The presence or type of background

therapy did not influence response. Infliximab is

typically used in combination with methotrexate in

the therapy of RA; the addition of methotrexate

seems both to increase efficacy and decrease toxicity

[79,80]. The necessity of combination therapy with

methotrexate in PsA has yet to be determined.

Etanercept is a recombinant fusion protein com-

bining the extracellular portions of two p75 TNF

receptors with the Fc fragment of a human IgG1. This

TNF-a antagonist has been studied for the treatment

of PsA in two placebo-controlled trials [81]. In a

small, single center trial, 60 patients with PsA were

randomized to receive etanercept, 25 mg twice-

weekly (N = 30), or placebo (N = 30) [81]. End

points included the PsARC and the ACR20. After

12 weeks of treatment, 87% of the patients in the

etanercept group met the PsARC compared with 23%

of the patients in the placebo group. An ACR20 was

achieved by 73% of the patients in the etanercept

group compared with 13% in the placebo group.

The results of the single center trial were corrobo-

rated in a large, multicenter trial of etanercept, which

enrolled 205 patients with PsA. In this study, 59% of

etanercept-treated patients achieved an ACR-20 at

12 weeks compared with 15% of placebo-treated

patients. An ACR-50 was achieved by 38% of the

etanercept-treated patients and an ACR-70 by 11%

[82]. This trial also demonstrated that radiographic

progression in the treated group was significantly

reduced when compared with placebo [83]. As in

treatment for RA, the most common treatment-related

adverse events seen with etanercept therapy for PsA

have been injection site reactions.

On the basis of these data, etanercept has become

the first biologic agent approved in the United States

for the treatment of PsA. Registry trials for infliximab

and adalimumab, a fully human anti-TNF antibody

approved for treatment of RA, are currently under-

way. Concern has been raised in clinical practice

about the potential increased risk for infection that

may accompany TNF inhibition, including bacterial

infections and opportunistic and atypical infections,

such as tuberculosis [84–86]. PPD screening before

the initiation of treatment and appropriate vigilance

during treatment are important elements of therapy

with these agents.

Other biologic response modifiers are being stud-

ied in psoriasis and PsA. Alefacept, which modulates

T-cell response by blockade of the IL-2 receptor, has

shown promising results in the treatment of plaque

psoriasis. A small pilot study in PsA has shown that

alefacept improves clinical joint score along with skin

disease [87].

Summary

Psoriatic arthritis is increasingly perceived as a

common disease that causes progressive joint damage

and disability. With earlier recognition and diagnosis,

clinicians have the chance to intervene before signifi-

cant permanent damage has occurred, reducing long-

term disability and enhancing quality of life. With

skin disease typically developing much earlier than

joint disease, dermatologists can play a key role in

identifying the onset of PsA. Dermatologists will

frequently be the first physicians to recognize a

diagnosis of PsA and will need to work closely with

rheumatologists to establish the diagnosis and select

treatments that will address both the skin and the joint

disease. Cooperative management, with input from

both specialties, will result in the most efficient and

effective care for both the skin and joint manifesta-

tions of this disease.

Newer therapeutic agents, such as the TNF-aantagonists and other biologic response modifiers,

offer the potential for improved efficacy without

some of the toxicities that have limited traditional

therapies. However, these agents are not for all

patients. As with the use of these agents in psoriatic

skin disease, the financial cost of these agents is high.

Patients with mild joint symptoms or only a few

involved joints may not require biologic agents to

manage their arthritis, sparing them both the cost and

the potential toxicity. On the other hand, those with

aggressive, destructive disease would benefit from

effective treatment before they develop permanent

joint damage. Ongoing research into the epidemi-

ology and outcomes of PsA can provide insight into

the patient characteristics, such as multiple involved


joints, that may be indicators of poor outcomes.

Appropriate patient selection will be critical to ensure

that resources are used wisely on patients who will

benefit, and that those who would benefit the most

are treated appropriately.

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Dermatol Clin 22 (2004) 487–492

Practical considerations in future psoriasis therapies

Christy Riddle, MDa, Melodie Young, MSN, RNb,c,*, Alan Menter, MDa,c

aDepartment of Internal Medicine, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USAbGraduate School of Nursing, The University of Texas at Arlington, Arlington, TX, USA

cTexas Dermatology Associates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA

Revolutionary new therapies for psoriasis are psoriasis experts have collaborated to develop bio-

likely to allow dermatologists, even those who con-

sider themselves nonpsoriasis experts, the ability to

provide more targeted treatments that can offer a

significant number of patients the ability to reclaim

their lives. This new frontier in therapy significantly

broadens the choices dermatologists and their patients

have available from which to choose. For decades,

psoriasis therapy has been limited to Goeckerman

treatment, phototherapy, and several systemic drugs

that although effective are limited by toxicities that

frequently precluded long-term maintenance therapy.

It is hoped that the introduction of these new biologic

drugs allows dermatologists to share in the excitement

and enter the psoriasis therapy arena. For the pa-

tient, this means wider access and potentially fewer

risks. As discussed elsewhere in this issue, psoriasis

researchers, pharmaceutical companies, and front-line


doi:10.1016/S0733-8635(03)00128-1

Alan Menter has the following conflicts of interest: (1)

research: Abbott, Allergan, Allermed, Amgen, Astralis, Bio-

gen, Centocor, Connetics, Corixa, Dermik, Dow, Ferndale,

Fujisawa, Galderma, Genzyme, GlaxoSmithKline, Inamed,

Lumenis, Medicis, Novartis, Otsuka, Photocure, Regenera-

tio, Pharma AG, Scirex, Serono, Thermosurgery; and (2) con-

sultancies and honoraria: Allergan, Amgen, Biogen,

Centocor, Genentech, ICN, Novartis, Serono, Thermosur-

gery, Warner-Chilcott. No stock ownership.

Melodie Young has the following conflicts of interest:

Nurse Advisory Boards for Biogen, Fujisawa, and Genen-

tech. Presentations for Allergan, Amgen, Biogen, Fujisawa,

Genentech, Healthpoint, and ICN.

* Corresponding author. Texas Dermatology Associ-

ates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230.

E-mail address: [email protected] (M. Young).

logic therapies that directly target specific steps in the

immunopathologic process of psoriasis and other

immune-mediated diseases. Fortuitously, the side ef-

fects and cumulative toxicities in the short-term at

least seem to be less burdensome than those of the

traditional workhorses of psoriasis (ie, methotrexate,

cyclosporine, retinoids, and psoralen plus UVA).

Critical in this revolution is the recognition by the

dermatologist of the value in assisting the psoriasis

sufferer in assessing the impact of this disease on his

or her quality of life. Pain and suffering are obviously

subjective characteristics of any chronic debilitating

disease that do not always correlate with the objective

severity gauged by the treating physician. There are

now validated tools for psoriasis patients to measure

their deficiencies, both physical and emotional [1].

Improvement in individualizing therapy depends on

having the clinician evaluate the impact of psoriasis

on the patient’s quality of life and the value of having

the patient also recognize the physical and emotional

impact or damage sustained from living with psoria-

sis. The Koo-Menter Psoriasis Index (KMPI) is a tool

requiring the input of both the patient and the

clinician and encourages changing the paradigm

whereby a clinician alone decides what is best or

having a patient deny the quality of life issues

inherent in psoriasis and its treatment. This index

provides guidance in deciding on a patient’s eligibil-

ity for a systemic treatment. It legitimizes the

patients’ quality of life concerns, their joint symp-

tomatology, and degree of psoriasis involvement,

thereby allowing the clinician to determine if more

aggressive therapies are warranted. Like rheumatolo-

gists, gastroenterologists, and neurologists who have

had access to new technologic therapies over the past

s reserved.

C. Riddle et al / Dermatol Clin 22 (2004) 487–492488

10 years, dermatologists now have the opportunity to

offer psoriasis patients the hope of clearer skin and

the encouragement of looking forward to a brighter

outlook on life.

This article discusses practical issues that allow

dermatologists the ability to implement the expanding

psoriasis armamentarium into their practices. Individ-

ual dermatologists are faced with an internet-savvy

patient population who will no doubt have many

questions about the new therapies. The increasing

use of direct-to-consumer marketing tools by phar-

maceutical companies also increases patient aware-

ness and interest in biologics. Because the authors

earnestly believe the correct therapy can help psori-

asis patients reclaim their lives, they outline the steps

necessary to integrate these new therapies into busy

dermatology practices. Each practice must decide the

extent to which it will offer currently available and

future systemic and biologic therapies based on

patient demand, support staff, available space, and

the economic considerations unique to that office.

