Vol. 20 • No.3 • 2008

MATERIA SOCIO MEDICA

New Treatments for Psoriasis: Biologic Agents Asja Prohic1, Dubravka Simic2 , Emina Kasumagic-Halilovic1 Department of Dermatovenerology, University Clinical Center, Sarajevo, Bosnia and Herzegovina1 Clinical Hospital Mostar, Bosnia and Herzegovina2

Review SUMMARY Psoriasis is a chronic inflammatory immune skin disease that has a multifactorial genesis. The recognition of psoriasis as a T-cell mediated disease has enabled new treatments that selectively target a specific portion of the immune system. This therapeutic approach is in contrast to current systemic therapies that act predominantly on hyperkeratinization and epidermal infiltrate, or broadly and non-specifically suppress the immune system. Three distinct types of proteins synthesized through recombinant DNA techniques so called “biologics”, are designed to provide long lasting remission with less toxic systemic side effects. They include monoclonal antibodies, fusion proteins and recombinant cytokines. Four basic strategies that focus on steps involved in the pathogenesis of psoriasis are: reduction of the number of pathogenic T cells, inhibition of T-cell activation and migration, modulation of the immune system, and blockage of the activity of inflammatory cytokines. Each of these steps provides an opportunity for biologics to intervene at specific points in the immune pathways. There are currently five biologic agents recognized for treating moderate-to-severe psoriasis. These agents include alefacept (strategy I), efalizumab (strategy II), and etanercept, infliximab and adalimumab (all strategy IV). In this article we review the steps involved in the immune response leading to psoriasis, explore how biologics can target each of these steps and present their mechanism of action, efficacy and safety profiles. Key words: psoriasis, therapy, strategies, biologic, alefacept, efalizumab, etanercept, infliximab, adalimumab

1. Introduction

Psoriasis vulgaris is a lifelong, chronic, immune mediated, inflammatory skin condition affecting approximately 2% of the general population (1). Up to 40% of patients with psoriasis may develop psoriatic arthritis (PsA), usually within 5–10 years after onset of the cutaneous disease (2). Despite showing benign progression, psoriasis is emotionally disabling, currying with it significant psychosocial difficulties (3). Although topical medications usually suffice, about 25% patients with moderateto-severe psoriasis will need additional systemic therapy, phototherapy or both. The most frequently used such therapies include methotrexate, cyclosporine, oral retinoids and phototherapy (PUVA, which is psoralen plus ultraviolet light) (4). Because of the chronic and relapsing nature of psoriasis, these therapies bear a considerable Reviews

potential for serious side effects, including hepatotoxicity (methotrexate) (5), nephrotoxicity (cyclosporine) (6), prolonged teratogenicity (oral retinoids) (7), and cutaneous neoplasms (phototherapy) (8). These long-term organ toxicities can be partially explained by the fact that these traditional systemic therapies were not custom designed to target one particular step within the pathogenesis of psoriasis. One of the major areas in psoriasis research over the past 10 years has been the development of numerous biologic agents that selectively interfere with the pathogenic psoriatic cascade and are associated with less toxic side effects than traditional therapies.

2. Immunopathogenesis of psoriasis

Research in the past two decades has brought much progress in the understanding of the immunopathogenesis and genetics of psoriasis. Originally, researchers believed that psoriasis was primarily a disorder of epidermal hyperproliferation, decreased epidermal turnover time, with resulting abnormal terminal differentiation and associated impaired barrier function of the epidermis (9). However, substantial evidence suggests that psoriasis is an immune-mediated, organ-specific (skin, or skin and joints) inflammatory disease, in which increased numbers of activated T cells and greater expression of a number of immunologic cytokines play a pivotal role (10,11). This concept is supported by histological and immunohistochemical examinations of lesional skin, which reveal infiltration of activated memory-effector CD4+ or CD8+ (denoted by CD45R0+) T cells in the dermis (which are primarily CD4+ cells) and epidermis (which are predominantly CD8+ cells) (12). To reach the effector state, naïve (denoted by CD45RA+) T cells (CD4+ or CD8+) must first be activated by antigen presenting cells (APCs), such as dendritic cells. This process of activation requires 2 signals between the T cells and the APCs (13). The initial signal is antigen-specific and originates after binding of the antigen or its peptide fragments to an APC. Protein complexes on the APC that bind the antigen are human leukocyte antigen major histocompatibility complex (MHC) molecules, termed

