A�

rchivum Immunologiae et Therapiae Experimentalis, 2002, 5�

0,� 411–420P�

L ISSN 0004-069X

Review

Experimental Therapies for PsoriasisK. Asadullah et al.: Psoriasis Treatment

KHUSRU AS�

ADULLAH1* , HA�

NS-DI�ETER VO

�LK2, MARKUS FRIEDRICH3 and WOLFRAM STERRY3

1 Corporate Research Business Area Dermatology, Schering AG, D-13342 Berlin, Germany, 2 Department of Immunology, 3�

Departmento� f Dermatology and Allergology, University Hospital Charité, Berlin Humboldt University, D-10098 Berlin, Germany

Abstract. There is a high medical need for better therapies for psoriasis. Based on new insight into the patho-p hysiology of this frequent immune disease, a number of novel systemic immunomodulatory therapies are cur-rently in clinical development. These include approaches targeting antigen presentation a nd costimulation, T cella ctivation and leukocyte adhesion, action of proinflammatory mediators, and modulating� the cytokine balance.Although mainly only preliminary data are available so far, these trials contribute to a further understanding oft

�he disease and will eventually lead to new therapeutic options for psoriasis. Moreover, since psoriasis can be

c� onsidered as a visible model disease for T cell-mediated disorders characterized by a type 1 cytokine pattern ing� eneral, such approaches may have impact for other immune disorders as well. Here we review the rationale andt

�he initial clinical data of these important recent experimental therapies.

Key words: psoriasis; immunotherapy; cytokines; costimulation; biologicals.

I�ntroduction

Tremendous progress in the understanding of thep athophysiology of psoriasis has been achieved duringt

�he last few decades. Psoriasis is now known to bea T cell-mediated (auto)immune disease in which cy-t

�okines play an essential part7

�, 9. Arguments for con-

sidering psoriasis as a T cell-mediated dermatosis in-c� lude:• the presence of activated T cells in the skin lesions,• cure of the disease by bone marrow transplantationfrom healthy persons and transfer of the disease byt

�ransplantation of bone marrow from psoriatic patients,

• the demonstration of the impact of immunocytes bySCID mice experiments,• the therapeutic effects of immunosuppressants target-ing T lymphocytes (e.g. cyclosporin A, anti-T cell anti-b

�odies).

T�

his new pathophysiological understanding offersfor the first time a chance of developing new and bet-t

�er-aimed therapeutic strategies7

�.

R�

emarkably, there are certain common features be-t

�ween psoriasis and immunological diseases that mani-

fest themselves in other organ systems, such as rheu-m� atoid arthritis, multiple sclerosis, Crohn’s disease,u� lcerous colitis and rejection of organ transplants. Newimmunomodulatory forms of therapy could thereforep rove useful for various diseases in this group. The skina s an “outwardly visible immune organ” and psoriasisa s an “outwardly visible immunological disease witha type 1 cytokine pattern” could thus serve as a modelo� rgan and model disease for the development of newt

�herapeutic strategies. The validation of a therapeutic

a pproach, i.e. the “proof of concept” in phase 2 clinicalstudies, is substantially easier in psoriasis than, fore xample, in transplantation medicine. Thus, the recent

* Correspondence to: Dr. Khusru Asadullah, M.D., Corporate Research Business Area Dermatol�ogy, Schering AG, D-13342 Berlin,

G�

ermany, e-mail: khusru.asadullah@schering.de

c� linical trials in psoriasis may finally lead to novelt

�herapeutic options for several entities, underlyinga general impact of the early experimental therapiesc� urrently being investigated. The understanding of pso-riasis as a model disease has practical implications fort

�he development of new drugs for other indications as

w� ell. Whereas in the past new treatments were adaptedfor use in skin diseases after they had been used e.g. int

�ransplantation medicine, movement in the opposite di-

r� ection is now beginning to take place. Experimentald

�ermatology could thus become the vanguard of medi-

c� al progress7�.