Table 1

Biologics pending approval or currently available for moderate to

Product Approval status Administration

Alefacept Approved for moderate

to severe psoriasis

IM 15 mg each

week for 12 doses,

in-office

Efalizumab Approved for moderate

to severe plaque

psoriasis

1 mg/kg weekly

subcutaneous injection

by the patient

Etanercept Approved for juvenile

and adult rheumatoid

and psoriatic arthritis

and ankylosing

spondylitis, approval

for moderate to severe

plaque psoriasis

imminent

25–50 mg

subcutaneous by the

patient twice weekly

Infliximab Approved for Crohn’s

disease and rheumatoid

arthritis

5 mg/kg IV infusion

in-office at weeks

0, 2, 6, and q

8 weeks thereafter

Adalimumab Approved for

rheumatoid arthritis

40 mg every other

week subcutaneous

Abbreviations: CNS, central nervous system; PASI, Psoriasis Area

Data from Psoriasis for the clinician: a new therapeutics era (the ‘

The available armamentarium

Now and over the next few years, more and more

biologics will be introduced for moderate to severe

plaque psoriasis. The science, clinical efficacy, and

side effect profiles of each of these drugs have been

discussed in detail elsewhere in this issue. This arti-

cle addresses information related to the practical as-

pects of their use. Already approved is alefacept

(Amevive), which is administered in-office only by

the intramuscular injection (IM) route. Efalizumab

(Raptiva) given by subcutaneous weekly injection

was approved at the end of 2003 for treatment of

moderate to severe psoriasis. Biologics available for

other indications but not yet approved for psoriasis

are the tumor necrosis factor-a (TNF-a) antagonistdrugs etanercept (Enbrel), infliximab (Remicade), and

adalimumab (Humira). Enbrel is a subcutaneously

self-administered biologic, currently approved for

psoriatic arthritis, rheumatoid arthritis, juvenile rheu-

matoid arthritis, and ankylosing spondylitis, but ex-

severe plaque psoriasis

Short-term efficacy data Monitoring and side effects

33% obtained PASI

75 at 14 weeks

CD4+ counts weekly

while dosing; chills

s

28% obtained PASI

75 at wk 12

Monitor platelets, flu-like

symptoms, rebound

34% obtained PASI

75 at 12 wk

Optional laboratory

monitoring, injection site

reactions, CNS symptoms

and infections

88% obtained PASI

75 at wk 10

TB testing; VS and infection

monitoring pre-, during, and

postinjection; premedica-

tion: acetaminophen, diphen-

hydramine, and prednisone

53% obtained PASI

75 at week 12

As for above 2 TNF-a agents

and Severity Index; TB, tuberculosis; VS, vital signs.

‘biologics’’) beckons. J Am Acad Dermatol 2003;49.

C. Riddle et al / Dermatol Clin 22 (2004) 487–492 489

pecting an indication for plaque psoriasis in 2004.

Infliximab (Remicade) is currently indicated in the

treatment of Crohn’s disease and rheumatoid arthritis

and is administered as an in-office intravenous (IV)

infusion. Adalimumab (Humira) is another subcuta-

neously self-administered TNF-a monoclonal anti-

body approved for rheumatoid arthritis. Both of

these latter drugs are in phase two and three develop-

ment for psoriasis and psoriatic arthritis. Table 1 pro-

vides a summary of the available injectable biologics.

Other systemic therapies under development for

psoriasis include oral pimecrolimus (Elidel) and oral

tazarotene (Tazorac), both familiar to dermatologists

as topical agents used for atopic dermatitis, acne,

and psoriasis.

Staffing requirements

Dermatology nurses in most dermatologic prac-

tices already are familiar with injectable medications,

such as triamcinolone and methotrexate. The addition

of subcutaneously and intramuscularly administered

biologics, such as alefacept, efalizumab, etanercept,

and adalimumab, necessitates only a small amount

of change in the nursing role. Because etanercept,

efalizumab, and adalimumab may be self-injected

each week by the patient, the nurse provides counsel-

ing and instruction at the beginning of treatment and

then assists in managing patients between office visits.

The technique for reconstituting and self-injecting

medications is precise and requires all staff interact-

ing with patients to have extensive training in these

procedures. Thereafter, the nurse is available to an-

swer questions and dispense medications on subse-

Table 2

Suggested codes for biologic therapy

Function Code Allowable

Nurse only CPT 99211 $20–$25 per

Subcutaneous or

intramuscular injection

CPT 90782 $5–$7 per in

Venipuncture CPT 36415 $4–$5

CD4+ evaluation Lab code 83681 $20–$30

IV push CPT 90784 $23

IV infusion up to 1 h CPT code 90780 $45

IV infusion for each

additional h

CPT code 90781 $23

Infliximab J1745 $65.70 per un

Unclassified drugs

for Medicare

J3490 $875 per vial

Unclassified drugs

non-Medicare

J3590 Variable

quent office visits. For IM alefacept, the patient

requires weekly visits with the nurse for drawing

laboratories and drug administration. Registered

nurses (RNs), licensed vocational nurses, and some

medical assistants are trained in IM administration

techniques and can inject IM alefacept. The nurse or

allied health professional monitors the alefacept in-

ventory, procures the drugs from the pharmaceutical

company or contracted pharmacy, and schedules

patients accordingly.

Coding and billing for subcutaneous and IM in-

jectables is consistent with 99,211 level visits ($20 to

$25) if the patient only interacts with a nurse. The

actual injection procedure is billed as Current Proce-

dural Terminology (CPT) code 90,782 ($5 to $7).

Reimbursement for medication obtained from con-

tracted pharmacies or distributors is billed by the

appropriate J-code [2]. Phlebotomy and laboratory

codes may also apply 36,415 ($4 to $5) for venipunc-

ture and 86361 ($20 to $30) for CD4+ evaluation.

Refer to Table 2 for the recommended code use.

Because most dermatology practices do not em-

ployee RNs, starting an infusion center to administer

IV therapies requires the greatest amount of change

in the practice. Qualified staff has to be hired and

trained. Other changes include developing space, ob-

taining necessary equipment, and safety considera-

tions. A RN with infusion therapy experience and

fully trained in the management of potential side ef-

fects becomes a central and irreplaceable part of the

team. His or her role includes procurement of the

drug, patient education, obtaining informed consent,

IV access, documentation, laboratory review, drug

administration, and multiple patient assessments. For-

tunately, codes for reimbursement of these RN ser-

Description

visit Evaluation and teaching

jection If administered by nursing staff

Blood draw

Laboratories obtained and billed from practice

IV administration of a drug, may include access

IV access and administration of a drug

Continuous infusion beyond the first hour

it 10 units per vial

Total per dose

Reimbursed per third-party contract with

each practice


vices are available, but the degree to which they are

covered differs between third-party payers and from

state to state. Billing for IV infusion uses E, M, J,

and CPT codes. CPT level 90,784 level ($21) IV

push or the 90,780 level ($45) up to 1 hour and

90,781 for each additional hour depending on time

requirements for the procedure. When billing for

infliximab, use code J1745 with a Medicare reim-

bursement allowable rate of $65.70 per unit. For

alefacept or other ‘‘unclassified drugs,’’ code J3490

with a Medicare reimbursement allowable of $875 per

vial. For non-Medicare claims for alefacept, code

J34590 with reimbursement varying dependent on

the third-party contract (see Table 2).

Space considerations depend on the individual

office, but a private area with an infusion chair,

writing and work surface, and stool are essential. If

an extra examination room is available it may be

converted easily to an infusion room for daily or

perhaps only once-weekly use, depending on patient

volume. A licensed medical doctor must always be

present when performing infusions.

Infliximab infusions mandate additional changes.

The infusion time for this particular biologic runs

from 1.5 to 3 hours. The patient must also be moni-

tored for an hour afterward for postinfusion reactions.

At least one RN must be present to infuse and monitor

the patients, but a medical assistant or licensed voca-

tional nurse can assist with preparation and monitor-

ing of more than one patient. Also necessary is a

Fig. 1. Tiers of psorias

medical doctor immediately available for evaluation

and management. Advanced cardiac life-support

training is not mandatory, but is encouraged, and each

physician must weigh risks and benefits and malprac-

tice-related issues of advanced cardiac life-support

training. At a minimum, the office must be able to pro-

vide oxygen therapy, diphenhydramine, epinephrine,

and steroids to patients having an infusion reaction. In

this regard, other medicine and surgical subspecialties

have readily embraced these issues and offer derma-

tologists a great deal of published data to simplify this

process [3–5].

Several options are recommended for infusion

space configuration. The best arrangement depends

on the level of psoriasis care each practice wishes to

provide. If feasibility and volume dictate, additional

office space adjacent to the main office can be leased

and remodeled into a freestanding infusion center.

Space dedicated for waiting, reception, charts, and

infusion cubicles requires about 500 to 1000 sq ft.

