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Lupus Erythematosus LUPUS AT A GLANCE A group of heterogeneous illnesses that have in common the development of immunity to self-nucleic acids and their associated proteins, with skin-only disease at one end of the spectrum and severe visceral involvement at the other. Skin lesions may be specific to lupus or nonspecific and are seen in other conditions as well. Acute cutaneous lupus erythematosus (malar rash) is almost always associated with underlying visceral involvement, subacute cutaneous lupus patients meet systemic lupus erythematosus criteria about 50% of the time (but typically express only mild systemic clinical manifestations), and chronic cutaneous lupus (discoid lupus erythematosus, lupus panniculitis, chilblain lupus, and tumid lupus erythematosus) patients most often have skin-only or skinpredominant disease. Discoid lupus erythematosus causes scarring and can be permanently disfiguring. Subacute cutaneous lupus and acute cutaneous lupus erythematosus are highly photosensitive and are characteristically nonscarring. Lupus erythematosus-nonspecific skin lesions include nonscarring alopecia, mouth ulcers, photosensitivity, Raynaud’s phenomenon, and vasculitis/vasculopathy, among others. They often herald a systemic lupus erythematosus flare. Treatment consists of sunscreens, local and systemic (short-term) glucocorticoids, antimalarials, retinoids, immunosuppressives, thalidomide, and biologic therapies. Lupus erythematosus occurs much more commonly in women (9:1 female-male ratio). Both systemic lupus erythematosus and cutaneous lupus erythematosus are associated with upregulation of class I interferon signaling. LUPUS ERYTHEMATOSUS: A CHALLENGE TO DEFINE, CLASSIFY, AND TREAT Lupus erythematosus (LE) is the root designation for a diverse array of illnesses that are linked together by the development of autoimmunity directed predominantly at the molecular constituents of nucleosomes and ribonucleoproteins. Some patients present with life-threatening manifestations of systemic LE (SLE);

Lupus Erythematosus

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Lupus ErythematosusLUPUS AT A GLANCE

A group of heterogeneous illnesses that have

in common the development of immunity

to self-nucleic acids and their associated

proteins, with skin-only disease at one

end of the spectrum and severe visceral

involvement at the other.

Skin lesions may be specific to lupus or

nonspecific and are seen in other conditions

as well.

Acute cutaneous lupus erythematosus

(malar rash) is almost always associated

with underlying visceral involvement,

subacute cutaneous lupus patients meet

systemic lupus erythematosus criteria about

50% of the time (but typically express only

mild systemic clinical manifestations), and

chronic cutaneous lupus (discoid lupus

erythematosus, lupus panniculitis, chilblain

lupus, and tumid lupus erythematosus)

patients most often have skin-only or skinpredominant

disease.

Discoid lupus erythematosus causes scarring

and can be permanently disfiguring.

Subacute cutaneous lupus and acute

cutaneous lupus erythematosus are highly

photosensitive and are characteristically

nonscarring.

Lupus erythematosus-nonspecific skin

lesions include nonscarring alopecia,

mouth ulcers, photosensitivity, Raynauds

phenomenon, and vasculitis/vasculopathy,

among others. They often herald a systemic

lupus erythematosus flare.

Treatment consists of sunscreens,

local and systemic (short-term)

glucocorticoids, antimalarials, retinoids,

immunosuppressives, thalidomide, and

biologic therapies.

Lupus erythematosus occurs much more

commonly in women (9:1 female-male ratio).

Both systemic lupus erythematosus

and cutaneous lupus erythematosus are

associated with upregulation of class I

interferon signaling.LUPUS ERYTHEMATOSUS: A

CHALLENGE TO DEFINE, CLASSIFY,

AND TREAT

Lupus erythematosus (LE) is the root designation for

a diverse array of illnesses that are linked together by

the development of autoimmunity directed predominantly

at the molecular constituents of nucleosomes

and ribonucleoproteins. Some patients present with

life-threatening manifestations of systemic LE (SLE);

whereas others, who are affected with what likely

represents the same basic underlying disease process,

express little more than discoid LE (DLE) skin lesions

throughout their illness. It is convenient to conceptualize

LE as a clinical spectrum ranging from mildly

affected patients with only localized DLE skin lesions

to those at risk of dying from the systemic manifestations

of LE such as nephritis, central nervous system

disease, or vasculitis. The pattern of skin involvement

expressed by an individual patient with LE can provide

insight about the position on the spectrum where

the patients illness might best be placed.

The nomenclature and classification system originally

devised by James N. Gilliam divides the cutaneous

manifestations of LE into those lesions that show

characteristic histologic changes of LE (LE-specific

skin disease) and those that are not histopathologically

distinct for LE and/or may be seen as a feature of

another disease process (LE-nonspecific skin disease).

Within this context, the term LE-specific relates to

those lesions displaying an interface dermatitis. The

term cutaneous LE (CLE) is often used synonymously

with LE-specific skin disease as an umbrella designation

for the three major categories of LE-specific skin

disease: acute cutaneous LE (ACLE), subacute cutaneous

LE (SCLE), and chronic cutaneous LE (CCLE). This

will be the framework used in our discussion of the

extraordinarily diverse set of cutaneous lesions that

occur in patients with LE (Table 155-1).

The essence of LE is in its heterogeneity, and the

challenge for those who treat it is to recognize clinically

useful patterns within the mosaic of features that

constitute this protean illness. An overview of the systemic

manifestations of LE can be seen in the American

College of Rheumatologys (ACR) classification criteria

for SLE,1 which are presented in Table 155-2, and

from the outline of the systemic manifestations of SLE

presented in Table 155-3.

EPIDEMIOLOGY

The epidemiology and socioeconomic impact of LE in

general,2 and CLE specifically,3 have been reviewed. Skin disease is the second most frequent clinical manifestation

of LE after joint inflammation. As many as

45% of patients with CLE experience some degree

of vocational handicap. A recent quality of life study

suggested that the impact of skin manifestations in

patients with SLE was preceded only by pain and

fatigue related to their disease.4 The Dermatology Life

Quality Index and SF-36 have been used to measure

quality of life in patients with CLE. Both questionnaires

showed that patients with active skin lesions

had lower quality of life and that patients with associated

alopecia were particularly impacted.5

Malar, or butterfly rash (localized ACLE), has been

reported in 20%60% of large cohorts of patients with

LE. Limited data suggest that the maculopapular

or SLE rash of generalized ACLE is present in about

35%60% of patients with SLE. ACLE, like SLE in

general, is much more common in women than men

(8:1). All races are affected; however, the early clinical

manifestations of ACLE can be overlooked in a darkskinned

individual.

Patients presenting with SCLE lesions constitute

7%27% of LE patient populations. SCLE is primarily

a disease of white females, with the mean age of

onset in the fifth decade. Drug-induced SCLE patients

are somewhat older at disease onset, perhaps reflecting

greater exposure to drugs for age-related medical

problems (hypertension, cardiovascular disease).