P�

ractically all existing well-established methods fort

�he treatment of psoriasis have been developed empiri-

c� ally and all existing treatment methods have distinctl

�imitations. To this day there are no truly curative meth-

o� ds (and there are as yet none on the horizon). Thea vailable therapeutic approaches are ineffective ina significant proportion of the patients, or do not leadt

�o complete regression, or do not prolong the remission

i�ntervals. They are often troublesome to the patients

a nd/or require frequent visits to the doctor’s office or

e ven hospitalization. Bearing in mind the high pre-v� alence of psoriasis (approximately 2% of the popula-t

�ion), the economic burden on society is considerable.

T�

he annual resulting costs in the US alone are estimateda t some 3.2 billion dollars2

4. The psycho-social stress

o� n psoriasis sufferers due to their visible lesions is high.Surveys have revealed that patients would in principlep refer effective oral forms of treatment. However, thec� urrently available systemic treatments have a consid-e rable side-effect potential. Methotrexate, for instance,c� an cause hepatotoxicity, cyclosporin nephrotoxicity,a nd retinoids disturbances in fat metabolism. Therefore,t

�hey are generally used only in severe forms of pso-

riasis. All in all, there is a high medical need for bettert

�herapies, in particular therapies with an improved

safety profile (fewer side effects, suitability for long--t

�erm treatment).

The novel experimental treatments essentially aimt

�o regulate T cell activation, in some cases indirectlyb

�y acting on antigen-presenting cells (APC) and/or by

i�nhibiting the action of proinflammatory mediators pro-

d�uced by activated immune cells, including T cells

Fig. 1. Principal targets of new immunomodulatory antipsoriatics. Several cell populations, such as antigen-presenting cells (APC), T cellsa! nd endothelial cells, as well as their interactions, are promising targets for therapeutic intervention. The interaction between APC andT cells can be achieved by a blockade of antigen presentation and/or of costimulation (1). Specific action sites are indicated in Fig. 2, withe" xamples in Table 1. After adhesion to endothelial cells, activated T cells migrate into skin, the target organ. Inhibition of this adhesionis thus another attractive option (2). Activated immune cells (including APC, T cells, and endothelial cells) produce excessive quantitieso� f proinflammatory mediators and type 1 cytokines (red), such as TNF-α# , IL-2, IFN-γ$ , and IL-12, which, on their part, trigger theinflammatory reaction further and are therefore also of pathophysiological significance. In contrast to this, the antiinflammatory and type 2c% ytokines are formed in insufficient amounts (yellow). The ratio of proinflammatory to antiinflammatory and of type 1 to type 2 cytokinesd&etermines the presence or absence of psoriatic inflammation. Neutralization or antagonization of the proinflammatory and type 1 cytokines

('3( and 4)

) or replacement of antiinflammatory and type 2 cytokines (5

� and 6)

) thus represent further new therapeutic possibilities (AS

*ADULLAH

e" t al.7+))

412 K. Asadullah et al.: Psoriasis Treatment

(Fig. 1). An overview of current clinical developmentp rojects is shown in Table 1.

Experimental Therapies

I,nhibitors of costimulation

The processes of primary stimulation by T cell re-c� eptors alone are not sufficient for effective T cell ac-t

�ivation. Adequate costimulation is required in addition.

V-

arious experimental therapies involving a targetedb

�lockade of costimulation should therefore be effective.

Thus (Fig. 2),• LFA-3TIP (Amevive, Alefacept) blocks the interac-t

�ion between LFA-3 and CD2,

• a CTLA-4 fusion protein (CTLA-4 Ig BMS 188667)b

�locks the interaction of CD80 and CD86 with CD28,

• an anti-CD80 antibody (IDEC-114) blocks the inter-a ction of CD80 with CD28,• an anti-CD11a antibody (hu-1124) blocks the inter-a ction of LFA-1 with ICAM.