Fortunately, most committed dermatologists and other

specialists have been able to work within the frame-

work of their existing space or otherwise using a

much smaller amount of space. An 8-ft by 8-ft stall

with one wall curtained satisfies the Health Informa-

tion Portability and Accountability Act guidelines

for patient privacy and allows easy nursing access.

Furniture, a telephone system, computer and monitor-

ing equipment, crash cart, oxygen, and pulse oximeter

are the necessary equipment. Besides the RN with

is care providers.

C. Riddle et al / Dermatol Clin 22 (2004) 487–492 491

Advanced Cardiac Life Support Qualifications, a re-

ceptionist and an infusion billing specialist comprise

the staff [2]. Again, depending on the volume of

patients treated, they may be either full time with

the infusion center or shared with the general derma-

tology practice.

Because so many options are becoming available,

dermatologists have choices to make about the level

of psoriasis care to provide. Many of these newly

indicated drugs can be integrated easily into already

busy practices with only minimal changes in staff

and space. The authors foresee several tiers of pso-

riasis care based on services offered (Fig. 1). The

highest level is a psoriasis center of excellence similar

to the dedicated psoriasis day care centers of the 80s

and 90s. Currently, there are only a handful of centers

in the United States that truly offer expert medical

and nursing care, cutting edge therapy, clinical re-

search, and the full spectrum of traditional modalities

of systemic agents and phototherapy. At these cen-

ters, psoriasis patients have been receiving psoralen

plus UVA or narrow-band phototherapy; systemics,

such as methotrexate, cyclosporine, and etretinate;

second-tier drugs, such as hydroxyurea, 6-thiogua-

nine, and mycophenolate mofetil; and the new bio-

logics. These centers are likewise involved in clinical

trials with biologics seeking psoriasis and psoriatic

arthritis indications. They also may be in trials for

oral pimecrolimus, tazarotene, or other psoriasis ther-

apies, and are intimately involved with patient edu-

cation and advocacy with the National Psoriasis

Foundation and the American Academy of Derma-

tology in physician education. Reaching this level of

excellence requires time, staff, and space dedication

for phototherapy units, an infusion center, patient

education areas, and clinical research.

The next tier, with a lesser expenditure of re-

sources than the center of excellence, is known as a

‘‘psoriasis specialty clinic.’’ This resource allows for

some UV and systemic therapy and biologics, but not

necessarily at the comprehensive scope of the top

tier centers. This is very feasible for medically

oriented dermatologists who wish to take more ini-

tiative in treating their psoriasis patients with moder-

ate to severe disease. In some areas, they are the

referral center for physicians with limited expertise

and interest.

The medical dermatologist who does not wish

routinely to tackle the treatment of severe or moder-

ately affected psoriatic patients makes up the next tier

of care. This level of service provides limited treat-

ment options and does not invest resources in photo-

therapy or extensive offering of all available therapies.

For example, in this third tier, patients may receive the

option of methotrexate or a self-administered biologic,

which requires very little change in practice. It is

hoped that patients will be made aware of the new

sophisticated biologic therapies and provided appro-

priate information, such as literature, web sites, and

National Psoriasis Foundation referrals. Education

and training of staff on the use, effects, provision,

and billing of the new medication is, as in the prior

two tiers, undertaken at this level. The final tier and

the one least likely to provide a range of therapeutic

options for moderate to severe psoriasis is the general

community dermatologist or surgically oriented der-

matologist whose interests lie elsewhere within der-

matology. These physicians likely refer to a colleague

who has the interest, staff, and facilities to offer more

options, expertise, and quality of care to their patients.

Summary

This is an exciting time to be in dermatology, both

medical and nursing, especially for those interested in

helping to change the lives of psoriasis patients. For

too long the pace of new treatment modalities has

crept along with few breakthroughs and minimal

industry support. Now, as biologic therapy becomes

a major focus of research and approval of new drugs

gathers speed, dermatology is challenged to maintain

and even regain its standing in the medical subspe-

cialty arena. For a significant number of psoriasis

patients with recalcitrant disease (not just a tiny

minority) this means fresh hope that sophisticated

new therapies will provide a better quality of life with

potentially fewer side effects than the traditional

weapons. Dermatologists who previously did not

consider themselves psoriasis ‘‘experts’’ but who care

about making a significant difference in patients’

lives now have the opportunity to treat patients they

once referred effectively and safely in their own

offices. This revolution in psoriasis therapy is a chal-

lenging one for the specialty but it is hoped it is one

in which both patients and physicians win qualita-

tively and intellectually.

References

[1] Koo J, Menter A. The Koo-Menter psoriasis instrument

for identifying candidate patients for systemic therapy.

Psoriasis Forum, Summer 2003. p. 6–9.

[2] Craze M, Young M. Integrating biologic therapies into

a dermatology practice: practical and economic consid-

erations. J Am Acad Dermatol 2003;49:S139–42.



Baker DG, Gottlieb AB. Efficacy and safety of inflixi-

mab monotherapy for plaque-type psoriasis: a random-

ized trial. Lancet 2001;357:1842–7.

[4] Lipsky PE, Van der Heijde D, St. Clair W, Furst DE,

Breedveld FC, Kalden JR, et al. Infliximab and metho-

trexate in the treatment of rheumatoid arthritis. N Engl J

Med 2000;343:1594–602.

[5] Cheifetz A, Smedley M, Martin S, Reiter M, Leone G,

Mayer L, et al. The incidence and management of infu-

sion reactions to infliximab: a large center experience.

Am J Gastroenterol 2003;98:1315–24.

Dermatol Clin 22 (2004) 493–499

Psoriasis: future research needs and goals for the

twenty-first century

Christopher E.M. Griffiths, MD, FRCP

The Dermatology Centre, Hope Hospital, Irving Building, Salford, Manchester M6 8HD, UK

Most dermatologists are still involved with the Epidemiology

management of patients with psoriasis. Despite its

ubiquitous presence in outpatient clinics and mo-

nopoly of dwindling inpatient resources, psoriasis

remains an enigma. Few studies have accurately

addressed the prevalence and epidemiology of pso-

riasis outside secondary care. Molecular genetics in-

dicate what has been suspected for some time in that

clinicians are dealing with a continuum of ‘‘psoria-

sis’’ with similar phenotypes. Although no genes that

are specific for psoriasis have been identified it is

only a matter of time before a gene mutation is iden-

tified, perhaps leading to development of an animal

model faithful to the histologic, immunologic, and

clinical features of the disease.

The explosion in new therapies under trial for

psoriasis is a direct consequence of advances in the

understanding of the key pathogenic pathways in

psoriasis. Components of these pathways can be tar-

geted selectively by biologic agents. Despite such

progress clinicians are held back by lack of a good

evidence base for efficacy in that many of the thera-

pies for psoriasis are hindered by paucity of consen-

sus on clinically relevant outcome measures.

This article, inevitably speculative, part philo-

sophic, discusses what I believe are the future needs

in psoriasis research and how achievement of these

goals should lead to a greater understanding of, and

better therapy for, this disease (Table 1).


doi:10.1016/j.det.2003.12.001


Surprisingly, there are few comprehensive epide-

miologic studies of chronic plaque psoriasis. In

Europe and the United States the oft-quoted preva-

lence is 2% of the population [1] with caveats that

Northern Europe (ie, Scandinavia [2]) has a higher

prevalence than Southern Europe and that in China

psoriasis is rarer [3]. In the United Kingdom epide-

miologic surveys are confounded by the fact that not

all people with psoriasis seek medical help and that

only a minority of cases is seen by dermatologists. A

national survey, perhaps along the lines of a census, is

required to examine accurately the prevalence, pref-

erably on a regional basis, but this is dependent on

clinical examination of alleged sufferers. Often peo-

ple who are told they have psoriasis are shown sub-

sequently to have other skin disorders, such as

discoid eczema, dermatitis, and seborrheic dermatitis.

It is my view that the prevalence of chronic plaque

psoriasis is a good deal higher than 2%. In the United

Kingdom newer, better treatments and the promo-

tional awareness campaigns associated with them

probably bring more psoriasis sufferers to the atten-

tion of primary care practitioners. This promotional

bias may mask any real changes that have occurred in

prevalence. As far as can be ascertained there has

been no significant change in prevalence of psoriasis

over the past 20 years unlike atopic dermatitis where

cases have doubled. Prevalence figures for psoriasis

are important for planning of resources for manage-

ment. One of the drawbacks to achieving accurate

prevalence figures is the lack of reliable diagnostic

criteria for psoriasis (diagnosis is made purely on

clinical examination). Clinical diagnosis is acceptable

s reserved.

