Acta Derm Venereol 2002; 82: 401± 410
`
`REVIEW
`
`Trends and Developments in the Pharmacological Treatment of
`Psoriasis
`
`ROBERT GNIADECKI1, CLAUS ZACHARIAE2 and MARTIN CALVERLEY3
`
`1Department of Dermatology, Bispebjerg Hospital, Copenhagen, 2Department of Dermatology, Gentofte Hospital, Hellerup and 3Chemical
`Research Department, Leo Pharmaceutical Products, Ballerup, Denmark
`
`Robert Gniadecki, Department of Dermatology D92,
`Bispebjerg Hospital, Bispebjerg bakke 23, DK-2400
`Copenhagen NV, Denmark. E-mail:
`rgniadecki@
`hotmail.com
`
`(Accepted August 19, 2002.)
`
`Acta Derm Venereol 2002; 82: 401± 410.
`
`INTRODUCTION
`
`In the history of psoriasis pharmacotherapy , the mile-
`stone developments have largely occurred by chance.
`Serendipitous observations in single patients have led to
`the discovery of such important treatments as metho-
`trexate (1), deltanoids (active form of vitamin D and
`its analogues) (2), cyclosporin (3) and, most recently,
`tumour necrosis factor alpha (TNF-a) inhibitors (4).
`While these observations have been of
`therapeutic
`importance, they have also had a major impact on
`current views on the pathogenesis of this skin disease.
`From the initial model, where the hyperproliferation of
`epidermal keratinocytes was considered to be a central
`event, the current understanding places the immune
`system at the hub of the pathogeni c series of events.
`Vigorous research and constantly increasing insight into
`the mechanisms of psoriasis have led to the identi® ca-
`tion of a number of potential targets for therapeutic
`intervention. For the ® rst time, the rational, mechan-
`ism-based development of new anti-psoriatic therapeu-
`tic has become a reality.
`The purpose of this article is to present a systematic
`review of emerging drug therapies for psoriasis that,
`although in the early stage of development today, may
`enter the clinical practice of tomorrow. The current,
`established treatments are not mentioned; readers are
`referred to recently published excellent reviews on this
`subject (5 ± 8). The compounds included in this review
`have been selected from a screening of the Medline
`records; where references are not cited the information
`has been obtained from IDdb (Investigationa l Drugs
`Database, Current Drugs Ltd., http://www.iddb3.com/)
`and PharmaProjects (PJP Publications Ltd.# 2002,
`http://www.pharmaprojects.co.uk).
`
`IMMUNOSUPPRESSIV E AND ANTI-
`INFLAMMATORY DRUGS
`The autoimmune cutaneous reaction is believed to play
`a causative role in the development of skin lesions in
`psoriasis (9). Most of the compounds under current
`development for psoriasis belong to different classes of
`immunosuppressives and anti-in¯ ammatory drugs. The
`central cell in the current pathogeni c model is the memory
`(CD45RO+ ) T-lymphocyte mediating the type 1 immune
`response. A type 1 immune response is mediated by
`TH1 and TC1 lymphocytes secreting a speci® c cytokine
`le (IFN-g, TNF-a, IL-12). The recently reviewed
`pro®
`immunopathogenesi s of psoriasis (9, 10) will be men-
`tioned only to the extent necessary for an under-
`standing of
`the mechanism of action of
`the drugs
`included here. The memory T-lymphocytes secrete three
`major cytokines, IL-2, TNF-a and IFN-g. IL-2 acts at
`the early stages of T-cell activation and clone expan-
`sion, while TNF-a and IFN-g have a twofold role: to
`drive and stabilize the type I immune reaction (11) and
`by direct action on keratinocytes to stimulate their
`growth leading to epidermal hyperproliferatio n (12). The
`latter aspect is believed to be an aberrant regenerative
`response of the epidermal stem cells (12, 13).
`
`strategies
`therapeutic
`Immunomodulation. Current
`involve suppression of the type I autoimmune reaction
`and/or immunomodulation aimed at shifting from the
`type I to type II immune response. The proof of con-
`cept of the latter strategy has been provided in studies
`demonstrating a bene® cial role of type II lymphokines
`in psoriasis patients. IL-10 (14 ± 16) and IL-11 (17, 18)
`are type II cytokines whose ef® cacy has been proved in
`small, preliminary clinical trials. Another approach is
`vaccination with killed Mycobacteria (19) or manipula-
`tion at the signal tranduction level by affecting the
`activity of the transcription factors responsible for the
`T-cell differentiation (GATA 3, HLX, p38 MAPK,
`junB, c-maf) (20). In particular, the modulation of
`p38 MAPK can now be accomplished by synthetic
`molecules. Currently developed immunomodulator y
`agents are summarized in Table I.