167

MATERIA SOCIO MEDICA MHC class I or class II depending on their presentation of the antigen to the T cell receptor (TCR) on CD8+ or CD4+ T cells, respectively (13,14). At present, however, the specific antigen(s) involved in the interaction between T cells and APCs, apart from a few infections, such as streptococcal, are unknown. The second “costimulatory” signal completing the T cell activation process is antigen-non-specific, provided primarily by binding or pairing between cell-surface molecules on naïve T cells and APCs (15). The T cells get attached to the APCs through adhesion molecules, LFA-1 (leukocyte function associated antigen 1) and CD2 on T cells. The reciprocating cell adhesion molecules expressed on the surface of APCs are ICAM-1 (intercellular adhesion molecule 1) and LFA-3. After the T-cell-APC binding has occurred through their respective surface adhesion molecules, the antigen is presented to the T cells by the APCs (16). The activation of T cells by APCs involves a cascade of pathways that ultimately leads to the production of proinflammatory (type 1 or Th1) cytokines, which include IL-1, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. These cytokines result in the production of Th2 cytokine including IL-4, IL-10 and IL-11 (17). The final outcome is the formation of the psoriasis plaque through keratinocyte proliferation, an increase of activity and migration of other inflammatory cells and vascular changes (18).

3. Biologics

Biologics are pharmacologically active proteins extracted from animal tissue or synthesized through recombinant DNA techniques. They are designed to mimic the action of normal human proteins or to interact with circulating proteins or cellular receptors. There are three distinct classes of biologic agents: monoclonal antibodies, fusion proteins and recombinant cytokines or growth factors (19). Although the generic names of biologics may be confusing, a strict nomenclature has been applied. Drugs that end in the letters mab are monoclonal antibodies. If they end in ximab, they are chimeric monoclonal antibodies and therefore may form neutralizing antibodies. Humanized monoclonals end in letters zumab while human monoclonal antibodies end in letters umab. Drugs ending in the letters cept involve the fusion of a receptor to the Fc portion of human IgG1 (20). Based on current hypotheses regarding psoriasis immunopathogenesis, two main therapeutics approaches have emerged: modulating either T-cells activation or cytokines (21). Within these main two approaches, four basic strategies that focus on the steps involved in the immunopathology of psoriasis include: reduction of the number of pathogenic T cells, inhibition of T-cell activation and migration, modulation of the immune system to down-regulate the type 1 (Th1) response predominant in psoriasis, and blockage of the activity of inflammatory cytokines (19) (Fig. 1). There are currently five available biologic agents recognized for treating moderate-to-severe psoriasis:

168

Vol. 20 • No.3 • 2008 alefacept, efalizumab, etanercept, infliximab and adalimumab. Food and Drug Administration (FDA) currently approved only alefacept, efalizumab and etanercept for the management of moderate-to-severe plaque psoriasis in the United States. The European Medicines Agency (EMEA) has approved only etanercept, efalizumab and infliximab for the treatment of psoriasis in the European Union.

4. Strategies for immunomodulation 4.1. Strategy 1: Reduction of the Number of Pathogenic T Cells

T cells in psoriatic plaques are primarily activated, proliferating memory-effector T cells, with high levels of the cell-surface markers CD2. The increased expression of the CD2 occurs as T cells differentiate from naïve T cells to memory-effector T cells (22). By selectively blocking the CD2 receptor on memoryeffector T cells, potential therapies can lead to selective apoptosis of these pathogenic T cells while spearing naïve T cells (17). Such agents would be expected to be disease remitting as they selectively reduce pathogenic T cells thereby producing long-lasting remission. A representative drug in this group is alefacept. It is a human fusion protein combining a Fc portion of human IgG and the binding site of costimulatory LFA-3. The LFA-3 portion of this agent binds to CD2 on the surface of T cells and thereby blocks the interaction of CD2 with natural LFA-3. This interaction prevents one of costimulatory signals required for T-cell activation. (23). Alefacept also induces selective apoptosis of memory-effector T-cells by binding to the FcγRIII receptor on natural killer cells and macrophages (22,24). A course of alefacept therapy consists of 12 weeks of 15 mg once-weekly intramuscular (IM) injections, followed by 12 weeks of observation. (25). While the onset of action is slow, improvement with alefacept progress over time, and patients typically continue to exhibit improvement ever the last dose of curse. A major benefit of this medication is that it is a remittive therapy (26). Patients treated with alefacept have a transient reduction in memory-effector T cells, which correlates with improvement in psoriasis, but there is no evidence that this significantly affects overall immune function (22,27). The product labeling for alefacept states that this drug should not be initiated in patients with CD4+ T-lymphocyte counts below normal, and the therapy should be withheld if CD4+ cell counts fall below 250 cells/μl. (25). To date, no clinically significant signs of immunosuppression or opportunistic infections and no increase of malignancy have been observed (28). However, alefacept has been studied for a few years and long-term safety data are needed. 4.2. Strategy 2: Inhibition of T-cell activation and migration

T cells must be activated to induce psoriasis. Agents that block either the primary or costimulatory signals required for activation could potentially treat psoriasis Reviews