Table 1

Research needs and goals of psoriasis

Research needs Goals

Enhanced public awareness of psoriasis Increased funds available for research

Health economics studies Make case for burden of disease and economic impact

Identification of genes Animal model

Understanding of pathomechanisms

Gene therapy

Identification of autoantigen Understanding of pathomechanisms

Prevention and vaccination strategies

Investigation of innate immune responses

angiogenesis and Koebner phenomenon

Targets of therapy

Interrogation of the brain-skin axis and

psychosocial disability

Identification of patients who would benefit from

behavioural therapy and who are at risk of

stress-induced relapse

Classification of clinical phenotypes Prediction of prognosis and response to therapy

Outcome measures and trial design Studies relevant to real life management of psoriasis

Academia-industry collaboration Strategic application of research and development

C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499494

for dermatologists but not necessarily for other

health care personnel. There is no test, other than

skin biopsy, to aid diagnosis for the disease that

is analogous to rheumatoid factor for rheumatoid

arthritis or antinuclear antibodies for systemic lu-

pus erythematosus.

Clinical research is entering a new era, one that

has direct relevance to psoriasis. Modern day clini-

cians are becoming overreliant on diagnostic tests

and as a consequence are starting to lose or place less

value on clinical examination. Chronic plaque pso-

riasis is referred to as a single disease entity but those

working in psoriasis clinics and who see large num-

bers of psoriasis patients know that within this

umbrella definition are subsets of disease with rela-

tively distinct clinical patterns, such as small plaque,

follicular, thin plaque, seborrheic, and so forth [4].

These patterns may relate to prognosis. It is my view

that these patterns are relevant. As an analogy, pen-

guins as a genus are birds that are instantly recog-

nizable to most people. Within the generic definition

of penguin, however, there are different, distinct

species of penguins (Emperor, King, Rockhopper,

and so forth). What is required is for careful pheno-

type classification of psoriasis predicated on clinical

pattern. A diligent clinical research fellow is capable

of performing such an important task. Our dermato-

logic forefathers, such as Willan [5], had only clinical

observation at their disposal and were able to classify

and subclassify dermatologic disease on pattern; it is

beholden on us to recapture these skills. Quite pos-

sibly this phenotype mapping possesses fidelity with

genotype and allows clinic-based prediction of re-

sponse to therapy, prognosis, and so forth.

Genetics

Indubitably most research funding in psoriasis is

spent on immunogenetics: the search for the psoria-

sis genes. There are at least eight psoriasis sus-

ceptibility loci located on different chromosomes.

Psoriasis susceptibility locus-1 [6] close to HLA-

Cw6 [7] is a key determinant of early onset psoriasis

beginning on or before 40 years of age [8] but of itself

is not the psoriasis gene. A combination of genes is

undoubtedly required to reveal the psoriasis pheno-

type after exposure to an environmental trigger, such

as streptococcal pharyngitis or tonsillitis [9]. It is

possible that different families have different permu-

tations of genes and triggers leading to the skin

reaction pattern typical of psoriasis. The elucidation

of genes and gene products in psoriasis is of vital

importance if targeted therapies are to be designed

that may cure or even prevent the disease. Heteroge-

neity of disease probably precludes gene therapy for

the time being. Perhaps the most important conse-

quence of identifying psoriasis genes is the ability to

develop a transgenic animal model for psoriasis. No

such model exists; the nearest is a severe combined

immunodeficient mouse xenografted with biopsies of

human psoriasis [10]. An animal model allows rapid

and economic screening of potential therapeutic

agents. Diseases associated with psoriasis are impor-

C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499 495

tant clinical signposts to candidate gene approaches;

a good example is Crohn’s disease with its fivefold

increased prevalence of psoriasis [11]. Genes close

to caspase response domain-15 on chromosome 16

(a mutation that confers a 48-fold increased risk to

Crohn’s disease [12]) are attractive candidates for

psoriasis [13] as are other genes of the innate im-

mune response.

Pathomechanisms

The three classic histologic features of psoriasis

are the main subjects of research into pathomecha-

nisms: (1) abnormal epidermal keratinocyte prolife-

ration and differentiation, (2) inflammation, and

(3) angiogenesis. Current research into epidermal

components is in abeyance but if psoriasis is to be

considered an autoimmune disease then the putative

autoantigen is most likely a component of the epi-

dermis, probably an epitope of keratin. Investiga-

tions into this, particularly keratin cross-reactivity

with streptococcal M protein, are important [14].

The inflammatory response whether cellular or cyto-

kine is a critical focus of current research. The past

decade has witnessed detailed investigation of the

acquired immune responses in psoriasis: CD4-CD8 T

[15] cells and the Th1-Th2 cytokine pattern [16]. The

pendulum is starting to swing away from research

into the acquired immune response toward investiga-

tion of the role of the innate immune response in

psoriasis [17]. This is in line with research on other

autoimmune inflammatory diseases, such as Crohn’s

disease and multiple sclerosis. Severe combined im-

munodeficiency mouse xenotransplantation studies

have identified natural killer [18] cells as important

in promulgating the natural killer cell and T-cell ac-

tivity and keratinocyte proliferation, [19], and tumor

necrosis factor-a (TNF-a) [20] indicates the impor-

tance of this immune pathway in psoriasis. The role

of this pathway seems increasingly important with the

discovery of different natural killer cell receptors

[21], abnormalities or deficiencies in which may pro-

mote the inflammatory response. The central role that

TNF-a plays in this inflammatory response is un-

derscored by the efficacy of TNF-a blocking bio-

logics, such as infliximab [22] and etanercept [23], in

psoriasis. On this basis an inappropriate innate im-

mune response in the skin of patients with psoriasis

seems to be an attractive research hypothesis.

Perhaps the most underresearched area of psoria-

sis pathogenesis has been in the field of vascular

biology. Studies 20 years ago showed that changes

in the dermal capillary bed are among the earliest

in the evolution from uninvolved skin to plaque [24].

Research work on angiogenic factors derived from

epidermal keratinocytes, specifically vascular endo-

thelial growth factor (VEGF), have reawakened in-

terest in the vascular component of psoriasis [25]. A

single nucleotide polymorphism of the 405 CC ge-

notype of the VEGF gene confers susceptibility to

severe psoriasis of early onset [26] and a mouse

transgenic for overexpression of VEGF has a psoria-

siform phenotype [27]. The roles of VEGF isoforms

in psoriasis and their reciprocal relationship with

antiangiogenic factors (eg, thrombospondin-1) are a

further area for research, as are receptor-targeted

therapies (ie, anti-VEGF and VEGF-receptor).

Quality of life

There is little doubt that one of the hindrances

to obtaining significant research funding for psoria-

sis is the view (nondermatologic) that the disease is of

low priority, particularly because it has no apprecia-

ble mortality. The specialty of dermatology has only

recently, and belatedly, awoken to this misconcep-

tion. Although dermatologists and patients are well

aware of the psychosocial [28,29] and financial con-

sequences of psoriasis, comparatively little work has

specifically addressed these in an objective, struc-

tured manner. Studies have shown that psoriasis

produces significant impairment in quality of life, in-

deed to a level lower than that produced by diabetes

[30]. The psychosocial disability suffered by psoriasis

patients is immense. Stress caused by living with

psoriasis is the greatest stressor in patients’ lives [28],

so much so that most patients practice avoidance-

coping and automatic vigilance [31]. It is these

elements of psoriasis morbidity that require further

study, particularly the roles that stress and worry may

have on compliance with, and efficacy of, treatment

[32]. Major areas of research are whether self-help

and cognitive behavioral therapy can significantly

improve quality of life and enhance the efficacy of

traditional pharmacologic approaches to treatment.

Few dermatologists have received any form of train-

ing in how to recognize psychologic distress, particu-

larly depression and anxiety in their patients. This is

highly relevant for physicians who deal with chronic

adult medical dermatoses, such as psoriasis, that have

a significant impact on quality of life. Work is

required to assess strategies to improve compliance

and adherence with prescribed therapy coupled with

in-depth assessment of the health economics of

psoriasis care. What is the true burden of disease to

individual, family member, taxpayer, health care


system, and government? Such information is vital to

facilitate informed debate on the economics of treat-

ing these patients, particularly with the seemingly

expensive biologics. Such studies by necessity should

be performed on a country-by-country basis.

Triggers

Revelation of the psoriatic phenotype is the con-

sequence of a confluence of genetic predisposition

and environmental trigger. The triggers are as im-

portant, and probably as protean, as the putative

genetic mutations; however, comparatively little fund-

ing or endeavor is aimed at elucidating the nature of

these environmental triggers. A few triggers are

recognized, such as streptococcal infection, lithium,

Koebner’s phenomenon, and stress, but there is no

clear understanding as to how and in whom such an

exposure eventuates in psoriasis. Take Koebner’s

phenomenon, for example. First described in 1878,

the Koebner or isomorphic response is a characteristic

feature of active psoriasis [33]. There is no under-

standing as to how trauma to the epidermis results in

psoriasis; indeed, few researchers have specifically

addressed this issue. The appearance of psoriasis at

sites of skin trauma or pressure is probably indicative

of epidermal signaling leading to up-regulation or

induction of vascular adhesion molecules allowing

primed T cells to egress into the dermis. Lithium [34],

prescribed for manic depression, and HIV infection

[35] also trigger or exacerbate psoriasis and are

clinical clues to pathogenesis.