`
`Immunosuppression. Many currently used antipsoriati c
`drugs, such as methotrexate, cyclosporin, fumaric acid
`
`# 2002 Taylor & Francis. ISSN 0001-555 5
`
`Acta Derm Venereol 82
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`IPR2017-02194
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`402
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`R. Gniadecki et al.
`
`Table I. Immunomodulator y drugs
`
`Drug
`
`Status for psoriasis
`
`Mode of action/Remarks
`
`Atiprimod dimaleate
`(AnorMED)
`
`Preclinical
`
`T-cell switch factor
`(Boston Life Sciences )
`
`Preclinical
`
`PVAC (Corixa)
`
`Phase II
`
`Interleukin-10
`(Schering-Plough)
`
`Phase II
`
`Interleukin-11 (Neumega1)
`(Wyeth)
`
`Preclinical
`
`BIRB-796*
`(Boehringer-Ingelheim)
`
`Phase II
`
`RWJ-67657
`(Johnson & Johnson)
`
`Preclinical
`
`Azaspirane immunomodulators of unclear mechanism of
`action, developed mainly for rheumatoid arthritis. The
`azaspiranes demonstrated activity in adjuvant arthritis and in
`several transplant models.
`
`Gene therapy targeting the TH1/TH2 switch factor, c-Maf.
`Affects the balance between type 1 and type 2 immune
`response.
`
`Heat-killed Mycobacterium vaccae for intradermal
`administration. Works probably via skewing the immune
`response towards type 2. A study (21) of 20 patients with
`moderate to severe psoriasis showed that 65% showed
`marked improvement in the PASI (450% reduction).
`
`A recombinant IL-10 shown to ameliorate psoriasis due to
`skewing the immune response from type 1 to type 2 (15, 16).
`
`Human recombinant interleukin-11 showing promise in the
`therapy of psoriasis (17, 18).
`
`Selective p38 MAPK inhibitors developed for rheumatoid arthritis,
`psoriasis and Crohn’ s disease. In animal models shown to
`suppress type 1 immune response by inhibiting TNF-a and
`IL-1b.
`
`T-cell receptor peptides
`(Xoma)
`
`Preclinical
`
`*Chemical structure not disclosed.
`
`Synthetic T-cell receptor peptides for the treatment of
`autoimmune diseases, mostly multile sclerosis. The peptides
`suppress speci® cally the activity of pathogenic T-lymphocytes.
`
`esters, azathioprine or mycofenolate mofetil belong to
`this group. Although, as described below, current efforts
`aim at the development of speci® c immunosuppressiv e
`drugs, there is also considerable new progress within
`the non-speci® c immune-suppressing agents (Table II).
`Ascomycins and tacrolimus, whose mechanism of action
`resembles that of cyclosporin (22), have been devel-
`oped for topical use in in¯ ammatory skin diseases. They
`seem to work in atopic dermatitis, but their activity
`in psoriasis is relatively low and requires occlusion for
`optimal ef® cacy (23). These drugs might be useful, how-
`ever, for certain clinical types of psoriasis, such as
`inverse psoriasis, where preliminary evidence of topi-
`cal tacrolimus has been presented (24). An interesting
`development in systemic immunosuppressive drugs has
`been the introduction of purine nucleoside phosphory-
`lase (PNP) inhibitors (25). PNP is essential for T-cell
`proliferation and cellular immune response. Currently,
`the main targets for PNP inhibitors are rheumatologic
`
`autoimmune diseases and Crohn’ s disease and the
`antipsoriatic activity has not been tested in clinical
`trials. Other
`systemic
`immunosuppressive
`drugs
`with their mechanisms of action are summarized in
`Table II.
`the pharmaceutical
`The main effort of most of
`industry has been towards the development of speci® c
`immunosuppressive agents. Recent developments in
`biotechnology, such as the large-scale production of
`humanized, primatized or purely human antibodies (27),
`and advances in the anti-sense approach (28) have made
`the development of such agents possible. The easiest
`but least attractive way is to delete the subpopulation
`of T-cells participating in the autoimmune reaction.