The action of the anti-CD11a antibody seems toc� omprise not only an inhibition of the T cell/APC in-t

�eraction, but also decisive inhibition of cutaneous in-

filtration.B

.oth tolerability and antipsoriatic effects have been

d�emonstrated in early clinical studies with these “biol-

o� gicals” . Thus, in therapy with LFA-3TIP more thanhalf of the 24 patients showed a better than 50% im-p rovement after 8 weeks of treatment. Intravenous ad-ministration of CTLA-4 Ig in an open phase 1/2 studyl

�ed to a dose-dependent improvement, in 46% of the

Table 1. New immunomodulatory therapies for the treatment ofp/ soriasis

Action on the function of antigen-presenting cells CTLA-4 (BMS 188667) LFA-3TIP (Amevive/Alefacept) anti-CD80 antibodies (IDEC-114) calcitriols (Rocaltrol) fumaric acid esters (Fumaderm)T cell inhibitors macrolides (FK506, tacrolimus, Prograf, SDZASM981, pimecrolimus, sirolimus, Rapamycin) anti-CD2 (MEDI507, siplizumab) anti-CD3 antibodies (OKT3, HuM291) anti-CD4 antibodies (BB14) mycophenolate mofetil (CellCept) IL-2-coupled diphtheria toxin (DAB398IL-2) anti-CD25 antibodies (basiliximab, daclizumab)Inhibitors of adhesion anti-CD11a antibodies (hu-1124, efalizumab) anti-CD6 antibodies (ior-t1) anti-selectin-antibodies, selectin-inhibitorsInhibitors of proinflammatory cytokine/mediator action anti-IL-8 antibodies (ABX-IL8) anti-TNF-α# antibodies (infliximab, Remicade) soluble TNF-α# receptors (Etanercept, Enbrel) LTB4-receptor antagonist (VML 295) anti-IFN-γ$ antibodiesAdministration of antiinflammatory cytokines IL-4 IL-10 IL-11

The listed therapies are in clinical development (phase 1–3).The classification is schematic, each therapy being mentioned onlyo� nce, in the group where it fits best, but it must be noted that someo� f the strategies could be put in more that one group. For example,a! n administered cytokine (e.g. IL-10) could act as a T cell inhibitora! nd inhibit costimulation by antigen-presenting cells (modified tablef0rom AS

*ADULLAH et al.7

+)).

F1

ig. 2. Action sites for inhibition of APC/T cell interaction. APC/T cell communication seems to be" an early, crucial step in thep/ athogenesis of psoriasis. Thus, inhibition of their interaction is one of the most attractive targets for the development of new antipsoriatics.T cell activation occurs via the T cell receptor/CD3 complex after contact with a specific antigen, which is presented embedded in theMHC complex of APC. MHC-I molecules also interact with CD8, while MHC-II molecules interact with CD4, defining the correspondingT2

cell subpopulations (signal 1). For effective T cell activation, these processes alone are insufficient and require adequate costimulation('signal 2). The action site of various experimental therapies for blocking this costimulation is shown7

+: 1 – LFA-3TIP, 2 – anti-CD80 and

a! nti-CD86, 3 – CTLA-4 Ig, 4 – anti-CD11a

K. Asadullah et al.: Psoriasis Treatment 413

p atients by over 50%. In 9 of the 10 patients in thehighest-dose group, an at least 50% improvement waso� bserved1, 2. Promising results from a phase 2 trial witha n anti-CD80 monoclonal antibody were recently re-p orted (GOTTLIEB et al. poster at the congress of theAmerican Academy of Dermatology, 2001). Thirty-fivep atients received 4 intravenous infusions over a 3 to6

3 week period, ranging from 2.5–15 mg/kg. Therapy

w� as well tolerated and showed a considerable improve-m� ent of the skin lesions. A reduction of over 50% int

�he psoriasis area and severity index (PASI) was

a chieved in 40% of the patients.Summarizing, the approaches are essentially char-

a cterized by good tolerability and a certain efficacy.N

4evertheless, clearance is still quite rare, not all pa-

t�ients benefit from the therapy, and the desired effects

g� enerally appear only after several weeks.