Stress is another purported trigger. A study per-

formed in Manchester [36] showed that 60% of

psoriasis patients believed that stress was either a

trigger or an exacerbator of their disease, an observa-

tion familiar to any dermatologist dealing with pso-

riasis patients. Somewhat surprisingly, despite strong

circumstantial evidence, there has not been a detailed

prospective study of whether exacerbations of psoria-

sis are linked to stressful life events.

The ability of neuroendocrine responses to im-

pact on physiology is an area of increasing scientific

interest, and already under intense investigation in

inflammatory bowel disease, rheumatoid arthritis,

and multiple sclerosis [37]. Evidence exists that ex-

perimental psychosocial stress and the real life stress

of final examinations for medical students can impact

significantly on skin physiology, particularly on

the barrier function of the stratum corneum [38,39].

The brain-skin axis or neuroscience of the skin,

particularly as it pertains to psoriasis, is an exciti-

ng and relatively untrodden area of research both

from the standpoint of psychoneuroimmunology and

hypothalamic-pituitary-adrenal axis responses to

stress and the roles of neuropeptides in facilitating

skin inflammation.

Evidence base

An important component of managing a patient

with psoriasis is knowledge of how various treat-

ments compare with each other in terms of efficacy,

side effects, and patient acceptability. Current prac-

tice has not been subject to rigorous evaluation; the

evidence-base movement is only beginning to stimu-

late reflection on how and why clinicians use the

medicines they do for psoriasis management. A

recent survey [40] by the European Dermato-Epide-

miology Network of 226 randomized controlled trials

for psoriasis produced some important information:

only two randomized controlled trials had compared

two or more different systemic therapies (although to

some extent rectified by the recent comparative study

of methotrexate with cyclosporin) [41]; median study

duration was only on the order of 7 weeks (woefully

inadequate in a chronic, life-long disease); less

than 4% of studies considered maintenance of remis-

sion or relapse rates; less than 10% reported patient

preferences; and amazingly 43 different scoring sys-

tems were used to assess outcome.

There is a need to improve the quality of design

and reporting of future psoriasis studies; many

of these issues are addressed in the CONSORT

statement [42] about good practice in designing,

analyzing, and reporting clinical trials. In particular,

placebo-controlled trials should be confined mainly

to early development of new therapies; comparator

studies with standard practice should be performed

before acceptance of new treatments; and more long-

term studies are required to assess remission, relapse,

side-effects, and patient preference. In order that the

results of studies are directly relevant and important

to patients, patients themselves should be consulted

during the design stage [43].

Consensus is desperately needed as to the best

way to assess response of psoriasis to treatment. The

most commonly used measure of psoriasis severity,

the Psoriasis Area and Severity Index [44], a compo-

sition of surface area affected by psoriasis, scaling,

erythema, and plaque thickness, is unwieldy, re-

quires training in its use, and is poor at revealing or

identifying changes in mild-moderate disease. Fur-

thermore, current determinants of disease severity,

such as Psoriasis Area and Severity Index, physi-

cian’s global assessment, and body surface area, are


physical and take no account of psychosocial dis-

ability (the two do not correlate) [45]. Agreement is

urgently needed to reach consensus on relevant

measures of psoriasis severity, and as a consequence,

relevant outcomes for treatment. For instance, these

should incorporate, in a holistic manner, the other

determinants of psoriasis severity, namely psycho-

social disability and resistance to therapy as exem-

plified by the Salford Psoriasis Index [46].

New therapies

Research into new therapies needs to be collabo-

ration between academia and industry [47]. The era

of biologic therapies is exciting, not only because

there are new selective therapies for psoriasis, but

because the success or failure of such targeted ap-

proaches allows valuable insights into the biologic

pathways critical to the psoriatic process. This is

nothing new. The observation that cyclosporin is a

highly effective therapy for severe psoriasis [48]

finally paved the way to an acceptance that T cells

are central to the psoriatic process and subsequently

the development of a plethora of biologics for this

disease. Two observations from biologics illustrate

the yin and yang of this argument. Anti–TNF-aapproaches, such as infliximab [22] and etanercept

[23], have highlighted the central proinflammatory

role of TNF-a in psoriasis, whereas the nonefficacy

of an anti–E-selectin approach [49] demonstrates that

E-selectin and cutaneous lymphocyte-associated an-

tigen binding may be redundant in psoriasis. The

latter observation of nonefficacy of blocking T-cell

trafficking in psoriasis implies that biologics, proba-

bly those targeting T-cell activation and trafficking,

may be used more effectively and appropriately in

preventing relapse of psoriasis following clearance

with some other entity (ie, cyclosporin). The goal is

to place new therapies strategically and not to judge

solely on ability to induce clearance or remission;

a two-step approach is required.

In all the excitement over systemic biologics

that target T cells and cytokines one must not over-

look other targets and other drugs. Angiogenesis is an

attractive and highly pertinent target in psoriasis; the

field is well developed in cancer and new therapies

for cancer reliant on antiangiogenic approaches (eg,

anti-VEGF) are a logical choice for trials in psoriasis.

Nonbiologics, such as retinoids (eg, tazarotene [50]),

and retinoid-like drugs, such as liarozole [51], an

inhibitor of retinoic acid 4-hydroxylase without the

long-term risks of acitretin, are certainly worth pur-

suing. Other drugs, such as oral pimecrolimus, which

has cyclosporin-like efficacy seemingly without tox-

icity, are promising [52]. In the rush to use more sys-

temics, the place of effective, cosmetically acceptable

topicals should not be ignored.

The inexorable rise of appearance- and procedure-

based dermatology may produce some benefit for

those still involved in adult medical dermatology.

Development of new lasers and application of old

lasers for psoriasis shows some promise in that the

excimer 308-mm UVB laser is effective for small

recalcitrant plaques [53], and pulse dye laser treat-

ment of plaques can result in long-term remission

[54]. This, coupled with photodynamic therapy, may

be an opportunity for procedure-based treatment but

not prevention of psoriasis particularly if stable.

Summary

The research needs and goals for therapy of

psoriasis should be consonant. The research should

identify targets for treatment, may produce an ani-

mal model, and conceivably gene therapy. Therapies

should embrace these observations but need to un-

dergo trials in a way that is relevant to real life (ie, in

comparison with current clinical practice); with long-

term objectives; and with realistic outcome measures.

Research goals should, in no small way, be deter-

mined by the patients themselves working in close

collaboration with scientists, clinicians, and industry.

It is only by this concerted approach that progress can

be made. It should be borne in mind, however, that

serendipity and not reductionism has perhaps been

the greatest driver of change.

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Dermatol Clin 22 (2004) 501–508

Sclerotherapy basics

Margaret E. Parsons, MDa,b,*

aDermatology Consultants of Sacramento, 5340 Elvas Avenue, Suite 600, Sacramento, CA 95819, USAbDepartment of Dermatology, University of California at Davis, Davis, CA, USA

Every day dermatologists see patients with vari- 40% of cases [4]. Leg veins occur less often in the

cosities of the legs. Treatment of these vessels can be

rewarding to both the physician and the patient.

Sclerotherapy can improve the cosmetic appearance

of aberrant blood vessels and greatly benefit symp-

tomatic veins by decreasing pain, burning, and

cramps that many patients describe. Resolution of

larger varicosities can improve the risk of further

venous disease sequelae. Sclerotherapy continues to

be the gold standard in the treatment of lower

extremity small vessel disease. An understanding of

the indications, mechanisms, and treatment manage-

ment is essential. This article reviews the ‘‘basics’’ of

sclerotherapeutic treatment of the smaller vessels.

Varicose and telangiectatic veins affect both men

and women. In the United States, 8.65% of men and

12.9% of women have varicose veins. Telangiectatic

veins are reported at a higher rate of 28.9% of men

and 40.9% of women in the United States [1]. These

vessels can be visually unattractive and may also be

symptomatic. Venous disease contributes to the

changes of stasis dermatitis, pigmentary alteration,

and edema of the lower legs. Even mild venous

disease can cause ‘‘restless legs’’ syndrome and pain

[2]. Sometimes a patient will complain of a single

cluster of veins causing pain [3]. Sclerotherapy can

be very effective in decreasing the pain of varicose

and telangiectatic leg veins [4,5].