`Selective T-cell depletion, such as that achieved by a
`fusion toxin protein DAB389IL-2 (depletion of activated
`T-cells expressing IL-2 receptor) works, but the side
`effects are severe and prolonged immunosuppression
`can occur (29, 30). A smarter approach is a reversible
`
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`

`Table II. Non-speci® c immunosuppressive and cytostatic drugs
`
`Trends and developments in the pharmacologica l treatment of psoriasis
`
`403
`
`Status for psoriasis
`
`Mode of action/Remarks
`
`Drug
`
`A-86281 (ABT-281)
`(Abbott)
`
`Pimecrolimus (SDZ ASM 981)
`(Novartis)
`
`Sirolimus (Rapamycin)
`(Wyeth Ayerst)
`
`Phase I
`
`Phase II
`
`Phase II
`
`Immunosuppressive ascomycin analogue.
`
`Same as above. Pimecrolimus has now been registered
`for the topical use in atopic dermatitis.
`
`Immunosuppressive macrolide antibiotic, blocker of
`S6 kinase. Clinical effect in psoriasis in combination
`with cyclosporin (26).
`
`Well-known drug in oncology, b-tubulin antagonist.
`Probably anti-psoriatic activity in topical application.
`
`Paclitaxel gel (Angiotech)
`
`Phase II
`
`BCX-1777*
`(BioCryst Pharmaceuticals)
`
`Paldesine (BioCryst
`Pharmaceuticals)
`
`Preclinical
`
`Purine nucleoside phosphorylase antagonist.
`
`Phase II
`
`Purine nucleoside phosphorylase antagonist.
`
`Merimempodib (Vertex pharmaceuticals)
`
`Phase II
`
`A small molecule inositol-5-monophosphate (IMPDH)
`inhibitor. Like azathioprine and mycofenolate mofetil
`(both currently used for psoriasis) merimempodib is a
`blocker of the de novo synthesis of guanosine
`nucleotides selectively in lymphocytes.
`
`*Chemical structure not disclosed.
`
`function blocking of T-cells. This has been achieved
`mostly by directly targeting the critical surface proteins
`involved in the process of T-cell activation or by blocking
`the critical type I cytokines. Targeted surface molecules
`are mostly those involved in the interactions between T-
`cells and antigen-presentin g cells (Table III). An appro-
`ach that has already shown promise is the function
`blocking of type 1 cytokines (31, 32). During the immune
`response, there seems to exist a positive feedback loop
`IFN-g
`of
`type I cytokines where IL-12 augments
`release; IFN-g in turn stimulates TNF-a release and
`TNF-a upregulates itself (33). IL-6 is another pro-
`in¯ ammatory lymphokine involved in type I immune
`reactions and overexpressed in psoriasis (34, 35). Drugs
`neutralizing type I cytokines, such as TNF-a, are listed
`in Table IV.
`Several of the compounds listed in Tables III and IV
`have already shown considerable clinical ef® cacy in
`well-designed clinical studies. In a phase II multi-centre
`study on 145 patients, efalizumab (Xanelim1) brought
`about an improvement of more than 50% in the phy-
`sician’s global assessment after 8 weeks of treatment in
`48% of patients treated with anti-CD11a antibodies
`compared to 15% of patients treated with placebo (40).
`
`Biogen’ s alefacept (Amevive1) soon to be registered for
`psoriasis also showed a marked clinical effect in a
`placebo-controlled study involving 229 patients (36).
`The mean reductions in PASI were 38%, 53% and 53%,
`respectively, in the active groups compared to 21% in
`the placebo groups after 12 weeks of
`treatment
`intravenously. Alefacept caused a similar correlated
`decrease in CD45RO+ cells. In¯ iximab (Remicade1)
`(both anti-TNF-a) are in
`and etanercept (Enbrel1)
`phase III clinical studies (31, 32) and etanercept has
`recently been approved for the treatment of psoriatic
`arthritis.