Vol. 20 • No.3 • 2008

MATERIA SOCIO MEDICA

Table 1. Molecule Type, Mechanism of Action, Routes of Administration and Side Effects of Biologic Agents DRUG

Molecule Type

Alefacept

Human fusion protein

Efalizumab

Humanized monoclonal antibody

Etanercept

Infliximab

Mechanism of Action Reduces memory-effector T cells;binds CD2 on CD45RO+ cells

Dose / Duration

Administration

Side effects

15 mg Once weekly 12 weeks

IM

Decrease in CD+ count

Inhibits T-cell migration and activation; binds CD11 and LFA-1

0.7 mg/kg one dose, then I mg/ kg weekly (maximum single dose ≤200 mg)

SC

Fly-like symptoms Trombocytopenia Rebound upon discontinuation

Human fusion protein

TNF-α inhibitor

50 mg twice weekly 3 months then 50 or 25 mg weekly

SC

Chimeric monoclonal antibody

TNF-α inhibitor

3 mg/kg, 5 mg/kg or 10 mg/kg at week 0,2,5 than every 8 weeks

IV

by reducing the immune response driving psoriasis. Activation and migration are coupled in this model because many of the cell-cell interactions are mediated via the same receptors (29). Since pathogenic T cells are not reduced, such therapies would likely exhibit a diseasesuppressing effect. Efalizumab is a humanized IgG1 monoclonal antibody targeted against the T-cell surface molecule CD11a, one of two subunits that make up LFA-1. By binding CD11a, efalizumab blocks the interaction between LFA-1 and ICAM-1, its partner molecule on the surface of APCs, thus blocking both signal 2 and T-cell migration (30). This action blocks several T-cell processes important in the pathogenesis of psoriasis, including T-cell activation, T-cell trafficking from the circulation into the skin, and T-cell reactivation in the dermis and epidermis (31). Efalizumab is self-administered via a subcutaneous (SC) injection. The recommended dose is a single 0.7 mg/kg SC conditioning dose followed by weekly SC doses of 1 mg/kg (maximum single dose not to exceed a total of 200 mg) (32). Clinical trials have shown that efalizumab is generally well tolerated and has favorable safety profile over an initial 12 week treatment period. In clinical trials, the most common adverse events were mild-to-moderate flu-like symptoms (headache, chills, fever, nausea, myalgia) occurring within 48 hours after the first or second efalizumab injection. After the third and subsequent doses, the incidence of these acute adverse events was similar among efalizumab-treated and placebo-treated patients (33-35). The incidence of serious adverse events, infection, and malignancy was low and similar to that seen in the placebo group. In patients treated for long periods of time with efalizumab (up to 36 months of continuous treatment), there was no overall increase in adverse events over time, no evidence of organ toxicity, and no trend toward an increasing incidence of infection or malignancy (36,37). Rare cases of reversible thrombocytopenia were reported during efalizumab treatment in clinical trials, but the causal relationship between efalizumab and thrombocytopenia is unknown (32). The only major concern is the rebound of psoriasis, following discontinuation of therapy. Rebound is defined as a worsening of psoriasis or the conversion to more dangerous psoriasis variants such as erythrodermic or generalized pustular psoriasis, mainly in non-responding patients. (38,39). Reviews

Injection site reaction Aplastic anemia Demyelinating disorders ANA seroconversion Infusion reactions Reactivation of tuberculosis Neutralizing antibodies Congestive heart failure

4.3. Strategy 3: Modulation of the Immune System

T cells in psoriasis primarily release Th1 cytokines which include IL-2 and IFN-γ. These cytokines lead to the release of inflammatory cytokines such as TNF-α and IL-1 (40). Other subsets of T cells release Th2 cytokines (IL-4, IL-10 and IL-11) (41), which down-regulate Th1 T cells (42). Induction of immune deviation in psoriasis involves direct administration of a Th2 cytokines, to reduce the Th1 response, which would have a disease-suppressing effect. Recombinant Th2 cytokines presently in different phases of trial for treatment of psoriasis include IL-4 (43), IL-10 (44) and IL-11 (45). In early clinical trials, these agents have shown variable antipsoriatic efficacy. Further studies are needed for this biologics to be recognized and approved for the treatment of psoriasis. 4.4. Strategy 4: Blockage of the Activity of Inflammatory Cytokines