Many factors can affect an individual’s predispo-

sition to develop varicose veins. Genetics is believed

to play a major role in the development of leg veins,

and familial incidence has been reported in 15% to


doi:10.1016/j.det.2004.03.017

* Dermatology Consultants of Sacramento, 5340 Elvas

Avenue, Suite 600, Sacramento, CA 95819.


nonwhite population. Pregnancy also affects the in-

cidence of leg veins, and varicosities increase with

multiple pregnancies. The distensibility of the vessel

wall and increased blood volume during pregnancy

can also increase the formation of new blood vessels

and increase the diameter of existing blood vessels.

Similarly, occupations that require significant walk-

ing, standing, or long periods of sitting can contribute

to blood vessel pooling in the lower extremities and

therefore an increase in varicosities. Nurses, grocery

clerks, and teachers, therefore, are among some of the

patients often presenting with vessels for treatment.

Leg-crossing also can cause development of vessels

in the area of pressure of one leg on another.

Instructing patients about this causal factor can help

decrease further vessels in the area.

Anatomy

It is important to have an understanding of the

vasculature and anatomy of the lower extremities

when doing sclerotherapy. Although this article fo-

cuses on the smaller vessels, it is important to

understand general circulatory patterns. For example,

it has been demonstrated that telangiectasias can

communicate with the deep venous system [6]. The

volume of sclerosant at a treatment session should

therefore be limited to decrease the chance of the

sclerosing solution entering the deeper system where

it may potentially cause deep vein thrombosis [6].

When treating larger vessels, a thorough knowl-

edge of anatomy is essential. The deeper venous

system includes the femoral and popliteal veins,

which are affected by muscular compression. The

channels of connection between the deep and super-

s reserved.

M.E. Parsons / Dermatol Clin 22 (2004) 501–508502

ficial systems are called the perforating veins. They

provide the junction between the saphenous, femoral,

and popliteal systems. These perforating veins allow

for the return flow to the subcutaneous systems [7].

The superficial venous system includes the great

saphenous vein, the accessory saphenous vein, and

the lesser saphenous vein. The reticular and con-

necting branch veins provide for further connection

Box 1. Duffy system of classification

Type 1—telangiectasia ‘‘spider veins’’

0.1 to 1.0 mm in diameterRed to cyanotic in color

Type 1A—telangiectatic matting

Less than 0.2 mm in diameterRed color

Type 1B—communicating telangiectasia

Type 1 veins in direct communicationwith varicose veins of thesaphenous system

Type 2—mixed telangiectatic/varicoseveins

No direct communication with thesaphenous system

Type 3—nonsaphenous varicose veins(reticular)

2 to 8 mm in sizeBlue to blue-green

Type 4—saphenous varicose viens

Usually over 8 mm in diameterBlue to blue-green

From Goldman M. Sclerotherapy: treat-ment of varicose and telangiectatic. Legveins. 2nd edition. St. Louis, MO:Mosby; 1995. Modified from Duffy D.Small vessel sclerotherapy: an overview.In: Callen, et al, editors. Advances indermatology, vol. 3. Chicago: Yearbook;1988; with permission.

throughout the system. When treating larger vessels,

it is important to identify specific flow patterns

occurring in the patient by Doppler or Duplex studies.

It is helpful to understand the different types of

vessels that can be seen with visual examination. This

understanding facilitates knowledge of and planning

of treatment with sclerotherapy, and documenting this

treatment in the chart. A simple description of the

vessels with color and size can be sufficient. The

‘‘Duffy’’ classification is also useful for describing

vessels (Box 1). The diameter of the vessel also helps

determine which solution can be used for injection.

Etiology

Various factors contribute to the pathophysiology

of the development of varicosities. Aging of vessels

plays a major role in the cause of these conditions,

where many of the same factors as in the aging of the

skin are seen. The intima of a blood vessel becomes

thickened, the elastic lamina atrophies, and the ad-

ventitia becomes more fibrous. Because varicosities

usually have endothelial damage as part of their

development, they are therefore susceptible to scle-

rosing. In addition, the varicosities have a fibrosed

adventitia and an atrophic elastic layer accessible to

the sclerosant. Chronic hypertension can lead to

valvular insufficiency and dilatation of the vessels.

Hormonal effects of increased estrogen during preg-

nancy also contribute to distensibility of the blood

vessel wall. Patient history should also include the

patient’s use of hormonal replacement therapy or oral

contraceptive agents, but these are usually a low and

stable dose with minimal, if any, notable effects on

distensibility. Vin et al [8] showed that the effects of

estroprogestogen treatment on superficial venous sys-

tem is dose-dependent. Tamoxifen can also cause an

increase in hypercoaguability and should be noted

during the consultation appointment and reviewed

with the patient. The physical factors of leg-crossing

and tight clothing can play a role by causing focused

pressure in areas, and obesity or pelvic obstruction

from a tumor or lymph node can also cause stress on

the lower extremity vasculature. Valvular incompe-

tence can be caused by a genetic dysfunction or even

a decreased number of valves. Thrombophlebitis is

also related to valvular dysfunction.

Sclerosing agents

The concept and purpose of a sclerosing agent in

the treatment of varicosities is straightforward. Scle-

M.E. Parsons / Dermatol Clin 22 (2004) 501–508 503

rosants are injected into the vessel and affect the

vessel wall by initiating a vein wall injury. If the

injury causes sufficient damage to the vessel wall,

the vessel will be resorbed and fibrosed. The agents

cause some damage to the endothelial cell wall and

also to some of the deeper layers of the vessel wall.

This deeper damage is important to the success of

sclerotherapy and in decreasing the incidence of

recanalization [9].

There are three types of sclerosants: detergents,

osmotic agents, and chemical irritants (Box 2). Deter-

gents interact with the surface lipids of cellular mem-

branes and cause disruption of the endothelial cells.

Detergents are chemicals with polar (hydrophilic) and

nonpolar (hydrophobic) groups. The nonpolar group

of the detergent molecule aligns itself with the cell

membrane of the endothelial cell because the internal

space of the plasma membrane is also nonpolar. This

placement reduces surface tension of the cell mem-

brane, which leads to the disruption of the endothelial

layer. Similarly, detergents can disrupt the deeper

layers of the vessel wall as well. Osmotic agents cause

cellular dehydration by disrupting the water balance

of a cell and thereby causing damage to the cells of the

endothelial level. Osmotic agents also disrupt the

noncellular mural layers of the vessel, decreasing

the chance of recanalization [9]. There is a relation

between the concentration of the sclerosant and the

depth of the vessel wall damage. Chemical irritants,

the last class of sclerosants, have their effect through

various mechanisms to damage the vessel wall.

An ideal sclerosant would clear all veins that were

injected, have no side effects, and be painless to the

Box 2. Sclerosing agent classification

Detergents

Sodium tetradecyl sulfate (Sotradecol)Polidocanol (Aethoxysclerol)Sodium morruhate (Scleromate)Ethanolamine oleate (Ethamolin)

Osmotic agents

Hypertonic salineSaline/dextrose (Sclerodex)

Chemical irritants

Chromated glycerin (Sclermo)Polyiodinated iodine

patient; however, a perfectly ideal sclerosant does not

exist. Therefore, it is important to understand the

good and bad points of each sclerosing agent. There

are three sclerosing agents most commonly used in

the treatment of small vessels: hypertonic saline,

sodium tetradecyl sulfate, and polidocanol. Other

agents are used for some of the larger vessels,

some agents that are no longer used, and there are

other agents that are used outside the United States.

Hypertonic saline comes as a 23.4% solution of

sodium chloride. It is approved by the US Food and

Drug Administration (FDA) for use as an abortificant,

so its use in sclerotherapy is considered ‘‘off-label.’’

It provides for a ‘‘fast-fade’’ of vessels and has a very

low risk of allergenicity. It does sting and cause

discomfort to the patient, however. As a salt solution,

it can cause fluid overload if significant volumes are

used or if many very distal vessels are treated.

Hypertonic saline is caustic enough to cause skin

sloughing at the site of injection in some cases. If

it extravasates, ulceration can occur. If used ap-

propriately, however, it works very well in the treat-

ment of vessels. Appropriate dilution minimizes the

risk of ulceration and telangiectatic matting. For

treating smaller vessels, dilution of the 23.4% sodium

chloride solution with normal saline to an 11.7%

solution is important. In very fine vessels or in

vessels in the ankle area, a solution of approximately

6% sodium chloride may be appropriate. The 23.4%

solution can be used directly in reticular and larger

vessels [10].

Over the years, dilutions with lidocaine and hepa-

rin have been used. A solution of two parts 23.4%

saline and one part 1% lidocaine with epinephrine

(resulting in a 15.6% saline/0.33% lidocaine) solution

has been used. This solution introduces a possible

allergen and another agent that causes stinging,

however. Normal saline can be used for dilution.