Calcitriols

T�

hese vitamin D derivatives seem to exert their sys-t

�emic antipsoriatic action mainly by suppressing the

function of APCs. Thus, they reduce the expression ofMHC-II and costimulating molecules and the TNF-αsecretion capacity of the monocytes. In contrast to thee ffects after topical application of calcitriols, therefore,t

�he action mechanism is not a direct inhibition of thekeratinocyte proliferation. With the calcitriols availablea t the present time, oral administration is theoreticallyp ossible, but the therapy is problematic because it isstill associated with risks of provoking hypercalcemias.N

4evertheless, it has been demonstrated that this therapy

i�s effective. Thus, in 85 patients calcitriol (Rocaltrol)

led to a decrease in PASI from 18.4 to 9.7 after6

3 months and to 7.0 after 36 months. Improvement has

a lso been achieved in psoriatic arthritis. The calcitriold

�ose must be raised gradually, the patient’s calcium

intake must be limited by appropriate diet, and the cal-c� ium levels in serum and urine must be monitored toa void hypercalcemia and hypercalciuria19, 35. The devel-o� pment of immunosuppressive calcitriols that do notp rovoke hypercalcemia could open new possibilities int

�his form of therapy. Indeed we recently discovered

such vitamin D receptor binding molecules which dis-p lay such a dissociation46.

Fumaric acid esters

Since the biochemist SCHWECKENDIEK reported thesuccessful treatment of his psoriasis with fumaric acide sters (FAEs) in 1959, this therapy and its side effectshave been discussed. During recent years the im-

p ressive antipsoriatic effectiveness of systemic treat-ment with a mixture of the FAEs (Fumaderm) has beenp roven in several multicenter trials. Today, FAEs areo� nly approved in Germany, where they are frequentlyp rescribed. In a recent multicenter trial with 101 pa-t

�ients, 69% reported adverse effects, mainly consisting

o� f gastrointestinal complaints and flushing in the firstw� eeks of FAEs treatment29. However, they are usuallymild and non-persisting.

T�

he limited information available on the pharmaco-d

�ynamics, pharmacokinetics, and safety profile and

mode of action of these compounds has recently beenr� eviewed3

�0. Methylhydrogenfumarate (MHF), which is

formed by hydrolysis of dimethylfumarate, is believedt

�o be the most potent metabolite of this drug, which is

a ntiproliferative to keratinocytes. An effect on cytokineformation in peripheral blood lymphocytes and mono-c� ytes was demonstrated. An increase in IL-4 and IL-5,b

�ut not in IFN-γ5 and IL-2, production by stimulated

mononuclear cells and T cells by MHF was reported.T

�his augmentation of T helper 2 (Th2) cytokine re-

sponse may provide a mechanistic explanation of thee ffects of MHF. Moreover, MHF enhances the secre-t

�ion of proinflammatory (TNF-α)

6 and antiinflammatory

(IL-10, IL-1RA) cytokines in monocytes. Whereas thelong-lasting induction of IL-10 may contribute to thea ntipsoriatic effects, the MHF-induced early TNF-αformation may be responsible for several side effectso� f FAEs. Very recently it was reported that Dimethyl-fumarate is an inhibitor of cytokine-induced nucleart

�ranslocation of NF-κB

.1, giving a first insight into the

molecular effects of FAEs44.A

7ltogether, although FAEs have been used for de-

c� ades and show promising efficacy, further clinical ande xperimental investigations are necessary. The com-p lete clinical development of mono compounds seemse ssential before a global launch of such drugs could bee xpected.

I,mmunosuppressive macrolides

C8

yclosporin has been well established for the sys-t

�emic treatment of psoriasis for years. Recently, novel

macrolides have been developed for topical use10, 31, butt

�hey could become significant in systemic therapy, too.

In one double-blind study it was found that FK506 (ta-c� rolimus, Prograf) used in a dose of 0.05–0.15mg/kg/day in psoriasis patients led to an 83% improve-m� ent after 9 weeks4

90. The results of a placebo-controlle d

d�ouble-blind study were recently reported in which an

a scomycin derivative (pimecrolimus) was given orallyin doses of 5–60 mg/day. Tolerability was very good

414 K. Asadullah et al.: Psoriasis Treatment

a nd higher doses gave good clinical efficacy, with a 60t

�o 75% reduction in the PASI score after 4 weeks3

�6.

Little information is available on the use of sirolimus(Rapamycin), but the occurrence of severe side effects(capillary leak syndrome) has been reported2

0. Further

studies must be carried out to see whether the long-termsafety profile of these substances is superior to that ofc� yclosporin. In particular, altered lipidemia and throm-b

�ocytopenia must be carefully monitored.