The most common form of CCLE, a classic DLE

skin lesion, is present in 15%30% of SLE populations

selected in various ways. Approximately 5% of

patients presenting with isolated localized DLE subsequently

develop SLE. Rheumatologists have estimated

that SLE patients are sevenfold more common than isolated

cutaneous LE patients. However, dermatologists

have estimated that isolated cutaneous LE patients

may be 2-3 times more common that SLE patients.

Recently published population-based data have

argued strongly that the incidence and prevalence of

isolated forms of cutaneous LE are equivalent to those

of SLE.6 Although DLE can occur in infants and the

elderly, it is most common in individuals between 20

and 40 years of age. DLE has a female-male ratio of 3:2

to 3:1, which is much lower than that of SLE. All races

are affected, but investigations suggest that DLE might

be more prevalent in blacks.

ETIOLOGY AND PATHOGENESIS

The cause(s) of and pathogenetic mechanisms responsible

for LE-specific skin disease are not fully understood,

although recent work has provided many new

insights. The pathogenesis of LE-specific skin disease

is inextricably intertwined with SLE pathogenesis.

Simply put, SLE is a disorder in which the interplay

between host factors (susceptibility genes, hormonal

milieu, etc.) and environmental factors [ultraviolet

(UV) radiation, viruses, and drugs] leads to loss of

self-tolerance, and induction of autoimmunity. This is

followed by activation and expansion of the immune system,

and eventuates in immunologic injury to end organs

and clinical expression of disease7 (eFig. 155-0.1 in online

edition). Recent work has highlighted the important role

of interferon-signaling in the pathogenesis of both

SLE and LE-specific skin disease.

ENVIRONMENTAL FACTORS

Genetic predisposition for a lupus diathesis does not,

in itself, produce disease. Rather, it appears that induction

of autoimmunity in such patients is triggered by

some inciting event, likely an environmental exposure.

Drugs, viruses, UV light, and, possibly, tobacco, have

been shown to induce development of SLE.

Ultraviolet radiation (UVR) is probably the most

important environmental factor in the induction phase

of SLE and especially of LE-specific skin disease. UV

light likely leads to self-immunity and loss of tolerance

because it causes apoptosis of keratinocytes, which in

turn, makes previously cryptic peptides available for

immunosurveillance. UVB radiation has been shown

to displace autoantigens such as Ro/SS-A and related

autoantigens, La/SS-B, and calreticulin, from their

normal locations inside epidermal keratinocytes to the

cell surface.13 UVB irradiation induces the release of

CCL27 (cutaneous T cell-attracting chemokine), which

upregulates the expression of chemokines that activate

autoreactive T cells and interferon-(IFN-), producing

dendritic cells (DCs), which likely play a central

role in lupus pathogenesis.14,15

A recent, large, case-control study reported that

smokers are at a greater risk of developing SLE than

are nonsmokers and former smokers. A cross-sectional

analysis of a collaborative Web-based database established

by Werth and colleagues documented that

patients with treatment resistant CLE were much more

likely to smoke.16 Several authors have shown that

patients with LE-specific skin disease who smoke are

less responsive to antimalarial treatment.1719

Numerous drugs have been implicated in inducing

various features of SLE (Table 155-3). The drugs

that induce CLE can be linked by their photosensitizing

properties. It has been suggested that these drugs

cause an increase in keratinocyte apoptosis, exposure

of previously intracellular peptides on epidermal cell

surfaces, and enhance proinflammatory cytokines

such as TNF-and IFN-.20,21

There has been much speculation about the role of

infectious agents, particularly viruses, in the induction

of SLE and CLE. Seroconversion to Epstein-Barr virus

(EBV) among patients with SLE is nearly universal,

and recent data have demonstrated that patients with

SLE have defective control of latent EBV infection that

probably stems from altered T-cell responses against

EBV.

CLINICAL FINDINGS

(eFig. 155-0.2 in online edition)

CUTANEOUS LESIONS

eTable 155-3.1 in online edition compares the key clinical,

histopathologic, and laboratory features of patients

presenting with ACLE, SCLE, and CCLE (classic DLE)

subtypes of LE-specific skin disease, because the type

of skin involvement in LE can reflect the underlying

pattern of SLE activity. In fact, the designations acute,

subacute, and chronic, in regard to CLE, refer to the

pace and severity of any associated SLE and are not

necessarily related to how long individual lesions have

been present. For example, ACLE almost always occurs

in the setting of acutely flaring SLE, whereas CCLE

often occurs in the absence of SLE or in the presence

of mild smoldering SLE. SCLE occupies an intermediate

position in this clinical spectrum. Subclassification,

although important for assigning risk, is sometimes

difficult, as it is not uncommon to see more than one

subtype of LE-specific skin disease in the same patient,

especially in patients with SLE.

ACUTE CUTANEOUS LUPUS ERYTHEMATOSUS.

Although ACLE localized to the face is the

usual pattern of presentation, ACLE can assume a generalized

distribution. Localized ACLE has commonly

been referred to as the classic butterfly rash or malar

rash of SLE (Fig. 155-1). In localized ACLE, confluent

symmetric erythema and edema are centered over the

malar eminences and bridges over the nose (unilateral

involvement with ACLE has been described). The

nasolabial folds are characteristically spared. The forehead,

chin, and V area of the neck can be involved, and

severe facial swelling may occur. Occasionally, ACLE

begins as small macules and/or papules on the face

that later may become confluent and hyperkeratotic.

Generalized ACLE presents as a widespread morbilliform

or exanthematous eruption often focused over the

extensor aspects of the arms and hands and characteristically

sparing the knuckles (Fig. 155-2A). Although

perivascular nail fold erythema and telangiectasia can

occur (see Fig. 155-2B), they are considerably more

common and occur in more exaggerated forms in dermatomyositis

(see Fig. 157-5). Generalized ACLE has

been indiscriminately referred to as the maculopapular

rash of SLE, photosensitive lupus dermatitis, and SLE rash.

An extremely acute form of ACLE is rarely seen that

can simulate toxic epidermal necrolysis (TEN). This

form of LE-specific vesiculobullous disease results

from widespread apoptosis of epidermal keratinocytes,

and eventuates in areas of full-thickness epidermal

skin necrosis, which is subsequently denuded.

It can be differentiated between true TEN because it

occurs on predominantly sun-exposed skin and has a

more insidious onset.30 The mucosa may or may not be

involved, as in TEN.

ACLE is typically precipitated or exacerbated

by exposure to UV light. This form of CLE can be

quite ephemeral, lasting only hours, days, or weeks;

however, some patients experience more prolonged

periods of activity. Postinflammatory pigmentary

change is most prominent in patients with heavily

pigmented skin. Scarring does not occur in ACLE

unless the process is complicated by secondary bacterial

infection.

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS.

A disease presentation dominated by

SCLE lesions marks the presence of a distinct subset of

LE having characteristic clinical, serologic, and genetic

features. Although a finding of circulating autoantibodies

to the Ro/SS-A ribonucleoprotein particle

strongly supports a diagnosis of SCLE, the presence of

this autoantibody specificity is not required to make a

diagnosis of SCLE.