`treatment of
`approach to the
`An ingenious
`autoimmune diseases is a selective deletion or function-
`blocking of the autoreactive clone only. Methotrexate
`seems to work in part via the induction of selective
`apoptosis within the pool of autoreactive lymphocytes;
`however, a search for a methotrexate analogue devoid of
`the side effects has been unsuccessful. Another way is the
`blocking of T-cell antigen receptor (TCR) taking advan-
`tage of the fact that autoreactive T-cells in psoriasis are
`oligoclonal (44, 45). Several companies are working on
`small blocking peptides selectively binding to the Vb
`portion of TCR, and some progress has been made in
`
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`

`404
`
`R. Gniadecki et al.
`
`Table III. Targets for drugs inhibiting TH 1 and TC1 cells
`
`Surface protein Comment
`
`Targeting compound, status for psoriasis
`
`TCR
`
`CD2
`
`CD3
`
`CD4
`
`CD8
`
`CD28
`
`CD40L
`
`LFA-1
`
`Antigen receptor, crucial for the
`initiation of immune response. Binds
`to MHC-I or MHC-II on APC.
`
`Binds to LFA-3 on APC. Activated
`during proliferation and differentiation
`of T-cells.
`
`Zorcell (Immune Response): a combination of two T-cell derived peptides
`in Freund’ s adjuvant believed to inactivate autoreactive T-cells. Phase II.
`T-cell receptor peptides (Xoma): synthetic TCR peptides suppressing the
`activity of autoreactive T-cells. Preclinical.
`
`Alefacept (Amevive1, Biogen): LFA-3/IgG1 fusion protein. Prevents T-cell
`activation by binding to the CD2 receptor on memory effector T
`lymphocytes. Activity proven in clinical studies and soon to be launched
`(36).
`Siplizumab (Biotransplant): Humanized anti-CD2 antibody. In preliminary
`phase II clinical 70% of patients experienced at least 25% improvement in
`PASI. Phase II.
`
`A component of the TCR protein
`complex on all T-lymphocytes.
`
`Visilizumab (Protein Design): A probably discontinued anti-CD3 antibody,
`anecdotal evidence of therapeutic activity in psoriasis (37).
`
`A component of the TCR protein
`complex on TH.
`
`HuMax-CD4 (Genmab): Human monoclonal anti-CD4 antibody. In a
`preliminary phase II study, 85 patients received 4 weekly subcutaneous
`injections of the antibody in 4 concentrations. 38% patients obtained 425%
`reduction in PASI, 19% obtained 450% reduction (38).
`HumaT4 (Intracel): A human Fab fragment against CD4, preclinical
`development for the treatment of various autoimmune diseases
`OKT(R)cdr4a (Ortho): A probably discontinued, non-depleting anti-CD4
`humanized antibody. A study on 6 patients with recalcitrant plaque
`psoriasis showed the mean decrease in PASI score by 46% (39).
`
`A component of the TCR protein
`complex on TC.
`
`û 2 microglobulin (Avidex): û 2 microglobulin modi® ed to block CD8
`binding. Preclinical developed for autoimmune diseases.
`
`Binds to CD80 and CD86 on APC.
`Activated during proliferation and
`differentiation of T-cells.
`
`IDEC-114 (IDEC): anti-B7-1, primatized antibody genetically engineered
`from Cynomolgus macaque monkey and human components.
`Clinical phase II trials ongoing.
`
`Binds to CD40 on APC. Activated
`during proliferation and differentiation
`of T-cells.
`
`5D12 (Chiron): Humanized, anti-CD40 antibody under preclinical
`development for various autoimmune diseases.
`IDEC-131 (IDEC): Antibody against tiGp39 that is expressed on CD4 cells
`and serves as a ligand for CD40. Clinical phase II trials ongoing.
`
`Consists of 2 proteins: CD11a and
`CD18. Binds to ICAM-1 on APC.
`Involved in the initiation of the
`immune response.
`
`Efalizumab (Xanelim1, Genentech): Humanized monoclonal antibody
`against CD11a subunit of LFA-1. In a recent double-blind,
`placebo-controlled, phase II, multicenter study (40) on 145 patients with
`moderate psoriasis 48% of patients achieved 440% improvement when
`the drug was administered intravenously in 8 weekly doses of 0.3 mg/kg.
`Progressed to phase III.
`IC-747 (ICOS)
`
`Orally-active synthetic compound able
`to block LFA-1 (CD18/CD11a) and
`ICAM-1. Phase II.