A primary mediator of inflammation, TNF- plays a critical role in the pathogenesis of psoriasis. It is released from T cells, keratinocytes, dermal dendrocytes, macrophages and mast cells (46). Increased production of TNFleads to keratinocyte hyperproliferation, endothelial cell regulation, and recruitment function of memory T cells. Activated T cells secrete more cytokines, creating an inflammatory cascade (10, 47). Binding and eliminating these cytokines could alter the course of psoriasis. Since pathogenic T cells would still be present to initiate the inflammatory process once the activation-blocking therapies were removed, this approach would fall into the category of disease suppression. Several anti-TNF drugs have been used successfully to treat psoriasis and PsA. Etanercept is a recombinant fusion protein comprising domains of the 75-kDa human TNF receptor and Fc portion of human IgG1. This dimeric structure allows etanercept to function as a more potent binder of TNF-α than naturally occurring monomeric receptors in the body. Etanercept binds only soluble TNF-α and does not affect TNF-α already bound to cell membranes (48). This drug has demonstrated the efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis (49). Etanercept is self-administered via a SC injection. The recommended dose of etanercept for psoriasis is 50 mg twice weekly for 3 months, followed by a reduction to 50 mg weekly (or 25 mg twice weekly) thereafter (50). To

169

MATERIA SOCIO MEDICA

Vol. 20 • No.3 • 2008

Table 2. Efficacy of biologic agent DRUG

Dosage

Duration

PASI 50

PASI 75

Ref.

Mean DLQI unit improvement

Alefacept

15 mg IM once weekly

12 weeks

57% at week 12 42% at week 14

33% at week 12 21% at week 14 (2 weeks after last dose)

27

4.4 at week 14 (2 weeks after last dose)

Efalizumab

1mg/kg SC weekly

24 weeks

26.6% at week 12 43.8% at week 24

36

5.6 at week 12 5.9 at week 24

25 mg SC twice weekly Etanercept

50 mg SC twice weekly 3 mg/kg IV

Infliximab

Adalimumab

5 mg/kg IV 40 mg SC weekly 40 mg SC every other week

24 weeks 24 weeks

58.5% at week 12 66.6% at week 24 58% at week 12 70% at week 24 74% at week 12 77% at week 24

3 infusions at weeks 0, 2, 6

N/A

12 weeks

88% at week 12 76% at week 12

51

72% at week 10

62

80% at week 12 53% at week 12

7.0 at week 12 7.5 at week 12

88% at week 10

date it is estimated that more than 337.000 patients worldwide, including over 74.000 patients with psoriasis, have received etanercept (48). The most commonly reported adverse event was injection site reactions, which occurred in 14%-20% of patients in psoriasis studies (51). These are characterized by erythema and edema at injection sites and are usually mild. However, due to etanercept’s role as TNF-α modulating agent there is also concern over potential infections, including severe sepsis (52,53). Many of these infections occurred in those patients who were predisposed to infections because of an underlying immunosuppressive state brought on by previous immunosuppressive therapies. Rare cases of aplastic anemia (54) and central nervous system demyelinating diseases such as optic neuritis and multiple sclerosis (55) have also been described as potential adverse events. There have also been reports of antibody formation to etanercept as well as autoantibody formation; however it is only in rare cases, that these patients develop clinical manifestations such as lupus-like malar rash (56). Finally, there is concern of increased risk of malignancy, principally lymphoma, following prolonged etanercept therapy (57). Because patients with psoriasis have an increased risk of lymphoma at baseline, there is no causal relationship between etanercept and lymphoma (58). Infliximab is a mouse/human chimeric anti-TNF monoclonal antibody comprising a mouse variable region and human IgG1-α constant region (59). Infliximab is able to bind to the soluble and transmembrane TNF-α molecule, thereby neutralizing the effects of TNF-α. Because of inhibition of TNF-α activity, infliximab also indirectly inhibits production of other proinflammatory cytokines (60). Infliximab has been earlier approved for the treatment of psoriatic arthritis, rheumatoid arthritis (in combination with methotrexate), Crohn’s disease and ankylosing spondylitis. Infliximab is administered by intravenous (IV) infusion as monotherapy at 3 mg/kg, 5 mg/kg, and 10 mg/kg doses, initiated with an induction regimen of infusions at 0, 2, and 6 weeks, followed by ma-