Anti-T cell antibodies/fusion proteins

I:n view of the key role played by T cells in pso-

riasis, it is easy to see that their depletion could alsoh

;ave a therapeutic effect. Antibody therapies of this

k<ind have been tried since the early nineties. Monoclo-

nal anti-CD2 (MEDI507, Siplizumab) and anti-CD3a ntibodies (e.g. OKT3, HuM291), directed against allT

� cells, and anti-CD4 antibodies, directed predominant-

ly against T helper cells, were tested. The treatmentsa re reported to have produced impressive improve-m� ents rapidly. Maximum effects were observed 2–4w� eeks after the beginning of the infusions, which hadb

�een given over 5–8 days15, 28, 39, 41, 45. Whereas the first

a ntibodies used were of murine origin, newer ap-p roaches are using humanized antibodies in order toa chieve better tolerability and to avoid the formation ofneutralizing antibodies.

Targeting T cells is also attempted by usingDAB398IL-2, an IL-2-coupled diphtheria toxin. SinceI

:L-2 is an important growth factor for T cells, such

c� oupling with the toxin should result in an inhibition oft

�he lymphocytes. Systemic therapy with this agent in

fact proved to be very effective in around 40% of pa-t

�ients with severe psoriasis16. There were also appreci-

a ble side effects, which greatly restricts the use of thism� ethod8.

In principle, non-selective depletion of T cells or Thc� ells represents a very serious intervention in the im-mune system, with a considerable potential for the ap-p earance of side effects. The use of monoclonal anti--CD25 antibodies (basiliximab, daclizumab) could bea dvantageous in this context, since here only the actiono� f IL-2, important for lymphocytes, is inhibited bya blockade of binding to its receptors. Initial results doin fact indicate that the tolerability is good. In an openp hase 2 study, 19 patients were given daclizumab infu-sions, initially 2 mg/kg and then 1 mg/kg every2

= weeks. However, the antipsoriatic action was at best

moderate: only in a subgroup with low psoriasis activ-i

�ty prior to the therapy was there an approximately 30%

reduction after 8 weeks2 3. Case reports suggest that ba-

siliximab might be more effective and could lead too� utstanding action in combination with cyclosporin3

�2, 34.

M>

ycophenolate mofetil

Mycophenolate mofetil (MMF) (CellCept), a low--m� olecular, relatively lymphocyte-specific immunosup-p ressant, is used successfully in transplantation me-d

�icine. It exerts a non-competitive and reversible

b�lockade of the neosynthesis of guanine nucleotides,

w� hich are essential for RNA and DNA synthesis inlymphocyte proliferation. Antipsoriatic effects of oralt

�herapy with this substance have been described18. In

o� ne study, 5 patients with treatment-resistant psoriasisv� ulgaris and 6 patients with psoriatic arthritis receivedM

?MF monotherapy for a period of 10 weeks in a dose

o� f 2 g/day. The treatment was well tolerated. A moder-a te improvement in the findings was observed, but onlyi

�n the patients with moderate psoriasis and with psori-

a tic arthritis17. Recently, more promising data were re-p orted13, describing a mean decrease of the PASI from30.5 to 16.1 after 6 weeks of treatment in 11 patientsw� ith severe plaque psoriasis.

I,nhibitors of leukocyte adhesion

T�

he migration of activated immune cells into theskin constitutes another important point for pharmaco-logical intervention; inhibition of the adhesion of im-mune cells to the endothelium seems to be particularlyp romising. In an open study of 31 patients, a hu-manized monoclonal anti-CD11a antibody (hu-1124,e falizumab) was infused once at concentrations of 0.03t

�o 10 mg/kg. This antibody inhibits the interaction of

C8

D11a (LFA-1) with various ICAM molecules. ICAM-1(CD54) is expressed on activated endothelial cells. Thea ntibody therefore inhibits both the APC/T cell interac-t

�ion (Fig. 2) and the adhesion to endothelial cells and,

h;ence, transendothelial migration22. At doses above

1 mg/kg, a statistically significant, but only moderate,d

�ecrease in the PAS1 score was observed after 2–3

w� eeks14. A monoclonal anti-CD6 antibody (ior-t1) isa lso suggested to exert antipsoriatic effects by inhibit-ing lymphocyte migration into skin, but so far there hasb

�een only one preliminary report27.