`
`CTLA4
`
`Binds to CD86 on APC. Activated
`during proliferation and differentiation
`of T-cells.
`
`BMS-188667 (Bristol-Myers): Chimaeric immunosuppressant antibody
`against B7. No results from clinical trials on psoriasis reported, but in
`phase II for several autoimmune diseases.
`
`TCR: T-cell receptor, APC: antigen presenting cells.
`
`another autoimmune disease, multiple sclerosis (46). No
`reports are yet available on the use of TCR-binding
`peptides in psoriasis.
`
`Inhibition of chemotaxis and tissue migration. Reactive
`lymphocytes and leucocytes in®
`ltrate the skin due to
`the action of multiple chemokines (10, 47 ± 54) that
`
`assist in cell activation and stimulate the expression of
`several adhesion molecules involved in the interaction
`between the leucocytes and the endothelia (extravasa -
`tion) or the target tissue. Because of the importance in
`other autoimmune and infectious diseases (e.g. HIV
`infection) there is extensive research within the ® eld of
`chemokine-blocking drugs (Table V). The development
`
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`

`Table IV. Type 1 cytokines as targets for new drugs
`
`Lymphokine Function
`
`Targeting compounds, status for psoriasis
`
`Trends and developments in the pharmacologica l treatment of psoriasis
`
`405
`
`IL-2
`
`Proliferation and T-cell
`differentiation during the
`type-1 immune response.
`
`IL-6
`
`IL-12
`
`IL-15
`
`IL-20
`
`IFN-g
`
`TNF-a
`
`A pro-in¯ ammatory cytokine
`synthesized in the epidermis.
`
`Released from antigen
`presenting cells and T-cells.
`Stimulates immune response
`maturation into the type 1.
`Blocks keratinocyte apoptosis.
`
`Pro-in¯ ammatory cytokine
`synthesized by keratinocytes
`and upregulated in psoriasis.
`Blocks apoptosis of
`keratinocytes.
`
`A homolog of IL-10. IL-20
`and its receptor is upregulated
`on psoriatic keratinocytes;
`considered to be a pro-in¯ ammatory
`cytokine.
`
`Type-1 lymphokines secreted
`by TC1, TH1 and
`macrophages.
`
`Type-1 lymphokines secreted
`by TC1, TH1 and
`macrophages.
`
`Basiliximab (Simultec1, Novartis): A probably discontinued anti-IL-2 receptor
`antibody; case reports on the favourable effect of basiliximab in psoriasis (41, 42).
`Daclizumab (Protein Design): A humanized anti-IL-2 receptor chain launched for
`the treatment of organ transplant rejection. A small clinical study on 19 patients with
`psoriasis daclizumab was administrated at weeks 2, 4, 8 and 12. A 30% reduction in
`PASI was detected at 8 weeks (43). Phase II.
`Denileukin diftitox (Ligand): A fusion toxin composed of human interleukin-2 and
`fragments of diphtheria toxin (DAB389IL-2). Two papers (29, 30) on a total of
`33 patients showed bene® cial effect of this antibody; however, the treatment was
`associated with severe side effects and therefore probably discontinued.
`
`None available.
`
`None available.
`
`Anti-IL-15 Mab (Genmab): Monoclonal human anti-IL-15 antibody in preclinical
`developed for autoimmune diseases.
`
`IL-20 antagonist s (ZymoGenetics): synthetic inhibitors, structure
`not disclosed. Preclinical.
`
`Anti-c IFN (Protein Design): Monoclonal humanized antibody neutralizing IFN-g
`in phase I for psoriasis and Crohn’ s disease. Clinical ef® cacy in psoriasis unknown,
`but promising results in Crohn’ s disease. Preclinical.
`
`Etanercept (Enbrel1, Immunex): Potent anti-psoriatic activity in a randomized,
`double-blind, placebo-controlled, study on 60 patients with psoriatic arthritis and
`psoriasis (13) 26% of etanercept-treated patients achieved a 75% improvement in
`the PASI; the median PASI improvement was 46%. Launched for psoriasis
`arthritis.
`In¯ iximab (Remicade1, Johnson & Johnson): A monoclonal antibody
`against TNF-a. In a double-blind, placebo-controlled study (31) on 33 patients
`with moderate to severe plaque psoriasis, 82% showed a good or excellent
`response. Probably soon launched for psoriasis.