170

34% at week 12 44% et week 24 49% at week 12 59% at week 24

8.0 at week 10 10.0 at week 10

72

7.8 at week 12

intenance dosing every eight weeks (61). The commonest side effects with infliximab were headaches and infusion reactions, the vast majority of which were classified as mild (62,63); however, a severe adverse event such as anaphylactic reactions have been described, although in less than 1% of patients (64). Another concern is increased risk of reactivating latent tuberculosis (65,66) and invasive fungal infections, such as histoplasmosis (67). As a result, a tuberculin skin test (PPD, purified protein derivate) should be performed before starting therapy. Antibodies produced by the patient to infliximab may potentially neutralize the drug and block its effects, leading to dose escalation. Methotrexate may be co-administrated to prevent the development of neutralizing antibodies (68). Additionally, infliximab has also been associated with autoantibody formation, and there have been cases of lupus-like syndrome (69). Infliximab is contraindicated in patients with moderate-to-severe congestive heart failure because of infusion-related reactions of hypotension and dyspnea (70). The risk of lymphoma appears to be slightly increased (61), but this may be to a higher risk of lymphoma in the patient population in which this drug has been used (58). Adalimumab is a human IgG1 monoclonal antibody that specifically binds to TNF-α, blocking its interaction with the p55 and p75 cell surface receptors. It also lyses the cells that express surface TNF-α in the presence of complement. Adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques and helps in the restoration of their density (71). Although adalimumab is new to the world of dermatology, this drug has been approved for the treatment of rheumatoid arthritis in December 2002. Adalimumab is a suppressive therapy, and it is administrated as a continuous SC injection. There are currently two doses of adalimumab being studied for use in psoriasis patients: 40 mg SC once a week or 40 mg every other week (72). From the clinical trials for rheumatoid arthritis, the most common adverse events reported were headache, injection site reactiReviews

Vol. 20 • No.3 • 2008 ons, nausea, abdominal pain and respiratory infections (72,73). As with other anti- TNF-a, primary concerns are infection, specially reactivated tuberculosis and invasive fungal infection, anaphylactic reactions, malignancy and development of antibody formation, both antibodies to adamimumab and autoantiobodies (74). Rare side effects include: CNS demyelinating disease, worsening or initiation of congestive heart failure, a lupus-like syndrome, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease (73). Table 1 reviews molecule type, mechanism of action, routes of administration and side effects of biologic agents used in the treatment of psoriasis.

5. Efficacy of Biologic Agents in the Treatment of Psoriasis

MATERIA SOCIO MEDICA rized in table 2. The lack of head-to-head clinical trials limits confidence in the comparison of the efficacy of biological agents measured either by PASI 75 or DLQI improvement. Alefacept is an exception, as it is used as remittive therapy. Comparative data for infliximab, adalimumab, etanercept, alefacept, and efalizumab suggested that the number of patients achieving a PASI improvement of 75% or greater at week 12 was 88%, 80%, 49%, 33% and 26.6%, respectively (27,36,51,62,72). Using this approach, infiximab appears to be the most efficacious therapy for psoriasis. Available long-term for data for some biological drugs indicate that the improvements in psoriasis achieved during the first 12-24 weeks are maintained through at least 48 weeks of continuous therapy. Week 48 PASI 75 response rate was 62% for efalizumab-treated patients (81). Furthermore, the efficacy of efalizumab was maintained or even improved during 36 months of continuous therapy (82). In contrast to efalizumab, the efficacy of the TNF-α antagonists seems to decline over time. The efficacy of etanercept appears to be maintained through at least 48 weeks with PASI 75 response rate of 45%, but declines slightly as treatment extends to 96 weeks (83). Infliximab has demonstrated excellent response rates after the start of treatment. The PASI-75 response rate at week 50 for infliximab was approximately 70% in patients who did not miss more than 1 infusion, but declines modesty as therapy extends beyond this period (84). Similarly, available data for adalimumab suggest that responses are maintained for 60 weeks (72). Alefacept has demonstrated the longest psoriasis remission times among biological agents for psoriasis. Patients who achieved PASI 75 after a 12-week course of alefacept 15 mg weekly maintained at least a PASI-50 response for a median period of approximately 7 months (27). The effect of the biologic agents on patients’ QOL was determined using improvement in DLQI scores following

The Psoriasis Area and Severity Index (PASI) is used to assess the severity of the disease, which may vary from 0 to 72. The PASI score is based on the severity of erythema, induration, desquamation and body surface area affected (head, trunk, upper extremities, lower extremities). A PASI score above 10 is considered to be indicative of severe disease. A PASI 75 represents an improvement in the PASI score of at least 75% as compared with baseline (i.e., before the biologic was administered) (75). The patient population experiencing a 50% improvement in their PASI score (PASI 50) could also be considered a clinically significant endpoint (76). The dermatology life quality index (DLQI) is a simple 10-item questionnaire used to measure the impact of dermatologic disease and its treatment on subjects’ quality of life (QOL) (77). Scores on the DLQI range from 0 to 30, with a score of 30 indicating the most severe indication. A DLQI of 10 or more correlates well with severe disease requiring admission, phototherapy or second line therapy and an improvement in DLQI of 5 or more points is considered a worthwhile criterion for response (78). For evaluation of improvement in psoriasis, PASI and DLQI are recommended at 3 monSignal 1 = Biologic Agent ths initially and then every 6 months (79). C Ag MH TCR According to the guidelines provided by the CD8 CD4, British Association of Dermatologists, the Strategy 2 T-cell activation biologic agents should be utilized in patients LFA-1 ICAM-1 Antigenwith severe disease who have failed previous CD 28 B7 Naive presenting cell systemic therapies, where these therapies are T cell CD 2 LFA-3 contraindicated because of comorbid disease, Signal 2 or who have psoriatic arthritis. The patient Strategy 3 must have severe disease defined as PASI score Th1 differentiation of 10 or more and a DLQI >10 (80). A favorable or adequate response to biologic Effector Strategy 1 treatment includes 50% or greater reduction in T cell the baseline PASI score and a 5-point or greater improvement in DLQI within 3 months Cytokine secretion of initiation of treatment. Therapy should be Strategy 4 withdrawn after 3 months if these criteria are Th1 cytokines not fulfilled (79). The efficacies of the biologic agents deter- Fig.1. Sites of action of the different strategies for biologic therapy in the immunological mined by PASI score and DLQI are summa- cascade of psoriasis Reviews