SCLE initially presents as erythematous macules

and/or papules that evolve into hyperkeratotic papulosquamous

or annular/polycyclic plaques (Fig.

155-3). Whereas most patients have either annular

or papulosquamous SCLE, a few develop elements

of both morphologic varieties. SCLE lesions are

characteristically photosensitive and occur in predominantly

sun-exposed areas (i.e., upper back,

shoulders, extensor aspects of the arms, V area of

the neck, and, less commonly, the face). SCLE lesions

typically heal without scarring but can resolve with

long-lasting, if not permanent, vitiligo-like leukoderma,

and telangiectasias.

Several variants of SCLE have been described. On

occasion, SCLE lesions present initially with an appearance

of erythema multiforme. Such cases are similar to

Rowell syndrome (erythema multiforme-like lesions

occurring in patients with SLE in the presence of La/

SS-B autoantibodies). As a result of intense injury to

epidermal basal cells, the active edge of an annular

SCLE lesion occasionally undergoes a vesiculobullous

change that can subsequently produce a strikingly

crusted appearance. Such lesions can mimic Stevens-

Johnson syndrome/TEN. Pathogenesis is similar to

that described above for TEN-like ACLE. Rarely, SCLE

presents with exfoliative erythroderma or displays a

curious acral distribution of annular lesions. Pityriasiform

and exanthematous variants of SCLE have been

reported. The skin lesions of neonatal LE (transient,

photosensitive, nonscarring LE-specific skin lesions in

neonates who have received IgG anti-Ro/SS-A, and,

occasionally, other autoantibody specificities transplacentally)

share many features with SCLE.

Unlike ACLE skin lesions, SCLE lesions tend to be

less transient than ACLE lesions and heal with more

pigmentary change. They are also less edematous and

more hyperkeratotic than ACLE lesions. SCLE more

commonly involves the neck, shoulders, upper extremities,

and trunk, whereas ACLE more commonly affects

the malar areas of the face. When the face is involved

with SCLE, it is most often the lateral face, with sparing

of the central, malar regions. In comparison to

SCLE lesions, DLE lesions are generally associated

with a greater degree of hyper- and hypopigmentation,

atrophic dermal scarring, follicular plugging, and

adherent scale. A consistent clinical difference is that

DLE lesions are characteristically indurated, whereas

SCLE lesions are not; this difference reflects the greater

depth of inflammation seen histopathologically in DLE

lesions.

Approximately one-half of patients with SCLE meet

the ACRs revised criteria for the classification of SLE.

However, manifestations of severe SLE, such as nephritis,

central nervous system disease, and systemic vasculitis,

develop in only 10%15% of patients with

SCLE. It has been suggested that the papulosquamous

type of SCLE, leu-kopenia, high titer of antinuclear

antibody (ANA) (1:640), and anti-dsDNA antibodies

are risk factors for the development of SLE in a patient

presenting with SCLE lesions.

SCLE can overlap with other autoimmune diseases,

including Sjgrens syndrome, rheumatoid arthritis,

and Hashimotos thyroiditis. Other disorders that

have been anecdotally related to SCLE are Sweet

syndrome, porphyria cutanea tarda, gluten-sensitive

enteropathy, and Crohns disease. There has also

been the suggestion that SCLE can be associated with

internal malignancy (breast, lung, gastric, uterine,

hepatocellular, and laryngeal carcinomas as well as

with Hodgkin lymphoma).31

CHRONIC CUTANEOUS LUPUS

ERYTHEMATOSUS

Classic DLE. Classic DLE lesions, the most common

form of CCLE, begin as red-purple macules, papules,

or small plaques and rapidly develop a hyperkeratotic

surface. Early classic DLE lesions typically evolve into

sharply demarcated, coin-shaped (i.e., discoid) erythematous

plaques covered by a prominent, adherent

scale that extends into the orifices of dilated hair follicles

(Fig. 155-4).

DLE lesions typically expand with erythema and

hyperpigmentation at the periphery, leaving hallmark

atrophic central scarring, telangiectasia, and hypopigmentation

(Fig. 155-5). DLE lesions at this stage can

merge to form large, confluent, disfiguring plaques.

DLE in persons of certain ethnic backgrounds, such as

Asian Indians, can present clinically as isolated areas

of macular hyperpigmentation. When present on hairbearing

skin (scalp, eyelid margins, and eyebrows),

DLE causes scarring alopecia, which can lead to disfigurement

and markedly impact quality of life. Follicular

involvement in DLE is a prominent feature. Keratotic

plugs accumulate in dilated follicles that soon become

devoid of hair. When the adherent scale is lifted from

more advanced lesions, keratotic spikes similar in

appearance to carpet tacks can be seen to project from

the undersurface of the scale (i.e., the carpet tack

sign). DLE lesions can be difficult to diagnose in Caucasian

patients because the characteristic peripheral

hyperpigmentation is often absent. Such lesions are

often confused with actinic keratoses, squamous cell

carcinoma, or acne.

DLE lesions are most frequently encountered on the

face, scalp, ears, V area of the neck, and extensor aspects

of the arms. Any area of the face, including the eyebrows,

eyelids, nose, and lips, can be affected. A symmetric,

hyperkeratotic, butterfly-shaped DLE plaque is

occasionally found over the malar areas of the face and

bridge of the nose. Such lesions should not be confused

with the more transient, edematous, minimally scaling

ACLE erythema reactions that occur in the same areas.

Facial DLE, like ACLE and SCLE, usually spares the

nasolabial folds. It may be difficult to distinguish early

lesions of malar DLE from ACLE, but induration and

recalcitrance to topical steroids/calcineurin inhibitors

favors the former diagnosis. When DLE lesions occur

periorally, they resolve with a striking acneiform pattern

of pitted scarring. DLE characteristically affects the

external ear, including the outer portion of the external

auditory canal (Fig. 155-6A). Such lesions often present

initially as dilated, hyperpigmented follicles. The scalp

is involved in 60% of patients with DLE; irreversible,

scarring alopecia resulting from such involvement has

been reported in one-third of patients (see Fig. 155-6B).

The irreversible, scarring alopecia resulting from DLE

differs from the reversible, nonscarring alopecia that

patients with SLE often develop during periods of systemic

disease activity. This type of hair loss, so-called

lupus hair, may be telogen effluvium occurring as the

result of flaring systemic disease.

Localized DLE lesions occur only on the head or neck,

whereas generalized DLE lesions occur both above and

below the neck. Generalized DLE is more commonly

associated with underlying SLE and is often more recalcitrant

to standard therapy, frequently requiring layering

of antimalarial and immunosuppressive medications.

DLE lesions below the neck most commonly occur on

the extensor aspects of the arms, forearms, and hands,

although they can occur at virtually any site on the body.

The palms and soles can be the sites of painful, and at

times disabling, erosive DLE lesions. On occasion, small

DLE lesions occurring only around follicular orifices

appear at the elbow and elsewhere (follicular DLE). We

have observed that elbow/extensor arm lesions seem to

cooccur with acral finger lesions of DLE, and that patients

with this combination of findings more frequently have

active systemic disease. DLE activity can localize to the

nail unit. The nail can be impacted by other forms of CLE

as well as SLE, producing nail fold erythema and telangiectasia,

red lunulae, clubbing, paronychia, pitting,

leukonychia striata, and onycholysis.