Anti-IL-8 antibodies

I:L-8, a proinflammatory cytokine overexpressed in

p soriasis, has potential pathophysiological significance,since it is mitogenic for keratinocytes, chemoattractivefor granulocytes and T lymphocytes, and acts as an

K. Asadullah et al.: Psoriasis Treatment 415

a ngiogenesis-stimulating factor. In a phase 1–2 studyo� f 43 patients, 4 infusions of a humanized anti-IL-8a ntibody (ABX-IL8) were given, at intervals of 2–3w� eeks, at various doses (0–3.0 mg/kg). The therapy wasw� ell tolerated, but the results were rather poor. A re-d

�uction in the PASI was observed only with the higher

d�oses, and even then only by on average of around 20%

(ABDULGHANI et al., presentation at the congress ofAmerican Academy of Dermatology, 2001). These re-sults suggest that IL-8 plays no key role in the patho-p hysiology of psoriasis or that neutralizing its effectsin the skin by systemic antibody therapy is difficult.

Anti-TNF-α strategies

L@

esional and systemic elevated levels of the proin-flammatory cytokine TNF-α have been found in pso-riasis. Its proximal position in the effector cytokine cas-c� ade has made TNF-α an interesting candidate forinhibition of inflammatory reactions. Essentially, twod

�ifferent strategies are followed for inhibition of its

a ction through a blockade of receptor binding: neutral-ization by monoclonal anti-TNF-α antibodies and so-luble TNF-α receptors. They have already provedt

�hemselves successful in the treatment of rheumatoid

a rthritis and Crohn’s disease.T

�he humanized monoclonal anti-TNF-α antibody

(infliximab, Remicade) w� as initially used in a psoriaticp atient who was also suffering from an inflammatoryintestinal disease. A dramatic improvement in the skinl

�esions was observed as soon as 2 weeks after a singleinfusion3

�3. Good activity has also been reported in com-

b�ination with methotrexate21. Very recently, the effi-

c� acy and safety of infliximab monotherapy was dem-o� nstrated in a controlled randomized trial. Elevenp atients with moderate to severe plaque psoriasis eachr� eceived placebo or the antibody at 2 dosages (5 mg/kgo� r 10 mg/kg) intravenously at weeks 0, 2, and 6.E

Aighty-two percent in the infliximab 5 mg/kg group

a nd 73% of the 10 mg/kg group had at least 75% im-p rovement in the PASI (18% of patients in the placebog� roup). The mean PASI decreased from 22.1 to 3.8 (5m� g/kg) and 26.6 to 5.9 (10 mg/kg) by week 10. Themean time to response was 4 weeks11.

Similarly promising data were reported on the so-luble TNF-α receptor Etanercept (Enbrel) in the treat-ment of psoriatic arthritis. Sixty patients were includedin a placebo-controlled study. The treatment (25 mg bysubcutaneous injection twice weekly for 12 weeks) wasw� ell tolerated. A distinct improvement of the joint in-v� olvement was observed in 73% of the patients treated,c� ompared with 13% of the patients in the placebo

g� roup. In addition to this, the PASI fell by over 75 in25% of the actively treated patients. In all, a 46% re-d

�uction in PASI was achieved25.

T�

hese results indicate that inhibition of TNF-α couldb

�ecome a highly promising option in the treatment of pso-

riasis and psoriatic arthritis. However, severe infections insome of the patients treated with Etanercept underline theneed for careful control until further experience with thist

�reatment has been accumulated.

Anti-IFN-γ5

Since this proinflammatory type 1 cytokine is over-e xpressed in psoriasis and considered to be mainlyr� esponsible for the Th 1 immune deviation, its neutra-l

�izing represents another therapeutic approach. A hu-manized monoclonal antibody has recently been gener-a ted and is currently used in a phase 1–2 trial. Clinicald

�ata should become available soon.