`ISIS-104838 (ISIS): A second-generation antisense TNF-a inhibitor as an
`anti-in¯ ammatory for the treatment of rheumatoid arthritis (RA), psoriasis
`(topical cream) and Crohn’ s disease. Phase II.
`UR-1505 (Uriach): A small molecule blocker of TNF-a synthesis (structure not
`disclosed). Claimed to inhibit the mice oxazolone-induced delayed hypersensitivity
`(topically) and rat adjuvant-induced arthritis (oral). Preclinical.
`
`of selective drugs (which may be considered both anti-
`in¯ ammatory and immunosuppressive) is complicated
`by the fact that leucocyte chemokinesis is governed by a
`complicated network of many, partly redundant, che-
`mokines and their receptors. Neutrophil chemokinesis
`is mainly affected by IL-8 and GRO-a, both of which
`bind to the receptor CXCR2 (48). Pilot studies with the
`humanized anti-IL-8 antibody have shown a signi® cant
`clinical effect (10, 55). The lymphocyte-attractin g chemo-
`kines are less well investigated and fall into two major
`categories: the CXC and CC chemokine and receptor
`
`families. Many of these chemokines are detectable in
`signi® cant quantities
`in psoriasis
`lesions and are
`believed to be important (Table V). The chemokine-
`targeting drugs have been developed but none have
`been tried in psoriasis.
`Migration of lymphocyte s to the tissue is accomplished
`with the help of adhesion molecules, usually classi® ed within
`three major groups: 1. selectins (E, P, L selectins), 2.
`adhesion molecules from the immunoglobuli n superfamily
`(ICAM-1, ICAM-2, VCAM-1) and 3. integrins (including
`the already mentioned LFA-1, aEb7 integrin). In psoriasis,
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`406
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`Table V. Drugs inhibiting chemotaxis and lymphocyte adhesion
`
`Drug
`
`Status for psoriasis
`
`Mode of action
`
`HuDREG-55 Mab (Protein Design)
`Bimosiamose (Texas Biotech)
`
`Phase I
`
`Phase I
`
`Humanized antibody directed against L-selectin.
`
`E-selectin antagonist.
`
`VLA-4 inhibitor (Biogen)*
`
`Phase I
`
`A small molecule inhibitor of the very late antigen 4 (VLA-4).
`VLA-4 on T-cells binds to endothelial vascular cell adhesion
`molecule-1 (VCAM-1) mediating cell migration.
`
`CXCR2 antagonist (Celltech)
`
`Preclinical
`
`Small molecule chemokine receptor CXCR2 antagonists.
`
`CCR1 inhibitor (Millennium)*
`
`ABX-IL8 (Abgenix)
`
`Preclinical
`
`Phase II
`
`*Structure not disclosed.
`
`the E-selectins, ICAM-1 and VCAM-1 are upregulate d on
`endothelial cells and bind the T-cells via their surface
`receptors CLA, LFA-1 and VLA-4. Their importance is
`illustrated by the anti-in¯ ammatory effect of the synthetic
`inhibitor (BMS 190394). Several other adhesion molecules
`are available, but all are in early development , and apart
`from the already mentioned efalizumab (40), results on the
`antipsoriati c activity are lacking.
`
`DRUGS TARGETING NUCLEAR RECEPTORS
`FOR HORMONAL LIPIDS AND STEROIDS
`
`This successful group of compounds (including the already
`used glucocorticoids, retinoids, deltanoids ±
`vitamin D
`analogues ) remains a major area of investigation. The
`main breakthroug h in glucocorticoid research has been
`the demonstration that anti-in¯ ammatory activity
`depends on the inhibitory interaction between the
`speci® c domain of an activated glucocorticoid receptor
`and the pro-in¯ ammatory transcription factors, such as
`AP-1 and NF-kB (56). This opens a venue to the
`development of potent, purely anti-in¯ ammatory, side-
`effect-free glucocorticoid analogues (Table VI).
`Apart
`from the recent appearance of
`tazarotene,
`bexarotene and a few vitamin D analogues (maxacalci-
`tol,
`falecalcitriol),
`little development has occurred
`within the retinoids and deltanoids. Tazarotene and
`maxacalcitol have now been approved for the topical
`treatment of psoriasis, but their therapeutic ef® cacy
`
`Acta Derm Venereol 82
`
`A small molecule claimed to inhibit chemokine receptor CCR1
`
`Humanized monoclonal neutralizing antibody against IL-8. In a
`multicentre, multidose, placebo-controlled Phase I/II trial in
`45 mild-to-moderate psoriasis patients, ABX-IL8 was well tolerated,
`with a dose-dependent improvement in several measures of
`disease (55).