DLE lesions can be potentiated by sunlight exposure

but to a lesser extent than ACLE and SCLE lesions.

DLE, as well as other forms of LE skin disease activity,

can be precipitated by any form of cutaneous trauma

(i.e., the Koebner phenomenon or isomorphic effect).

The relationship between classic DLE and SLE has

been the subject of much debate.32 The following summary

points can be made: (1) 5% of patients presenting

with classic DLE lesions subsequently develop

unequivocal evidence of SLE and (2) patients with

generalized DLE (i.e., lesions both above and below

the neck) have somewhat higher rates of immunologic

abnormalities, a higher risk for progressing to SLE,

and a higher risk for developing more severe manifestations

of SLE than patients with localized DLE.

Roughly one-fourth of patients with SLE develop

DLE lesions at some point in the course of their

disease, and such patients tend to have less severe

forms of SLE. Figure 155-7 illustrates the relative risks

for systemic disease activity that are associated with

the clinical varieties of LE-specific skin disease.

Aside from Classic DLE, there are several other less

common variants of CCLE, which are subclasssified as

such because of their overlapping histologies and tendency

to occur in a low frequency in association with

underlying SLE.

Hypertrophic DLE. Hypertrophic DLE, also

referred to as hyperkeratotic or verrucous DLE, is a rare

variant of CCLE in which the hyperkeratosis normally

found in classic DLE lesions is greatly exaggerated. The

extensor aspects of the arms, the upper back, and the

face are the areas most frequently affected. Overlapping

features of hypertrophic LE and lichen planus have

been described under the rubric lupus planus. The entity

lupus erythematosus hypertrophicus et profundus appears

to represent a rare form of hypertrophic DLE, affecting

the face with the additional features of violaceous/

dull red, indurated, rolled borders and striking central,

crateriform atrophy. The name for this clinical entity is

ambiguous because LE panniculitis is not characteristic

of its histopathology. Patients with hypertrophic DLE

probably do not have a greater risk for developing SLE

than do patients with classic DLE lesions.

Mucosal DLE. Mucosal DLE occurs in approximately

25% of patients with CCLE. The oral mucosa is most frequently

affected; however, nasal, conjunctival, and genital

mucosal surfaces can be targeted. In the mouth, the

buccal mucosal surfaces are most commonly involved,

with the palate (see Fig. 155-6C), alveolar processes, and

tongue being sites of less frequent involvement. Lesions

begin as painless, erythematous patches that evolve to

chronic plaques that can be confused with lichen planus.

Chronic buccal mucosal plaques are sharply marginated

and have irregularly scalloped, white borders

with radiating white striae and telangiectasia. The

surfaces of these plaques overlying the palatal mucosa

often have a honeycomb appearance. Central depression

often occurs in older lesions, and painful ulceration

can develop. Rarely, oral mucosal DLE lesions

can degenerate into squamous cell carcinoma, similar

to longstanding cutaneous DLE lesions. Any degree

of nodular asymmetry within a mucosal DLE lesion

should be evaluated for the possibility of malignant

degeneration. Chronic DLE plaques also appear on the

vermilion border of the lips. At times, DLE involvement

of the lips can present as a diffuse cheilitis, especially on

the more sun-exposed lower lip.

DLE lesions may present on the nasal, conjunctival,

and anogenital mucosa. Perforation of the nasal

septum is more often associated with SLE than DLE.

Conjunctival DLE lesions affect the lower lid more

often than the upper lid. Lesions begin as focal areas

of nondescript inflammation most commonly affecting

the palpebral conjunctivae or the lid margin. Scarring

becomes evident as lesions mature, and the permanent

loss of eyelashes and ectropion can develop, producing

considerable disability.

LE Profundus/LE Panniculitis. LE profundus/

LE panniculitis (Kaposi-Irgang disease) is a rare form

of CCLE typified by inflammatory lesions in the lower

dermis and subcutaneous tissue. Approximately 70%

of patients with this type of CCLE also have typical

DLE lesions, often overlying the panniculitis lesions.

Some have used the term LE profundus to designate

those patients who have both LE panniculitis and DLE

lesions, and LE panniculitis to refer to those having

only subcutaneous involvement. Typical subcutaneous

lesions present as firm nodules, 13 cm in diameter.

The overlying skin often becomes attached to the subcutaneous

nodules and is drawn inward to produce

deep, saucerized depressions (Fig. 155-8). The head,

proximal upper arms, chest, back, breasts, buttocks,

and thighs are the sites frequently affected. LE panniculitis,

in the absence of overlying DLE, may produce

breast nodules that can mimic carcinoma clinically

and radiologically (lupus mastitis). Confluent facial

involvement can simulate the appearance of lipoatrophy.

Dystrophic calcification frequently occurs in older

lesions of LE profundus/LE panniculitis, and pain

associated with such calcification can, at times, be the

dominant clinical problem. Roughly 50% of patients

with LE profundus/panniculitis have evidence of SLE.

However, the systemic features of patients with LE

panniculitis/profundus tend to be less severe, similar

to those of patients with SLE who have DLE skin

lesions.

Chilblain LE. Chilblain LE lesions initially develop as

purple-red patches, papules, and plaques on the toes,

fingers, and face, which are precipitated by cold, damp

climates and are clinically and histologically similar to

idiopathic chilblains (pernio) (see Chapter 94). As they

evolve, these lesions usually assume the appearance

of scarred atrophic plaques with associated telangiectases.

They may resemble old lesions of DLE or may

mimic acral lesions of small vessel vasculitis. Histologic

findings include a superficial and deep lymphocytic

vascular reaction in addition to fibrin deposition

in reticular, dermal-based blood vessels. Patients with

chilblain LE often have typical DLE lesions on the

face and head. It is possible that chilblain LE begins

as a classic acral, cold-induced lesion that then koebnerizes

DLE lesions, thus explaining the spectrum of

clinico-histologic findings, which seem to vary based

on when, in the course of the lesion, the biopsy sample

is taken.