LTB4-receptor antagonists

C8

utaneous infiltration of leukocytes, due to the pro-d

�uction of chemoattractants, is a typical phenomenon

i�n psoriasis. One of the most potent chemoattractive

p roteins is leukotriene B4 (LTB4), a proinflammatorym� ediator formed from arachidonic acid by a 5-lipox-yB genase-dependent metabolism. Elevated levels ofLTB4 have been reported in psoriasis.

Inhibition of LTB4 activity was investigated asa therapeutic strategy, but treatment with pharmaco-logically active doses of an oral LTB4-receptor anta-g� onist (VML 295) did not have any relevant antipsori-a tic effect4

93. In a further study it was recently

d�emonstrated that LTB4-antagonist therapy also does

not prevent a relapse of previously cleared psoriasis26.I

:t may be concluded that LTB4 does not have any cen-

t�ral pathophysiological significance in psoriasis.

I,L-4 administration

IL-4 is a type 2 cytokine of decisive significance inr� egulating Th1/Th2 cytokine balance. In animal studiesit has been found that deviation of an existing type1 cytokine pattern into an IL-4-dominated type 2 pat-t

�ern can suppress inflammatory T cell-mediated auto-immune processes. Since IL-4 itself is a highly potentfactor for the induction of IL-4 in T cells, it was recent-l

�y tried in the therapy of psoriasis. In an open study, 22

p atients received injections of IL-4 in various doseso� ver 6 weeks. Side effects appeared only after the hig-hest dosage. Twenty patients completed the study. In

416 K. Asadullah et al.: Psoriasis Treatment

18 of them the PASI fell by 60–80% within the 6-weekp eriod. Particularly impressive effects were achievedw� ith higher doses42. These results indicate that IL-4m� ight have considerable clinical potential.

IL-10 administration

IL-10 possesses antiinflammatory properties and isa suppressor of cellular immunity. Its action on APCsa ppears to be of particular importance. Here, IL-10 in-hibits antigen presentation, the production of inflamma-t

�ory mediators (e.g. TNF-α)

6, and stimulates the produc-

t�ion of antiinflammatory mediators. IL-10 is also of

major significance for APC-controlled regulation of theT

�h1/Th2 balance, promoting a type 2 response5

C. Cuta-

nD eous IL-10 mRNA expression is significantly lower inp soriasis than in other T cell-mediated dermatoses, des-p ite the overexpression of proinflammatory cytokines,i

�ndicating a relative IL-10 deficiency6

E.

After a pilot study with IL-10 (8 µg� /kg/day for 24d

�ays in 3 patients) had shown that the treatment is well

t�olerated and an improvement had occurred6

E, two phase 2

studies were performed, each with 10 patients3�, 37. Good

c� linical efficacy (PASI reduction by 50–60%) wasa chieved after a 6–7-week subcutaneous therapy with4 or 8 µg� /kg/day or 20 µg� /kg 3 times a week. Figure 3shows a clinical example. The clinical improvementw� as accompanied by general normalization of the his-t

�ological and immunohistological findings typical of

p soriasis. Interestingly, IL-10 therapy led to a decreasei

�n cutaneous IL-8 and an increase in IL-4 expression,

b�oth of which might contribute to the antipsoriatic ef-

fect4, 38. Recently we analyzed the long term effects ofIL-10 in a placebo-controlled, double-blind, phase 2t

�rial in patients with chronic plaque psoriasis in re-

mission. Patients received subcutaneous injections withe ither IL-10 (10 µg� /kg body weight; n=7) or placebo(n=10) 3 times per week until relapse or study termi-nation after 4 month. The treatment was well tolerated.In the placebo group almost all patients (90%) showeda relapse during the observation period. In contrast tot

�his, only 2 out of 7 patients (28.6%) relapsed in the

IL-10-treated group. Kaplan-Meier analysis revealeda significantly lower relapse incidence in the IL-10 thanin the placebo group. The mean relapse-free time inter-v� al was 101.6±

F12.6 days in the IL-10 group in com-

p arison with 66.4±F

10.4 days in the placebo group. Theimmunological activity of IL-10 application was indi-c� ated by an increase in soluble IL-2 receptor plasmal

�evels and higher eG x vivo IL-4 secretion capacities. Re-

markably, a significant negative correlation was dem-o� nstrated between the IL-4 secretion capacity and PASIscore12. Overall these data suggest that IL-10 therapy isimmunologically effective in both improving psoriaticd

�isease activity and decreasing the incidence of relapse

a nd prolonging the disease-free interval in psoriasis. Itsv� alue should be further determined in larger trials.