`
`is moderate, requiring combination with other agents
`(such as the glucocorticoids or phototherapy) . A major
`developmental problem within this group is a poor
`correlation between in vitro assays, such as receptor
`binding avidity, and the therapeutic performance.
`Exciting new targets are the previously neglected
`nuclear
`receptors PPARs
`(peroxisome proliferator-
`activated receptors). PPARs are involved in lipid meta-
`bolism and have been shown to be crucial for skin
`barrier development. Later studies show the importance
`of PPARs in keratinocyte proliferation, angiogenesis
`and cutaneous in¯ ammation (57). The most abundan t
`species of PPARs in the epidermis are PPAR-d, followed
`by PPAR-g and PPAR-a. Although expression of
`PPAR-d is stable during differentiation, PPAR-a and
`PPAR-g increase in differentiated cells (58). Moreover,
`PPAR-d and -g species may be anti-in¯ ammatory.
`PPAR-d knockout mice demonstrate an exacerbated
`in¯ ammatory cutaneous response to phorbol esters (57).
`In psoriasis, there is a ® vefold increase in the PPAR-d
`and PPAR-g proteins (59). In the clinic, the oral anti-
`diabetic troglitazone, which was withdrawn in 2000
`because of hepatoxicity, a PPAR-g activator, was shown
`to ameliorate psoriasis (60). Ligands for PPAR-d and -g
`are thus promising candidates as antipsoriatic drugs.
`Development of PPAR ligands is an active area, mainly
`due to their potential use in diabetes and cancer
`treatment (61).
`
`6
`
`

`

`Trends and developments in the pharmacologica l treatment of psoriasis
`
`407
`
`Table VI. Ligands of the nuclear steroid receptors with possible anti-psoriatic activity
`
`Drug
`
`Status for psoriasis
`
`Mode of action
`
`AGN-194310 (Allegan)
`
`Phase II
`
`Ligand of RARa,b,g. Claimed to be active in psoriasis, no clinical
`data available.
`
`Bexarotene (Ligand)
`
`Launched
`
`Selective retinoid X receptor ligand (RXR) agonist available as oral
`formulation (Targretin) and a gel formulation. In clinical trials for a
`variety of cancers; activity in psoriasis unknown.
`
`BAL-2299 (Basilea)
`
`Phase II
`
`Oral vitamin D analogue, low potency VDR agonist.
`
`KH-1650 (Leo)*
`
`Preclinical
`
`Vitamin D analogue for topical application heralded as potential
`follow-up to calcipotriol.
`
`Falecalcitriol (Wisconsin Alumni
`Research Foundation)
`
`Phase II
`
`Topical vitamin D analogue.
`
`Maxacalcitol (Chugai)
`
`Launched
`
`Topical vitamin D analogue.
`
`*Structure not disclosed.
`
`OTHER POTENTIAL TARGETS
`The above review of emerging drugs in psoriasis indi-
`cates an absence of drugs speci® cally targeting the
`keratinocyte. Fascination with the anti-in¯ ammatory
`and immunosuppressive drugs and the belief that kerati-
`nocyte hyperproliferation is a mere secondary phenom-
`enon have lessened interest
`in the drugs affecting
`keratinocyte proliferation and differentiation. However,
`the view that the keratinocyte is a passive by-stander
`may be false. Experimental data showing that over-
`expression of some keratinocyte growth factors (e.g.
`amphiregulin (62)), or perturbation in differentiation by
`an aberrant expression of integrins (63), leads to the
`development of an in¯ ammatory reaction and ® nally
`psoriasis-like phenotype in otherwise healthy skin. Unfor-
`tunately, at present there are no drugs able to block the
`relevant growth factors or directly in¯ uencing kerati-
`nocyte differentiation. There is some development in
`the EGF blocking agents and mitogen-activate d protein
`kinase inhibitors in oncology (19), but these compounds
`are far too toxic to be used in a benign in¯ ammatory
`skin disease.