Heparin also has been used because it is believed to

decrease the risk of clotting. Its inclusion, however,

again introduces another agent with its own particular

complexities to the mixture, including the risk of

allergenicity [11].

Sodium tetradecyl (Sotradecol) has been widely

used in the United States. In recent years no major

manufacturer has been producing it. It is FDA

approved if a manufacturer meets production guide-

lines. Some smaller companies are currently prepar-

ing the solution. Negative effects include possible

ulceration, pigmentation, and necrosis, and this agent

can be painful in patients with thrombophlebitis. It

also has the potential to induce anaphylaxis. The fol-

lowing appropriate dilutions for vessel size will mini-

mize the potential for side effects: telangiectatic veins


less than 2 mm in diameter (0.1%–0.3% concentra-

tion); varicose veins, 2 to 4 mm (0.5%–1% concen-

tration); and larger ( > 4 mm) varicose veins (1.5%–

3% concentration.)

Polidocanol (also known as Aethoxysclerol) is

currently not FDA approved for use in the United

States, although it has been submitted for such

approval for some years. There is extensive experi-

ence with polidocanol in Australia [12,13], and it is

used in Europe as well. Because it is pain free

(ie, without the stinging caused by saline or Sotrade-

col), it is well liked by patients. It also has decreased

risk of skin sloughing and pigmentation. The agent’s

negative features are the slower fading of treated

vessels and risk of allergic reaction. Because of this

latter risk, a test dose of 0.5% solution should be

injected into a vessel before a treatment session. The

solutions should be diluted appropriately as follows:

0.25% to 0.75% for telangiectasias, 1% for vessels of

1 to 2 mm, and 2% solution for vessels of 2 to 4 mm.

There are total daily dose limitations with polidoca-

nol based on body weight (2 mg/kg/d) and detailed in

the manufacturer’s guidelines [11,14]. Sadick [15] has

shown comparable results between hypertonic saline

and polidocanol.

A solution that is composed of saline (10%),

dextrose (5%), propylene glycol, and phenethyl alco-

hol is manufactured under the brand name Sclerodex.

This substance is not FDA approved, although it is

approved in Canada. It has limited use because it can

only be used in very small vessels, those smaller than

1 mm in diameter. It has the risk of pigmentation, al-

lergenicity, and necrosis. Because there is a decreased

percentage of saline, there may be decreased cramp-

ing during treatment. The manufacturer recommends

a maximum volume of 1 cc at any injection site, with

a total per session of no more than 10 cc [16].

Sodium morrhuate (Scleromate) is an FDA-ap-

proved substance that is currently infrequently used

and is not indicated for use in telangiectasias. It must

be diluted to appropriate concentration. Its many

potential side effects limit its use (eg, necrosis, hyper-

pigmentation, pain, risk of pulmonary embolus, al-

lergenicity, and risk of anaphylaxis) [16].

Ethanolamine oleate (Ethamolin) is of historical

significance in sclerotherapy as one of the first FDA-

approved sclerosing agents. It is not used much now,

however, because it is a viscous solution with a risk

of a hemolytic reaction [11].

Chromated glycerin (Sclermo) has been used in

Europe but is not approved for use by the FDA. It can

be used for telangiectasias and has a low potential of

hyperpigmentation. Only a total of a 0.1-cc prediluted

solution can be used in a single session, and it can be

diluted with lidocaine. Chromated glycerin can be

painful to patients upon injection [11].

Polyiodinated iodine is the most powerful of all

sclerosants and is used in treatment of the sapheno-

femoral junction, a treatment beyond the scope of this

article. It is not FDA approved and can cause necro-

sis. Therefore, it is not appropriate for use in small

vessel sclerotherapy.

Patient history and physical examination

As with all medical and surgical treatments, it is

important to obtain a thorough patient history [17].

There are some contraindications for sclerotherapy.

Pregnancy, a history of hypercoaguability, and allergy

to any agents are very specific contraindications. A

patient with a history of hypercoaguability may be

revealed by history of thrombophlebitis, pulmonary

embolus, deep vein thrombosis, or having a positive

lupus anticoagulant status. Allergy to aspirin, heparin,

and anesthetics can also be important, depending on

the choice of sclerosant. Those patients who have a

history of easy bruising or bleeding, or those patients

who are on aspirin, nonsteroidal anti-inflammatory

drugs (NSAIDs), or vitamin E therapy, have increased

chances of bruising and bleeding with sclerotherapy.

Smokers and those on hormone replacement therapy

or oral contraceptive pills may have an increased risk

of clotting, although these factors are not specific

contraindications. Hormonal therapy has been shown

to have an association with increased telangiectatic

matting [18]. Systemic disease status must be

reviewed and include discussion of the following

conditions: hypertension, congestive heart failure,

diabetes, asthma, and infectious disease. Some of

these conditions can be relative contraindications

because of poor healing and risk of infection. A good

candidate for sclerotherapy is an active patient.

Activity status is also important in posttreatment

counseling because some high-impact activities must

be avoided immediately following sclerotherapy. The

status and results of other leg vein treatments, includ-

ing sclerotherapy, stripping, other surgical treatments,

or laser treatments should be reviewed with the

patient. The dermatologist should also know the

patient’s family history in relation to predisposition

to varicosity development.

It is important to examine the patient from hip to

toe, rather than just a patient’s calf or a similarly

focused area. Examination of the extent of the disease

with which the patient is presenting is important so

that the patient is treated appropriately and so that any

significant underlying venous disease is not over-


looked. Underlying venous or arterial disease can

result in risks such as emboli or ulceration and lead

to poor results with sclerotherapy treatment. During

examination, it is important to assess if there are just a

few scattered vessels or vessels throughout both legs.

Similarly, the physician should determine if there are

just spider telangiectasias and a few reticular veins

visible or if there are large varicosities visible. The

physician should examine the patient at the inner

upper thigh for any saphenous visibility. Examination

of the patient’s skin for evidence of venous disease,

such as pigmentation, stasis changes, and actinic

damage, may indicate the possibility of poor healing.

As appropriate, an examination for hernias and fascial

defects should be performed. Palpation of arterial

pulses and veins can also assist in examination.

Valsalva maneuvers can assist in checking for poor

venous flow in the groin area. Other physical maneu-

vers include the Perthes’ test, Brodie-Trendelenburg

test, and the percussion/Schwartz test. These modali-

ties are outlined in some of the textbooks on scle-

rotherapy and in an article by Fronek [19].

Lab work to evaluate hypercoaguability or bleed-

ing risks may be appropriate if something in the

patient history suggests further evaluation is war-

ranted. If the vessels are larger than 4 mm in diameter

or if there are significant signs of venous damage,

further evaluation by Doppler (unidirectional or bidi-

rectional), Duplex Ultrasound, or photoplethysmog-

raphy is indicated. These tests evaluate the extent of

venous disease and may indicate that larger vessels

need to be addressed. Excellent discussions of these

modalities are available in textbooks on sclerother-

apy, and training is available at the meetings of the

North American Society of Phlebology.

Materials

A basic sclerotherapeutic set-up can be simple.

The solutions a kit should include are as follows: the

sclerosing agent, normal saline, dilutant in case of

extravasation, and possibly nitroglycerin paste. The

choice between 3-cc syringes and 1-cc syringes is a

personal preference, but locking syringes are recom-

mended. The physician should try both sizes and

decide which is preferable. All syringes should be

well labeled as to what solution they contain and its

percentage strength. Disposable 30-gauge needles are

used for injection, with a larger-gauge needle used for

drawing up solutions. Alcohol wipes are used for

cleansing the area before treatment. It is often easier

to visualize veins in the area after wiping with alcohol.

Cotton balls and tape (paper tape, which is less

irritating, is preferred) are used after injecting for

immediate compression and to cover the bleeding

point of injection. Gloves are to be used as a universal

precaution. The current author was trained to use a

mid-to high-potency topical corticosteroid cream after

injection and before applying the cotton ball and

tape. Although there has not been a study to evaluate

the use of topical corticosteroid cream, patients

seem to find it soothing and it seems to decrease the

slight urticarial focal reaction some get at the site

of injection. Also, it may decrease skin sloughing

at the site of injection by decreasing local inflamma-

tory reaction.

Injection techniques

When injecting the patient with the sclerosant, it is

important to have good lighting and, if needed,

magnification. Injecting the patient with the needle

bevel angled up and with a slight bend at the hub

seems to be the most comfortable for the physician.

Also, with the bevel up, the physician can best judge

where the solution is going. It is important to inject

slowly. Rapid injection can cause extravasation and

increase the risk of telangiectatic matting. If the

needle moves, there is risk of scleroscent getting

out of the vessel, and extravasation is more likely.