Chilblain LE appears to be associated with anti-Ro/

SS-A antibodies,33 and is linked to Raynauds phenomenon

in many cases.34 Persistence of lesions beyond the

cold months, a positive ANA, or presence of one of the

other ACR criteria for SLE at the time of diagnosis of

chilblain lesions helps to distinguish chilblain LE from

idiopathic chilblains.35 Approximately 20% of patients

presenting with chilblain LE later develop SLE. Chilblain

LE is an underrecognized entity, yet it is likely

that it is one of the most common causes of digital

lesions in patients with LE. It is sometimes misdiagnosed

as vasculitis and may overlap with acral DLE

as mentioned above. An autosomal dominant, familial

form of Chilbalin LE has recently been described, and

is caused by a missense mutation in the TREX 1 (endonuclease

repair) gene.36

Lupus Erythematosus Tumidus. Lupus erythematosus

tumidus (LET; tumid LE) is a variant of

CCLE in which the dermal findings of DLE, namely,

excessive mucin deposition and superficial perivascular

and periadnexal inflammation, are found on

histologic evaluation. The characteristic epidermal

histologic changes of LE-specific skin disease are only

minimally expressed, if at all. This results in succulent,

edematous, urticaria-like plaques with little surface

change (Fig. 155-9). Annular urticaria-like plaques can

also be seen. The paucity of epidermal change often

produces confusion concerning the diagnosis of LET

as a form of CCLE.37,38

There have been several recent reports that support

this subclassification and further characterize this subtype

of CCLE.3944 Although described to occur in some

patients with SLE, most patients with LET have a negative

ANA and a benign disease course. LET appears

to be the most photosensitive subtype of cutaneous

lupus, and typically demonstrates a good response to

antimalarials. Additionaly, LET lesions tend to resolve

completely without either scarring or atrophy.

There continues to be debate about the validity of

LET as an authentic form of LE-skin disease. Some

argue that LET lesions may in fact not be a form of

CLE45 while others feel that LET deserves to be recognized

as a distinct type of CLE (intermittent cutaneous

LE) equivalent in importance to acute cutaneous LE,

subacute cutaneous LE, and chronic cutaneous LE.46

Other Variants. Other rare forms of chronic cutaneous

LE have been described. These include LE

hypertrophicus et profundus, lichenoid DLE, LE vermiculatus,

LE telangiectaticus, linear CLE, and LE

edematous (probably a historical designation for urticaria-

like plaque DLE. Further information on these

clinical entities has recently been presented.47

LABORATORY TESTS

eTable 155-3.1 in online edition summarizes the major

laboratory findings associated with the varieties of LEspecific

skin disease, and Table 155-5 presents the autoantibody

associations of SLE. Because of the strong

association between ACLE and SLE, the laboratory features

of ACLE are those associated with SLE (high-titer

ANA, anti-dsDNA, anti-Sm, and hypocomplementemia).

The laboratory markers for SCLE are the presence

of anti-Ro/SS-A (70%90%) and, less commonly,

anti-La/SS-B (30%50%) autoantibodies. ANA are

present in 60%80% of patients with SCLE, and rheumatoid

factor is present in approximately one-third.

Other autoantibodies in patients with SCLE include

false-positive serologic tests for syphilis (VDRL rapid

plasma reagin) (7%33%), anticardiolipin (10%16%),

antithyroid (18%44%), anti-Sm (10%), anti-ds-DNA

(10%), and anti-U1 ribonucleoprotein (10%). Patients

with SCLE, particularly those with systemic involvement,

may have a number of laboratory abnormalities,

including anemia, leukopenia, thrombocytopenia,

elevated erythrocyte sedimentation rate, hypergammaglobulinemia,

proteinuria, hematuria, urine casts,

elevated serum creatine and blood urea nitrogen, and

depressed complement levels (resulting from genetic

deficiency or increased complement consumption).

ANA are present in low titer in 30%40% of patients

with DLE; however, fewer than 5% have the higher

ANA levels that are characteristic of patients with

overt SLE (1:320). Antibodies to single-stranded DNA

are not uncommon in DLE, but antibodies to dsDNA

are distinctly uncommon. Precipitating antibodies to

U1RNP are sometimes found in patients whose disease

course is dominated by DLE lesions; however,

such patients usually have only mild manifestations of

SLE or overlapping connective tissue disorders such as

mixed connective tissue disease. Precipitating Ro/SS-A

and La/SS-B autoantibodies are rare in patients with

DLE; low levels of anti-Ro/SS-A antibody detected by

enzyme-linked immunoassay are more common. A

small percentage of patients with DLE have low-grade

anemia, biologic false-positive serologic tests for syphilis

(VDRL rapid plasma reagent), positive rheumatoid

factor tests, slight depressions in serum complement

levels, modest elevations in globulin, and modest

leukopenia. It has been suggested that such findings

are risk factors for the development of SLE. ANA are

present in 70%75% of patients with LE profundus/

panniculitis, but anti-dsDNA antibodies are rare.

The laboratory findings associated with SLE, as well

as with CLE, in both adults and newborns, have been

reviewed.71,72

HISTOPATHOLOGY

The LE-specific skin disease histopathology is a distinctive

constellation of hyperkeratosis, epidermal

atrophy, vacuolar basal cell degeneration, dermalepidermal

junction basement membrane thickening,

dermal edema, dermal mucin deposition, and mononuclear

cell infiltration of the dermal-epidermal junction

and dermis, focused in a perivascular and periappendageal

distribution (eFig. 155-9.1 in online edition). Variable

degrees of these features are encountered in the

different forms of LE-specific skin disease (see Chapter

6). Differences of opinion exist as to whether ACLE,

SCLE, and DLE lesions can be distinguished reliably on

the basis of their histopathologic appearances alone.7274

ACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

The histopathologic changes in ACLE lesions are generally

less impressive than those in SCLE and DLE

lesions, and are mainly those of a cell-poor interface

dermatitis. The lymphohistiocytic cellular infiltrate is

relatively sparse. Some authors have noted an increase

in the number of neutrophils in the infiltrate. A mild

degree of focal vacuolar alteration of basal keratinocytes

can be seen, in addition to telangiectases and

extravasation of erythrocytes. One may see individually

necrotic keratinocytes, and in its most severe form,

ACLE can display extensive epidermal necrosis similar

to TEN. The upper dermis usually shows pronounced

mucinosis and may be very helpful in distinguishing

ACLE from other causes of a cell-poor interface dermatitis.

It is uncommon to see basement membrane zone

thickening, follicular plugging, or alteration of epidermal

thickness in ACLE, although epidermal atrophy is

sometimes present.73,74

SUBACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

SCLE also frequently presents as an interface dermatitis,

with foci of vacuolar alteration of basal keratinocytes

alternating with areas of lichenoid dermatitis.

Pronounced epidermal atrophy is often present. SCLE

is in the differential diagnosis of atrophic lichenoid dermatitis,

along with atrophic lichen planus and lichenoid

drug eruptions. Dermal changes include edema,

prominent mucin deposition, and sparse mononuclear

cell infiltration usually limited to areas around blood

vessels and periadnexal structures in the upper onethird

of the dermis. Lesser degrees of hyperkeratosis,

follicular plugging, mononuclear cell infiltration of

adnexal structures, and dermal melanophages might

help distinguish SCLE lesions from DLE lesions. It has

not been possible to differentiate papulosquamous

from annular SCLE by histopathologic criteria alone.72

CHRONIC CUTANEOUS LUPUS

ERYTHEMATOSUS

In classic DLE lesions, epidermal changes include

hyperkeratosis, variable atrophy, and interface changes

similar to those described for SCLE. The epidermal

basement membrane is markedly thickened. Dermal

changes include a dense mononuclear cell infiltrate

composed primarily of CD4 T lymphocytes and macrophages

predominantly in the periappendageal and

perivascular areas, melanophages, and dermal mucin

deposition. The infiltrate is often quite dense and typically

extends well into the deeper reticular dermis

and/or subcutis, which may help to distinguish it

from ACLE or SCLE. In chronic scarring DLE lesions,

the dense inflammatory cell infiltrate subsides and is

replaced by dermal fibroplasia. A folliculotropic variant

of DLE, in which the inflammatory infiltrate is predominantly

around hair follicles, has been described,

as have lymphomatoid variants, in which there are

extremely dense infiltrates that may contain atypical

lymphoid cells.73

IMMUNOHISTOLOGY

Immunohistology is often helpful in confirming a diagnosis

of LE-specific skin disease and has been shown

to boost the sensitivity and specificity of diagnosis.73

Because it is not uncommon to see negative immunofluorescence

studies in patients with acute, subacute,

and chronic LE, and false-positive studies in healthy

individuals, immunohistology must be interpreted in

the context of clinical and histologic findings in a given

patient.