`Another target of potential future interest is the nervous
`system, especially various neuromediator s believed to play
`a role in in¯ ammation. The role of the nervous system is
`illustrated by clinical observation showing an associa-
`tion between psychological stress and disease activity.
`
`Moreover, stroke and resulting hemiparesis sometimes
`lead to the clearance or exacerbation of psoriasis at the
`affected site (64). Surgical denervation often brings
`about the resolution of psoriasis (65), but b-adrenergic
`blocking drugs exacerbate it. The link between the nervous
`system and cutaneous immune reaction has led to the deve-
`lopment of the concept of the neuroimmunocutaneou s
`system (66). Numerous neuromediators, among them for
`example acetylcholine receptor subtypes, are differen-
`tially expressed on maturating keratinocytes, suggesting
`an involvement of this receptor in the regulation of
`epidermal growth (67). Concentrations of some mediators
`(VIP, nerve growth factor, b-endorphin) are increased in
`lesional psoriasis skin, whereas substanc e P is decreased.
`Many neuromediator s (such as a-MSH) have a profound
`effect on skin in¯ ammation (68, 69). Neuromediator s may
`thus be a target for antipsoriati c therapy.
`inhi-
`Lastly,
`the potential
`role of angiogenesis
`bitors should be mentioned. Angiogenesi s is a prominent
`microscopic feature of lesional skin in psoriasis and
`seems to be caused by an elevated expression of
`vascular endothelial growth factor (VEGF) and its
`PLC-g-coupled receptors
`(70). Receptor activation
`causes calcium-mediated signalling resulting in the
`activation of calcineurin and NFAT (nuclear factor of
`activated T-cells). This pathway is potently blocked by
`cyclosporin A and according to some views enhances
`
`Acta Derm Venereol 82
`
`7
`
`

`

`408
`
`R. Gniadecki et al.
`
`the antipsoriatic activity of this immunosuppressan t
`(71). Small molecules and antibodies
`capable of
`blocking the VEGF receptor (72) are currently in
`clinical trials for the treatment of solid tumours (73)
`and acute myeloid leukaemia (74) and it remains to be
`established whether they demonstrate any antipsoriatic
`activity.
`
`CONCLUDING COMMENTS
`Psoriasis is a chronic skin disease affecting on average
`2% of the population in developed countries. It has a
`considerable impact on quality of life, psychological and
`physical disability (75 ± 77). Although the world market
`for psoriasis treatment seems to be large in absolute
`terms (over $3 billion), it is relatively small compared
`to chronic diseases such as rheumatoid arthritis or
`autoimmune in¯ ammatory bowel disease. For that
`reason alone the antipsoriatic compounds are still
`likely to emerge in large part from drug development
`programmes designed for ``bigger’’ diseases. By the same
`argument, the main development is likely to continue
`within immunosuppressiv e and anti-in¯ ammatory agents.
`The development has been greatly facilitated by the
`advancement of basic immunological knowledge and
`the biotechnology approach. Large-scale production of
`entirely human antibodies and recombinant proteins is
`feasible. The ef® cacy of several biotechnology drugs,
`such as those targeting TNF-a (in¯ iximab, etanercept)
`or T-cell surface markers (alefacept, efalizumab),
`is
`already proven. These drugs are soon to be registered
`for clinical use in psoriasis. Still, however, the therapeu-
`tic results of a particular antibody or lymphokine are
`dif® cult to predict on a theoretic basis; drug discovery
`by serendipity rather than by rational systemati c approach
`is likely to continue for a while yet. Since considerable
`functional redundancy in the cytokine and chemokine
`signalling networks poses another problem, the devel-
`opment of less selective, small-molecule immunomodu-
`lating agents should not be abandoned.
`Despite recent advancements, the ideal anti-psoriatic
`medication has not yet been found. What is needed is a
`safe, orally administrate d compound providing a 480%
`reduction in disease activity in a signi® cant (470%)
`number of patients. The combination of two or more
`anti-psoriatic compounds is likely to enhance therapeu-
`tic activity and in many instances reduce toxic effects.
`Rotation therapy will be more achievable (78). The
`further development of anti-psoriatic drugs is therefore a
`welcome trend. Any drug showing ef® cacy over placebo
`should be included in the therapeutic armament, even if
`its ef® cacy is lower than that of existing therapies (79).
`
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