Therefore it is important to inject slowly, stop when

there is resistance, and not rush while doing the

procedure. The amount of sclerosant per site ranges

from 0.1 to 0.5 cc. It is recommended to proceed from

proximal to distal sites in larger vessels [20], but the

reality is that, for small vessel sclerotherapy, the

dermatologist usually addresses the vessels that

bother the patient the most. The shin, distal lower

leg near the ankle, and popliteal areas cause more

discomfort and have a somewhat higher risk of

ulceration. Therefore these locations are not a good

place to start a sclerotherapy treatment plan. If a

patient has significant reticular disease, it is usually

recommended that the reticular vessels be treated

first. Dr. David Green has shown some excellent

results in which patients just wanted to treat the

spider telangiectasias and not reticular veins (Ameri-

can Academy of Dermatology session, 1999 annual

meeting). Subsequently, the current author has found

that to be true for her patients. As with all treatments,

documentation is important. Some physicians find

that stamps or predrawn sheets are helpful in docu-

menting leg vein treatment.

If a patient describes burning pain, it is likely that

extravasation is occurring. There is a small group of

patients, however, who have significant pain with


accurate sclerotherapy. If extravasation occurs, the

sclerosant should be diluted with normal saline or 1%

lidocaine to decrease the risk of ulceration. Hyal-

uronidase has been shown to decrease the risk of

extravasation-related ulceration. A dose of 75 units of

hyaluronidase injected into the extravasated area can

be effective in decreasing ulceration [21,22]. There-

fore, it is important to have a syringe filled and ready

with your choice of a countertreatment agent. If a

patient has cramping while the physician is in the

process of injecting, the physician should knead or

massage the area or go on to the other leg for a while.

As discussed, the ankle area has a higher risk

of ulceration and should never be first in a patient’s

treatment plan. It is important to use diluted solution

in this region and only do a small amount of

treatment in the ankle area in a session.

Reticular veins are rewarding to treat. The treat-

ment of reticular veins usually causes less stinging to

the patient. For these vessels, a smaller amount of

sclerosant in each syringe is preferred (eg, 0.5 cc).

This is because when treating reticular vessels, the

physician should draw back on the needle to get a

flash of blood to ensure that he or she is in the vessel.

Once there is flashback, inject slowly. Resistance is

felt when the solution is reaching a valve or tortuosity

and is an indication to stop injecting. Compression

with cotton and tape is done immediately after

removing the needle.

Compression

Compression improves the results of sclerother-

apy and decreases the risk of recanalization, hyper-

pigmentation, phlebitic reactions, and telangiectatic

matting [23,24]. Compression is normally accom-

plished with hose stockings. These stockings are

rated in terms of their compressive ability, with the

common ranges of 12 to 40 mm Hg. Support hose

have a more even and graduated compression than

bandaging or wrapping. Patients who only undergo

spider vessel treatment can wear lighter compression

hose, in the range of 12 to 20 mm Hg. Patients with

reticular vein treatments should wear hose in the 20 to

30 mm Hg range. Hose in the 30 to 40 mm Hg range

may be too strongly compressive if the patient is

lying down much of the day. Overcompression could

be a risk factor for ulceration [25]. Patients are

instructed to put their hose on just after therapy and

ideally before standing at all. They wear the hose

overnight the first night after treatment and then

during the day as well. For spider and small vein

treatment, approximately 5 to 7 days of wearing

compression hose use is appropriate. For reticular

vein treatment, 2 to 3 weeks is preferred. Patients are

advised to be ambulatory, because inactivity can

increase the risk of clotting. They are also advised

to avoid high-impact activity, such as jogging, aero-

bics, and kick-boxing. Patients are also advised that

wearing some level of daily support hose should

improve their lower extremity vessel status. Some

patients find that their legs are less ‘‘tired’’ at the end

of the day and prefer to wear the hose on a regular

basis, which is especially important in occupations

where the patient stands all day [26].

Side effects/complications

Overall, sclerotherapy is a safe and well-tolerated

procedure. There are some areas to be aware of,

however, and it is important to caution patients about

these areas in your consultation appointment and

informed consent.

Bruising at the site of injection can occur and is

more likely if the patient takes aspirin or NSAIDs.

This effect clears with time. Localized urticaria can

occur at the site of injection and seems to be relieved

by the use of topical corticosteroids applied before the

application of dressings and compression hose. The

urticaria is transient and can occur with most agents.

The theory is that it is caused by the irritation of the

endothelial wall of the injected vessel [11]. Many pa-

tients complain of some pain at the time of procedure.

Hyperpigmentation can occur in up to 10% to

30% of vessels but is more likely to occur in vessels

larger than 2 mm [25]. Compression therapy and the

avoidance of tanning decrease this likelihood. Hyper-

pigmentation clears with time or can be managed

with topical tretinoin or hydroquinones, or the physi-

cian’s hyperpigmentation treatment of choice.

Crusting at the site of injection has been reported

up to 10% of the time and is caused by out-leak

of sclerosant.

Telangiectatic matting can also occur, especially if

the sclerosant is injected too quickly and possibly if

the concentration percentage is too strong. Matting

has been shown to occur in up to 15% to 20% of pa-

tients [25,27]. Management with treatment at a future

visit is usually appropriate. Laser or light therapy

may play a role in treatment of vessels that are too

small to inject.

Edema can also occur with sclerotherapy. The

lower part of the leg, particularly the ankle area, is

prone to this side effect. Compression therapy and

caution regarding the volume of sclerosant used in a

session can minimize edema.


Superficial thrombophlebitis can occur with ves-

sels of 3 to 5 mm and can be managed with

compression, NSAIDs, heat, and sometimes intra-

muscular corticosteroids. Nodular fibrosis can occur

with the larger vessels and needs to be minimized

with compression and managed with reassurance

and time.

Necrosis can be caused by out-leaks of the scle-

rosant, and needle placement issues warrant patience

and caution when sclerosing vessels. Sometimes

dilution with lidocaine, normal saline, or hyaluroni-

dase can minimize necrosis.

Ulcers can occur with injection of sclerosants.

Extravasation or injection into an arteriole can also

lead to ulceration. If extravasation is suspected,

dilution with normal saline, lidocaine, or hyaluroni-

dase can help as previously discussed. Also, if the

physician sees a white blanching suggestive of arte-

riole infiltration, application of topical nitroglycerin

paste at the site may decrease the potential for

ulceration by increasing the microcirculation, which

can flush the sclerosant from the arteriole [28]. If an

ulcer occurs, patience, frequent visits, and good ulcer

care management are important.

Patient management

Before performing sclerotherapy on a patient, it is

important to have a thorough consultation appoint-

ment. During this appointment, details of the patient’s

history are obtained. A standardized form for patients

for sclerotherapy can simplify the history-taking. A

complete examination as previously discussed should

be performed. Risks, benefits, and side effects should

be reviewed with the patient as appropriate for an

informed consent. The patient’s treatment plan can be

reviewed with the patient, helping to ensure realistic

outcomes. It is important to advise patients that

vessels may take up to a month to fade after treat-

ment. The number of sessions will vary with the

extent of the disease, amount of therapy done in each

session, and the rate of success of treatment. Addi-

tional sessions are usually not scheduled until 4 to

6 weeks after therapy. Appropriate compression

hose should be discussed, because the patient will

need these with them at the time of treatment. Patients

are advised that they may need to modify exercise

programs to avoid high-impact activities from 1 to

3 weeks after therapy (1 wk for telangiectasias and up

to 3 wks for reticular veins). Patients are also advised

at consultation to avoid shaving or moisturizing the

24 hours before (or day of) procedure.

A follow-up examination with the patient after

sclerotherapy usually occurs at approximately

1 month, unless they have any problems or questions

and need to be seen sooner. Patients are usually

advised that some vessels may take up to a month

to fully clear after therapy, and further treatment, if

needed, can be planned at that time.

New developments

New areas of discussion in sclerotherapy include

the use of foam sclerosant. Foam is formed by mixing

air with the sclerosant [29,30]. Sclerotherapy is also

being used on vessels of the face, hand, and chest

[31]. These areas are more complex and should be

reviewed with someone experienced in treating these

areas. Laser therapy continues to evolve with new

modalities. Currently, however, laser and light thera-

pies should be considered in patients who do not

tolerate sclerotherapy because of a fear of needles or

failure of previous therapy, or in those who are prone

to telangiectatic matting [32].

Summary

Sclerotherapy is a good procedure to include in

dermatology practice. As with all procedures, the

dermatologist should proctor with a colleague and

learn further details about the procedure before be-

ginning independent practice. Sclerotherapy of small

vessels requires minimal equipment and has a high

satisfaction for both the patient and physician.

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Documents

2004, Vol.22, Issues 4, Psoriasis