IgG, IgA, IgM, and complement components (C3,

C4, Clq, properdin, factor B, and the membrane attack

complex C5b-C9) deposited in a continuous granular or

linear band-like array at the dermal-epidermal junction

have been observed in the lesional and nonlesional skin

of patients with LE since the early 1960s (Fig. 155-10).

However, debate about terminology in this area continues

to cloud the field. Some restrict the use of the term

lupus band test to refer to the examination of nonlesional

skin biopsies for the presence of this band-like array of

immunoreactants at the dermal-epidermal junction.

Others qualify the LBT as being either lesional or

nonlesional. Less confusion might exist if the terms

lesional LBT (lesional lupus band) and nonlesional LBT

(nonlesional lupus band) were uniformly adopted.

ACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

The sparse data that exist suggest that 60%100% of

ACLE lesions display a lesional lupus band. However,

the realization that sun-damaged skin from otherwise

healthy individuals can display similar immunopathology

has diluted the clinical value of this finding.

SUBACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

Initial studies indicated that approximately 60% of

patients with SCLE had lesional lupus bands. A dustlike

particle pattern of IgG deposition focused around

epidermal basal keratinocytes has been suggested to

be more specific for SCLE by reflecting the presence of

in vivo bound Ro/SS-A autoantibody.

CHRONIC CUTANEOUS LUPUS

ERYTHEMATOSUS

Early reports suggested that more than 90% of classic

DLE lesions had lesional immunoreactants at the

dermal-epidermal junction, often extending along the

basement membrane of the hair follicle, but subsequent

studies report somewhat lower rates. Lesions on

the head, neck, and arms are positive more frequently

(80%) than those on the trunk (20%). The lesional lupus

band also appears to be a function of the age of the

lesion being examined, with older lesions (3 months)

being positive more often than younger ones. Ultrastructural

localization of immunoglobulin at the dermalepidermal

junction confirms that these proteins are

deposited on the upper dermal collagen fibers and

along the lamina densa of the epidermal basement

membrane zone.

In LE profundus, immunoglobulin and complement

deposits are usually found in blood vessel walls of the

deep dermis and subcutis. Immunoglobulin deposits

at the dermal-epidermal junction may or may not be

present, depending on the site biopsied, the presence

or absence of accompanying SLE, and the presence or

absence of overlying changes of DLE at the dermalepidermal

junction.

NONLESIONAL LUPUS BAND TEST

There has been much debate over the past three decades

regarding the diagnostic and prognostic significance of

an immunoglobulin/complement band at the dermalepidermal

junction of nonlesional skin taken from

patients with LE.72 When totally sun-protected nonlesional

skin (e.g., buttocks) is sampled, the diagnostic

specificity for SLE appears to be very high when three

or more immunoreactants are present at the dermalepidermal

junction. Prospectively ascertained followup

data also suggest that the presence of a nonlesional

LBT correlates positively with risk for developing LE

nephritis. However, the nonlesional LBT has fallen out

of favor as a clinical tool largely because the information

gained has not been proven to be of significantly

greater value than the results of more readily available

serologic assays such as antibody to dsDNA.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of CLE is outlined in Box

155-1 and eBox 155-1.1 in online edition. In addition,

reticulated erythematosus mucinosis (REM) has been

suggested by some to be a form of photosensitive cutaneous

LE perhaps related to LE tumidus. REM presents

as a reticulated array of macules and/or papules on the

upper chest and back.

PROGNOSIS AND CLINICAL

COURSE

ACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

Both localized and generalized forms of ACLE lesions

flare and abate in parallel with underlying SLE disease

activity. Therefore, the prognosis for any given patient

with ACLE is dictated by the pattern of the underlying

SLE. Both 5-year (80%95%) and 10-year (70%90%) survival

rates for SLE have progressively improved over the

past four decades as a result of earlier diagnosis made possible

by more sensitive laboratory testing and improved

immunosuppressive treatment regimens. Ominous prognostic

signs in SLE are hypertension, nephritis, systemic

vasculitis, and central nervous system disease.

SUBACUTE CUTANEOUS LUPUS

ERYTHEMATOSUS

Because SCLE has been recognized as a separate

disease entity for only two decades, the long-term

outcome associated with SCLE lesions has yet to be

determined. It is the authors experience that most

patients with SCLE have intermittent recurrences

of skin disease activity over long periods of time

without significant progression of systemic involvement

(we are aware of only one death directly attributable

to SLE in approximately 150 patients with

SCLE). Other patients enjoy long-term if not permanent

remissions of their skin disease activity. A few

patients have experienced unremitting cutaneous

disease activity.

It has also been the authors experience that approximately

15% of the patients with SCLE develop active

SLE, including lupus nephritis. This subgroup of

patients is marked by the presence of papulosquamous

SCLE, localized ACLE, high-titer ANA, leukopenia,

and/or antibodies to dsDNA. Long-term follow-up

studies of SCLE are required to determine the true

risk of severe systemic disease progression in patients

presenting with SCLE skin lesions. CCLE lesions, typically

classic DLE, have also arisen in patients initially

presenting with SCLE.

Evidence suggests that overlap occurs between

SCLE and Sjgrens syndrome. Patients with SCLE

who develop Sjgrens syndrome are at risk for developing

the extraglandular systemic complications associated

with Sjgrens syndrome, including vasculitis,

peripheral neuropathy, autoimmune thyroiditis, renal

tubular acidosis, myositis, chronic hepatitis, primary

biliary cirrhosis, psychosis, lymphadenopathy, splenomegaly,

and B-cell lymphoma.

CHRONIC CUTANEOUS LUPUS

ERYTHEMATOSUS

Most patients with untreated classic DLE lesions suffer

indolent progression to large areas of cutaneous

dystrophy and scarring alopecia that can be psychosocially

devastating and occupationally disabling.

However, with treatment, skin disease can be largely

controlled. Spontaneous remission occurs occasionally,

and the disease activity can recrudesce at the sites of

older, inactive lesions. Rebound after discontinuation

of treatment is typical, and slower taper of medications

during periods of inactivity is recommended. Squamous

cell carcinoma occasionally develops in chronic

smoldering DLE lesions.