171

MATERIA SOCIO MEDICA approximately 12 weeks of administration of biologic agent. According to the mean DLQI unit improvements from the five suitable trials (33, 85-88), infliximab again appears to be the most efficacious therapy, followed by adalimumab, etanercept, efalizumab and alefacept.

6. Conclusion

Remarkable progress during the last two decades has brought much progress in the understanding of the immunopathogenesis and genetics of psoriasis, leading to the development of more targeted therapies. These therapies have a common therapeutic goal: to reduce or eliminate the pathogenic effects of T cells in psoriasis. Current systemic therapies for psoriasis interact broadly on the immune system. The clear advantage of biologics is that they target specific components of the immune system rather than dampening down the entire system, resulting in fewer side effects when administrated over the long term. T-cell antagonists modulate the specific arm of the psoriatic immune response and are more selective than TNF-α antagonists. These differences may explain why TNF-α antagonists, particularly the monoclonal antibodies, are more effective than T-cell antagonists. The biologics also differ in some aspects of their side effects profile that influence the choice of treatment. Although these agents do not have the organ-toxicity associated with traditional systemic agents utilized for psoriasis, the patient must be carefully selected and monitored to avoid or identify and manage potential adverse reactions. Despite side effects, these agents provide dermatologist new options for the long-term management of psoriasis, more prolonged remission and improved psychosocial well-being. Potential limitations in the use of biologic agents include the high annual costs for treatment (around €10 000), lack of long-term follow up and selective nature of the patient populations thus far.

References

1.

Christophers E. Psoriasis-epidemiology and clinical spectrum. Clin Exp Dermatol, 2001; 26: 314–20. 2. Winterfield IS, Menter A, Gordon K, Gottlieb A. Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis, 2005; 64: 87-90. 3. Arruda LHF, Moraes APF. The impact of psoriais on quality of life. Br J Dermatol, 2001; 144: 33-6. 4. Mrowietz U. Advances in systemic therapy for psoriasis. Clin Exp Dermatol, 2001; 26: 362-7. 5. Kujjpers AL, van de Kerkhof PC. Risk-benefit assessment of methotrexate in the treatment of severe psoriasis. Am J Clin Dermatol, 2000; 1: 27-39. 6. Zachariae H. Renal toxicity of long-term cyclosporin. Scand J Rheumatol, 1999; 28: 65-8. 7. Van Zander J, Orlow SJ. Efficacy and safety of oral retinoids in psoriasis. Expert Opin Drug Saf, 2005; 4: 129-38. 8. Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: a cohort study. J Invest Dermatol, 2003; 121: 252-8. 9. Krueger GG, Bergstresser PR, Lowe NJ, Voorhees JJ, Weinstein GD. Psoriasis. J Am Acad Dermatol, 1984; 11: 937-47. 10. Lee MR. Cooper AJ. Immunopathogenesis of psoriasis. Australas J Dermatol, 2006; 47: 151-9. 11. Gaspari AA. Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol, 2006; 54: 67-80.