I,L-11 administration

IL-11 is a multifunctional cytokine which exertsa range of effects on hematopoietic and nonhemato-

F1

ig. 3. Example of the clinical effects of IL-10. The situation before (A), during (B) [day15], and the end of IL-10 therapy (C)) [day 50]

a! re shown. The patient received IL-10, 20 µH gI /kg of body weight, 3 times per week. (AS*

ADULLAH et al.3J,� reproduction with permission of

tKhe American Medical Association)

K. Asadullah et al.: Psoriasis Treatment 417

p oietic cells. Because of its stimulant action on mega-karyocytopoiesis and thrombocytopoesis, it has alreadyb

�een approved for the treatment of thrombocytopenia

i�nduced by chemotherapy. In addition to this, IL-11

a lso possesses considerable immunosuppressant anda ntiinflammatory activity. In vitro IL-11 reduces thep roduction of TNF-α, IL-1β, and IL-12, and in variousa nimal models it alleviates inflammatory activity.

In a recent open phase 1–2 study, psoriasis patientsw� ere treated with recombinant IL-11: 12 patients wereg� iven daily subcutaneous injections for a period of8 weeks. In 7 of the 12 patients antipsoriatic effectsw� ere observed, with PASI falling by 20–80%. The re-sponse to therapy was accompanied by a reduction int

�he gene expressions of IFN-γ5 , IL-8, IL-12, TNF-α,

I:L-1β, and CD87

�.

Conclusions

T�

he data from the recent clinical trails with ex-p erimental therapies for psoriasis allows predictingsome general upcoming possibilities and critical issuesinvolving these novel immunotherapies (Table 2).

Some of the approaches currently under investigationw� ill actually lead to the registration of new drugs fort

�he treatment of psoriasis and to supplementation of

e xisting therapeutic options, which is considerable pro-g� ress. The majority of the novel immunological ther-a pies currently in early clinical development are biol-o� gicals: fusion proteins, antibodies, and recombinantc� ytokines. Therefore, they must be administered by in-j

Lection, which is quite inconvienient for the patients,

t�hey are expensive, and the induction of neutralizing

a ntibodies has to be excluded. Side by side with theseb

�iologicals, however, new immunosuppressants are

b�eing developed, which are also suitable for oral ad-

m� inistration. The overall results of the first clinicalt

�rials have been variable and are partly preliminary.

Data from controlled phase 2 and phase 3 studies areh

;ighly needed and will allow a better evaluation of the

p otential of the individual treatments. However, the pic-t

�ure already emerging that for the majority of the spe-

c� ifically acting biologicals, each individual treatmentg� enerally achieves a complete remission in onlya small number of patients (usually less than 40%).T

�herefore, is must be identified which patients are suit-

a ble for which therapy. The crucial question will beh

;ow to do this. Perhaps analyses of cytokine receptor

e xpression or polymorphismens may help. Only if thisc� an be done effective immunotherapies with few sidee ffects conceivably be tailored to suit individual pa-t

�ients. Moeroever, it also has to be established which

c� ombinations of the various approaches will yield sy-nD ergistic effects, improving the often still insufficiente fficacy. Finally, the results of clinical trials are contri-b

�uting significantly to our further understanding of the

d�isease, indicating which mechanisms play a greater or

l�esser part in its development. This in turn will generate

momentum for still better targeted pharmacological ac-t

�ion in the future.

AM

cknowledgment. We would like to thank Dr. Doecke for criticalreading; and Ms. Schoepe, Ms. Goerlich, Mr. Willett (Berlin) forediting the manuscript as well as Dr. Giesen (Berlin) for helpfuldiscussion.

RN

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Received in June 2002Accepted in August 2002

420 K. Asadullah et al.: Psoriasis Treatment