Death from SLE is distinctly uncommon in patients

who present initially with localized DLE. As discussed

in Section Epidemiology, patients presenting with

localized DLE have only a 5% chance of subsequently

developing clinically significant SLE disease activity.

Generalized DLE and persistent, low-grade laboratory

abnormalities appear to be risk factors for such disease

progression. Unrecognized squamous-cell carcinoma

developing within a longstanding DLE skin lesion

could be a cause of morbidity and mortality.

OUTCOMES MEASURES

The recent development of a validated instrument to

measure activity of CLE, the Cutaneous Lupus Erythematosus

Area and Severity Index (CLASI), has made it

possible to objectively follow patients disease course

and response to therapy. The instrument has separate

scores for damage (scarring) and activity which is

important, because one would not expect a burnedout

scarred area to normalize with drugs that were

meant to abate LE activity.76 It has been validated as a

useful tool to measure clinical response.77

TREATMENT

The initial management of patients with any form of

CLE should include an evaluation to rule out underlying

SLE disease activity at the time of diagnosis. All

patients with CLE should receive instruction about

protection from sunlight and artificial sources of UVR

and should be advised to avoid the use of potentially

photosensitizing drugs such as hydrochlorothiazide,

tetracycline, griseofulvin, and piroxicam. With regard

to specific medical therapy, local measures should be

maximized and systemic agents used if significant

local disease activity persists or systemic activity is

superimposed.

ACLE lesions usually respond to the systemic immunosuppressive

measures required to treat the underlying

SLE disease activity that so frequently accompanies

this form of CLE (e.g., systemic glucocorticoids, azathioprine,

and cyclophosphamide). Increasing evidence

suggests that aminoquinoline antimalarial agents such

as hydroxychloroquine can have a steroid-sparing

effect on SLE, and these drugs can be of value in ACLE.

The local measures discussed in Local Therapy below

can also be of value in treating ACLE. Because the

lesions of SCLE and CCLE are often found in patients

who have little or no evidence of underlying systemic

disease activity, unlike the lesions of ACLE, nonimmunosuppressive

treatment modalities are preferred for

SCLE and CCLE (Table 155-6). For the most part, SCLE

and CCLE lesions respond equally to such agents.

LOCAL THERAPY

SUN PROTECTION. Advise patients to avoid direct

sun exposure, wear tightly woven clothing and broadbrimmed

hats, and regularly use broad-spectrum,

water-resistant sunscreens [SPF 30 with an efficient

UVA blocking agent such as a photostabilized form

of avobenzone (Parsol 1789), micronized titanium

dioxide, micronized zinc oxide, or Mexoryl SX]. UVblocking

films should be applied to home and automobile

windows, and acrylic diffusion shields should

be placed over fluorescent lighting. Corrective camouflage

cosmetics such as Dermablend and Covermark

offer the dual benefit of being highly effective physical

sunscreens as well as aesthetically pleasing cosmetic

masking agents. An in-depth discussion of practical

and theoretical photoprotection and local therapy for

autoimmune connective tissue skin disease has been

discussed in detail (see Chapter 223).78

LOCAL GLUCOCORTICOIDS. Although some

prefer intermediate-strength preparations, such as triamcinolone

acetonide 0.1%, for sensitive areas such

as the face, superpotent topical class I agents, such as

clobetasol propionate 0.05% or betamethasone dipropionate

0.05%, produce the greatest benefit in CLE.

Twice-daily application of the superpotent preparations

to lesional skin for 2 weeks followed by a 2-week

rest period can minimize the risk of local complications

such as steroid atrophy and telangiectasia. Alternatively,

a topical calcineurin inhibitor can be used daily

during the 2-week rest period from topical corticosteroids.

Ointments are more effective than creams for

more hyperkeratotic lesions such as hypertrophic DLE.

Occlusive therapy with glucocorticoid-impregnated

tape (e.g., flurandrenolide) or glucocorticoids with

plastic food wrap (e.g., Saran or Glad Press-N-Seal)

can potentiate the beneficial effects of topical glucocorticoids

but also carries a higher risk of local side effects.

Class I or class II topical glucocorticoid solutions and

gels are best for treating the scalp. Unfortunately, even

the most aggressive regimen of topical glucocorticoids

by itself does not provide adequate improvement for

most patients with SCLE and CCLE.

TOPICAL CALCINEURIN INHIBITORS. Pimecrolimus

1% cream and tacrolimus 0.1% ointment have

demonstrated efficacy in the treatment of ACLE, DLE,

and SCLE.7981 A double blind, placebo controlled pilot

study showed that pimecrolimus 1% cream had equal

efficacy with betamethasone valerate 0.1% cream in

treating facial DLE,82 and a different study demonstrated

the efficacy of topical tacrolimus 0.3% compound in clobetasol

propionate 0.05% for recalcitrant CLE.83

INTRALESIONAL GLUCOCORTICOIDS. Intralesional

glucocorticoids (e.g., triamcinolone acetonide

suspension, 2.55.0 mg/mL for the face with higher

concentrations allowable in less sensitive sites) are

more useful in the management of DLE than SCLE.

Intralesional glucocorticoids themselves can produce

cutaneous and subcutaneous atrophy (deep injections

into the subcutaneous tissue enhances this risk).

A 30-gauge needle is preferred because it produces

only mild discomfort on penetration, especially when

injected perpendicularly to the skin. The active borders

of lesions should be thoroughly infiltrated. Intralesional

therapy is indicated for particularly hyperkeratotic

lesions or lesions that are unresponsive to topical

glucocorticoids, but most patients with CLE have too

many lesions to be managed exclusively by intralesional

glucocorticoid injections.

SYSTEMIC THERAPY

ANTIMALARIALS. One or a combination of the aminoquinoline

antimalarials can be effective for approximately

75% of patients with CLE who have failed to

benefit adequately from the local measures described

in Section Local Therapy.84 The risks of retinal toxicity

should be discussed with the patient, and a pretreatment

ophthalmologic examination should be performed.

However, the risk of antimalarial retinopathy is extremely

rare, particularly in the first 10 years of therapy, if recommended

daily dose maximum levels of these agents

are not exceeded (hydroxychloroquine, 6.5 mg/kg/day

based on ideal body weight; chloroquine, 3 mg/kg/day).

Patients should have follow-up ophthalmologic evaluations

every 612 months while on therapy.

Hydroxychloroquine sulfate (Plaquenil), 66.5 mg/

kg, should be given daily, either once daily or in two

divided doses to prevent GI side effects. Patients

should be informed about 23 month delayed onset

of therapeutic benefit. If no response is seen after 812

weeks, quinacrine hydrochloride, 100 mg/day (currently

available in the United States only through

compounding pharmacies), can be added to the

hydroxychloroquine without enhancing the risk of retinopathy

(quinacrine does not cause retinopathy). If,

after 46 weeks, adequate clinical control has not been

achieved, consideration should be given to replacing

the hydroxychloroquine with chloroquine diphosphate

(Aralen), 3 mg/kg to prevent retinopathy. Doses may

need to be adjusted for patients with decreased renal

or hepatic function. In Europe, chloroquine is generally

felt to be more efficacious than hydroxychloroquine intreating CLE, perhaps due to the earlier therapeutic

time period required to reach steady state blood levels

with chloroquine as compared to hydroxychloroquine.