172

Vol. 20 • No.3 • 2008 12. Nickoloff BJ. The immunologic and genetic basis of psoriasis. Arch Dermatol, 1999; 135: 1104-10. 13. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med, 2000; 343: 37-49. 14. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med, 2000; 343: 108-17. 15. Wingren AG, Parra E, Varga M, Kalland T, Sjogren HO, Hedlund F, et al. T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. Crit Rev Immunol, 1995; 15: 235-53. 16. Lowes MA, Lew W, Krueger JG. Current concepts in the immunopathogenesis of psoriasis. Dermatol Clin, 2004; 22: 349-69. 17. Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med, 1999; 341: 1817-28. 18. Hern S, Allen MH, Sousa AR, Harland CC, Barker JN, Levick JR. et al. Immunohistochemical evaluation of psoriatic plaques following selective photothermolysis of the superficial capillaries. Br J Dermatol, 2001; 145: 45-53. 19. Singri P, West DP, Gordon KB. Biologic therapy for psoriasis: the new therapeutic frontier. Arch Dermatol, 2002; 138: 657-63. 20. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol, 2002; 46: 1-25. 21. Kirby B, Griffiths CE. Novel immune-based therapies for psoriasis. Br J Dermatol, 2002; 146: 546-51. 22. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med, 2001; 345: 248-55. 23. Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol, 2003; 148: 784-8. 24. Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol, 1994; 152: 2753–67. 25. Biogen Idec Inc, Amevive® (alefacept) package insert; 2005 Cambridge, MA, USA. 26. Krueger GG. The remittive effects of alefacept. J Cutan Med Surg, 2004; 8: 10-3. 27. Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE, et al. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol, 2003; 139: 719–27. 28. Schmitt J, Stoller E, Wozel G. Alefacept. Successful long-term therapy of a severe psoriasis. Hautarzt, 2005; 56: 360-2. 29. Damle NK, Klussman K, Linsley PS, Aruffo A. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol, 1992; 148: 1985-92. 30. Jullien D, Prinz JC, Langley RG, Caro I, Dummer W, Joshi A, et al. T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): mechanisms of action. Dermatology, 2004; 208: 297–306. 31. Gottlieb A, Krueger JG, Bright R, Ling M, Lebwohl M, Kang S, et al. Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis. J Am Acad Dermatol, 2000; 42: 428-35. 32. Genentech Inc, Raptiva® (efalizumab) package insert; 2005 South San Francisco, CA, USA. 33. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, et al. Efalizumab for patients with moderate to severe plaque psoriasis: A randomized control trial. JAMA, 2003; 23: 3073-80.   34. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med, 2003; 349: 2004-13. 35. Gottlieb AB, Gordon KB, Lebwohl MG, Caro I, Walicke PA, Li N, et al. Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis. J Drugs Dermatol, 2004; 3: 614-24. 36. Menter A, Gordon K, Carey W. Hamilton T, Glazer S, Caro I, et al. Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol, 2005; 141: 31-8. 37. Leonardi CL, Papp KA, Gordon KB, Menter A, Feldman SR, Caro I, et al. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol, 2005; 52: 425-33. 38. Golda N, Benham SM, Koo J. Rebound of psoriasis during treatment with efalizumab. J Drugs Dermatol, 2006; 5: 63-5. 39. Gaylor ML, Duvic M. Generalized pustular psoriasis following withdrawal of efalizumab. J Drugs Dermatol, 2004; 3: 77–9.

Reviews

Vol. 20 • No.3 • 2008 40. Austin L, Ozawa M, Kikuchi T, Cardinale I, Austin LM, Coven TR, et al. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon- γ, interlukin-2, and tumor necrosis factor- , defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol, 1999; 113: 752-9. 41. Seifert M, Sterry W, Effenberger E, Rexin A, Friedrich M, Haeussler-Quade A, et al. The antipsoriatic activity of IL-10 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes. Arch Dermatol Res, 2000; 292: 164-72. 42. Adorini L, Trembleau S. Immune deviation towards Th2 inhibits Th1-mediated autoimmune diabetes. Biochem Soc Trans, 1997; 25: 625-9. 43. Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, et al. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med, 2003; 9: 40-6. 44. Kimball AB, Kawamura T, Tejura K, Boss C, Hancox AR, Vogel JC, et al. Clinical and immunologic assessment of patients with psoriasis in a randomized, double-blind, placebo-controlled trial using recombinant human interleukin 10. Arch Dermatol, 2002; 138: 1341-6. 45. Trepicchio WL, Ozawa M, Walters IB, Kikuchi T, Gilleaudeau P, Bliss JL, et al. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest, 1999; 104: 1527-37. 46. Borish LC, Steinke JW. Cytokines and chemokines. J Allergy Clin Immunol, 2003; 111: 460-75. 47. Ozawa M, Aiba S. Immunopathogenesis of psoriasis. Curr Drug Targets Inflamm Allergy, 2004; 3: 137-44. 48. Bissonnette R. Etanercept for the treatment of psoriasis. Skin Therapy Lett, 2006; 11: 1-4. 49. Scherer HU, Burmester GR. Biologicals in the treatment of rheumatic diseases. Dtsch Med Wochenschr, 2006; 131: 2279-85. 50. Immunex Corporation, Enbrel®; (etanercept) package insert; 2005 Thousand Oaks, CA USA. 51. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med, 2003; 349: 2014-22. 52. Baghai M, Osmon DR, Wolk DM, Wold LE, Haidukewych GJ, Matteson EL. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc, 2001; 76: 653-6. 53. Sanchez Carazo JL, Mahiques Santos L, Oliver Martinez V. Safety of etanercept in psoriasis: a critical review. Drug Saf, 2006; 29: 675-85. 54. Kuruvilla J, Leitch HA, Vickars LM, Galbraith PF, Li CH, Al-Saab S, et al. Aplastic anemia following administration of a tumor necrosis factor-alpha inhibitor. Eur J Haematol, 2003; 71: 396-8. 55. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum, 2001; 44: 2862-9. 56. Kormeili T, Lowe NJ, Yamauchi PS. Psoriasis: immunopathogenesis and evolving immunomodulators and systemic therapies; U.S. experiences. Br J Dermatol, 2004; 151: 3-15. 57. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum, 2002; 46: 3151-8. 58. Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol, 2006; 126: 2194-201. 59. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine, 1995; 7: 251-9. 60. Kleyn CE, Griffiths CE. Infliximab for the treatment of psoriasis. Expert Opin Biol Ther, 2006;6:797-805. 61. Centocor Inc., Remicade®; (infliximab) package insert; 2005 Malvern, PA, USA. 62. Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol, 2004; 51: 534-42. 63. Winterfield I, Menter. Psoriasis and its treatment with infliximab-mediated tumor necrosis factor alpha blockade. Dermatol Clin, 2004; 22: 437-47. 64. Chavez-Lopez MA, Delgado-Villafana J, Gallaga A, Huerta-Yanez G. Severe anaphylactic reaction during the second infusion of infliximab in a patient with psoriatic arthritis. Allergol Immunopathol (Madr), 2005; 33: 291-2. 65. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al.