Hydroxychloroquine and chloroquine should not be

used simultaneously because of enhanced risk for retinal

toxicity. There is some evidence that chloroquine

may be more retinotoxic than hydroxychloroquine.

Multiple side effects other than retinal toxicity are

associated with the use of antimalarials. Quinacrine is

associated with a higher incidence of side effects, such

as headache, gastrointestinal intolerance, hematologic

toxicity, pruritus, lichenoid drug eruptions, and mucosal

or cutaneous pigmentary deposition, than is either

hydroxychloroquine or chloroquine. Quinacrine commonly

produces a yellow discoloration of the entire

skin and sclera in fair-skinned individuals, which is

completely reversible when the drug is discontinued.

Quinacrine can produce significant hemolysis

in patients with glucose-6-phosphate dehydrogenase

deficiency (this adverse effect has also been reported

to occur rarely with hydroxychloroquine and chloroquine).

Each of the aminoquinoline antimalarials can

produce bone marrow suppression, including aplastic

anemia, although this effect is exceedingly rare with

the current dosage regimens. Toxic psychosis, grand

mal seizures, neuromyopathy, and cardiac arrhythmias

occurred with the use of high doses of these drugs in

the past; these reactions are uncommon with the lower

daily dose regimens used today.

Before therapy with hydroxychloroquine and chloroquine

is begun, complete blood cell counts, as well

as liver and renal function tests, should be performed;

these tests should be repeated 46 weeks after therapy

has been initiated, and every 46 months thereafter. A

screen for hematologic toxicity when quinacrine is used

is recommended more often. Patients with overt or subclinical

porphyria cutanea tarda are at particularly high

risk for developing acute hepatotoxicity, which often

simulates an acute surgical abdomen, when treated

with therapeutic doses of antimalarials for CLE. It is

also recommended to check urine levels of -human

chorionic gonadotropin initially in women with childbearing

potential, although recent evidence indicates

that the risk to pregnant women of currently recommended

dose regimens of antimalarials is minimal.

NONIMMUNOSUPPRESSIVE OPTIONS FOR

ANTIMALARIAL-REFRACTORY DISEASE.

Some patients with refractory CLE (SCLE more than

DLE) respond to diaminodiphenylsulfone (dapsone).85

An initial dose of 25 mg by mouth twice daily can be

increased up to 200400 mg/day, if necessary. Significant

dose-related hemolysis and/or methemoglobinemia

can result from the use of dapsone, especially in

individuals deficient in glucose-6-phosphate dehydrogenase

activity, and, therefore, complete blood counts

and liver function tests should be performed regularly.

Isotretinoin, 0.52.0 mg/kg/day, and acitretin, 1050

mg/day, have also been used in this setting, but their

efficacy is limited by their side effects (teratogenicity,

mucocutaneous dryness, and hyperlipidemia).

In addition, breakthrough of CLE activity has been a

problem with the long-term use of retinoids.

Thalidomide (see Chapter 235) (50200 mg/day) is

strikingly effective for CLE that is refractory to other

medications. Numerous studies have cited response

rates between 85% and 100%, with many patients experiencing

complete remission.86 However, strict prescribing

regulations put in place in the United States

in 1998 because of severe teratogenicity, make thalidomide

challenging to dispense to women of childbearing

potential. Sensory neuropathy is another toxicity

associated with thalidomide, and 25%75% of patients

with CLE develop peripheral neuropathy while taking

the drug. Most cases are reversible when therapy

is stopped. Neuropathy seems to correlate with total

treatment times so that short courses are preferred.

Relapses after the drug is stopped are common. Excess

somnolence as well as constipation and other minor

side effects sometimes limit its use, although these

effects usually abate with lower daily doses.87 Thromboembolism

is a serious adverse event that may occur

in patients with a preexisting hypercoagulable state

(e.g., presence of antiphospholipid antibodies). Oncologists

who use thalidomide for multiple myeloma frequently

initiate concomitant anticoagulation therapy

to prevent this side effect. Lenalidomide (Revlamid,

Celgene) is a thalidomide analog that is more efficacious

but has similar rates of teratogenicity, peripheral

neuropathy, thromboembolism, and also has the additional

potential side effect of profound leukopenia.88

Other drugs reported to be of value in the treatment

of refractory CLE are gold and clofazimine; however,

the benefit varies from case to case and both of these

agents are associated with the risk of significant side

effects. Vitamin E, phenytoin, sulfasalazine, danazol,

DHEA, and phototherapy (UVAI phototherapy, photopheresis)

have also been reported in uncontrolled trials

to be of value in CLE.

SYSTEMIC GLUCOCORTICOIDS. Every effort

should be made to avoid the use of systemic glucocorticoids

in patients with LE limited to the skin. However,

in occasional patients who have especially severe and

symptomatic skin disease, intravenous pulse methylprednisolone

has been used. In less acute cases, moderate

daily doses of oral glucocorticoids (prednisone,

2040 mg/day, given as a single morning dose) can be

used as supplemental therapy during the loading phase

of therapy with an antimalarial agent. The dose should

be reduced at the earliest possible time because of the

complications of long-term glucocorticoid therapy,

especially avascular (aseptic) bone necrosis, a side effect

to which patients with LE are particularly susceptible.

Because steroid-induced bone loss occurs most rapidly

in the first 6 months of use, all patients who do not

have contraindications should begin agents to prevent

osteoporosis with the initiation of steroid therapy. An

excellent review describing current recommendations

for prevention of bone loss and other side effects of systemic

glucocorticoids has been published.89 When the

disease activity is controlled, the daily dosage should

be reduced by 5- to 10-mg decrements until activity

flares again or until a daily dosage of 20 mg/day is

achieved. The daily dose should then be lowered by

2.5-mg decrements (some physicians prefer to use 1-mg

dose decrements below 10 mg/day). Alternate-day

glucocorticoid therapy has not been successful in suppressing

disease activity in most patients with CLE or

SLE. Prednisolone rather than prednisone should be

used in patients who have significant underlying liver

disease, because prednisone requires hydroxylation in

the liver to become biologically active. Any amount of

prednisone given as a single oral dose in the morning

has less adrenal-suppressing activity than the same

amount given in divided doses throughout the day.

However, any given amount of this drug, taken in

divided doses, has a greater LE-suppressing activity

than does the same amount of drug given as a single

morning dose.

PREVENTION

Predicting and preventing the initial clinical manifestation

of LE, whether it is skin disease or systemic, is

not feasible at this time. However, as many LE patients

exhibit worsening of their skin disease activity with

UV light exposure, physical protection from sunlight

and artificial sources of UV light as well as the regular

use of broad-spectrum sunscreens having a SPF of 30

or greater should be encouraged.