Reviews

MATERIA SOCIO MEDICA

66. 67. 68.

69. 70. 71. 72.

73. 74. 75. 76. 77. 78. 79. 80. 81. 82.

83. 84. 85. 86. 87. 88.

Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med, 2001; 11; 345: 1098-104. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum, 2004; 50: 372-9. Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med, 2002; 112: 78. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum, 1998; 41: 1552-63. Elkayam O, Caspi D. Infliximab induced lupus in patients with rheumatoid arthritis. Clin Exp Rheumatol, 2004; 22: 502-3. GottliebAB. Infliximab for psoriasis. J Am Acad Dermatol, 2003; 49: 112-7. Mease PJ. Adalimumab: an anti-TNF agent for the treatment of psoriatic arthritis. Expert Opin Biol Ther, 2005; 5: 1491-504. Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol, 2006; 55: 598-606. Scheinfeld N. Adalimumab: a review of side effects. Expert Opin Drug Saf, 2005;4:63741. Rychly DJ, DiPiro JT. Infections associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy, 2005; 25: 1181-92. Jacobson CC, Kimball AB. Rethinking the Psoriasis Area and Severity Index: the impact of area should be increased. Br J Dermatol, 2004; 151: 381-7. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis. J Am Acad Dermatol, 2004; 50: 859-66. Finlay AY, Khan GH. Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use. Clin Exp Dermatol, 1994; 19: 210-6. Khilji FA, Gonzalez M, Finlay AY. Clinical meaning of change in Dermatology Life Quality Index scores. Br J Dermatol, 2002; 147:50. Smith CH, Anstey AV, Barker JN, Burden AD, Chalmers RJ, Chandler D, et al. British association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol, 2005; 153: 486-97. Sterry W, Barker J, Boehncke WH, Bos JD, Chimenti S, Christophers E, et al. Biological therapies in the systemic management of psoriasis: International Consensus Conference. Br J Dermatol, 2004; 151: 3-17. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res, 2006; 298: 7-15. Gottlieb AB, Hamilton T, Caro I, Kwon P, Compton PG, Leonardi CL et al. Long-term continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: updated results from an ongoing trial. J Am Acad Dermatol, 2006; 54: 154-63. Papp KA, Tyring S, Lahfa M, Prinz J, Griffiths CE, Nakanishi AM, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol, 2005; 152: 1304-12. Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet, 2005; 366: 1367-74. Feldman SR, Menter A, Koo JY. Improved health-related quality of life following a randomized controlled trial of alefacept treatment in patients with chronic plaque psoriasis. Br J Dermatol, 2004; 150: 317-26. Krueger GG, Langley RG, Finlay AY, Griffiths CE, Woolley JM, Lalla D, et al. Patientreported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial. Br J Dermatol, 2005; 153: 1192-9. Feldman SR, Gordon KB, Bala M, Evans R, Li S, Dooley LT, et al. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol, 2005; 152: 954-60. Shikiar R, Willian MK, Okun MM, Thompson CS, Revicki DA. The validity and responsiveness of three quality of life measures in the assessment of psoriasis patients: results of a phase II study. Health Qual Life Outcomes, 2006; 4: 71.

Corresponding author: Ass. Prof. Asja Prohić, MD, PhD. Department of Dermatovenerology University Clinical center in Sarajevo, B&H. Sarajevo. Bolnička 25. Tel/Fax: + 387 33 213 490. E-mail: [email protected]

173