REVIEW Targeting psoriasis with new therapies

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1 REVIEW Targeting psoriasis with new therapies A. Prohić, H. Helppikangas, J. Muhović Department of Dermatovenerology, Sarajevo University Clinical Centre, Sarajevo, Bosnia and Herzegovina ABSTRACT The pathogenesis of psoriasis is quite complex, but there is compelling evidence that T-cell activation and resultant overproduction of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), are critical for the development and maintenance of psoriatic lesion. The recognition of psoriasis as a T-cell mediated disease has led to the development of the new biologic agents that provide selective, immunologically directed intervention with fewer side-effects and long lasting remission than traditional therapies. These agents are custom-made, protein-like molecules that include monoclonal antibodies, fusion proteins and recombinant cytokines. Several biologic agents are currently recognized for the treatment of moderate to severe psoriasis and psoriatic arthritis. These agents can be categorized into two broad classes based on their mechanism of action: the T cell inhibitors (alefacept and efalizumab) and TNF-α inhibitors (etanercept, infliximab and adalimumab). In this review, we will present an update on the progress of the new biologic agents. The mechanism of each drug will be reviewed, as well as the most recent efficacy and safety data. Key Words: psoriasis, biologic, alefacept, efalizumab, etanercept, infliximab, adalimumab INTRODUCTION Psoriasis is an inflammatory, immune-mediated skin disease characterized by periods of spontaneous remission and relapse (1). For some patients there is an additional burden of psoriatic arthritis which occurs in up to 40% of psoriatic patients (2). Conventional systemic therapies for moderate-to severe psoriasis such as methotrexate, cyclosporine, acitretin or phototherapy have been successfully used as continuous therapy for an extended period. However for some patients, the long-term use of these drugs may be limited by well-established organ toxicities including hepatotoxicity, neprotoxicity and skin cancer (3,4). Before 1980 it was believed that psoriasis was primarily a disease of epidermal keratinocyte hyperproliferation and loss of differentiation, with cutaneous inflammation as secondary feature (5). Psoriasis is now recognized as a T-cell mediated disease in which pathogenic T cells accumulate in diseased skin (6). New understanding of the immunologic basis of psoriasis has led to the emergence of rationally targeted biologic agents that Corresponding author: A.Prohić, Department of Dermatovenerology University Clinical center Bolnička 25, Sarajevo, Bosnia and Herzegovina Tel/Fax: asjaprohic@hotmail.com specifically target the immunopathogenic mechanism of disease (7). The aim of these new therapies is to improve the treatment of psoriasis, particularly moderate to severe psoriasis, with agents that are well tolerated and safe for long-term use. IMMUNOPATHOGENESIS OF PSORIASIS Psoriasis is an immunologically mediated disease caused by activation of T lymphocytes in dermis (which are primarily CD4+ cells) and epidermis (which are predominantly CD8+ cells) (8). The activation of T-cells is dependent upon its binding with the antigen presenting cells (APCs). This process is mediated through surface molecules used for adhesions including leukocyte function associated antigen (LFA)-1 and CD2 on the T cells and intercellular adhesion molecule (ICAM)-1 and LFA-3 on the APCs (9,10). The T-cell receptor (TCR) for the specific T-cell recognizes an antigen presented on the major histocompatibility complex (MHC I or II) by the APC (11). Activated T cells proliferate and enter the circulation via trafficking through the interaction between LFA-1 and ICAM-1 and extravasate via diapedesis through the endothelium at site of inflammation in the skin. At this point, the T-cells propagate the immunologic process through the secretion of proinflam- 56

2 Medicinski glasnik, Volume 4, Number 2, August 2007 matory (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 (12, 13). Each type of cytokine downregulates the other s responses (14). 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 (7,15). CONVENTIONAL SYSTEMIC THERAPIES FOR PSORIASIS Moderate to severe psoriasis is considered to be a disease for which additional systemic therapy is appropriate. The most frequently used conventional systemic therapies include methotrexate, cyclosporine, retinoids or phototherapy. Methotrexate has traditionally been used for the treatment of moderate-to-severe psoriasis, especially if arthritis or nail involvement is present (16). This drug has been associated with adverse effects including hepatotoxicity, myelosuppression, oral ulcers and pulmonary fibrosis with chronic usage (17). A liver biopsy is recommended after 1.5 g of methotrexate (18). Cyclosporine is another systemic agent used in the treatment of severe psoriasis. An advantage of this medication is its effectiveness in obtaining rapid clearance of psoriasis (19, 20). Like methotrexate, cyclosporine is associated with adverse effects, the most commonly being hypertension and nephrotoxicity that limit longterm use (21). The first two drugs give significant clearing, greater than 75% in the majority of cases (22), whereas systemic retinoids (e.g. acitrein or etretinate) are significantly less effective as monotherapy, but may approach methotrexate and cyclosporine in efficacy if combined with phototherapy (23). Serious adverse effects associated with retinoids include teratogenicity and mucocutaneous toxicity (24). The most commonly used way of phototherapy is PUVA which is which is psoralen plus ultraviolet light. PUVA decreases cellular proliferation by interfering with DNA synthesis, and also induces a localized immunosuppression by its action on T lymphocytes (25). Long-term complications include increased risk of photo damage and skin cancer (26,27). Due to the long-term potential toxicities of these therapies, an effective strategy is needed to wean patients from these systemic agents. BIOLOGIC THERAPIES FOR PSORIASIS Biologics are a set of different engineered proteins that are used to modify immune reactions. There are three distinct classes of biologic agents: monoclonal antibodies, fusion proteins and recombinant cytokines or growth factors (28). One of the advantages of some biological agents is that they have been used for several years in other indications, such as rheumatoid arthritis (29) and Crohn s disease (30), and have established safety profiles that dermatologists can use as a guide in treatment. The nomenclature of the biologics is clinically important. Generic names of chimeric monoclonals end with -ximab, humanized monoclonals end with -zumab and human monoclonal antibodies end with -umab. Receptor-antibody fusion proteins end with -cept (7). According to the guidelines provided by the British Association of Dermatologists, the biologic agents should be utilized in patients with severe disease who have failed previous systemic therapies, where these therapies are contraindicated because of comorbid disease, or who have psoriatic arthritis. The patient must have severe disease defined as Psoriasis Area and Severity Index (PASI) score of 10 or more (31). PASI is the primary endpoint used in studies assessing the efficacy of biologics for the treatment of psoriasis. PASI reference 75 signifies a 75% reduction of the pretreatment index and is used to evaluate therapeutic success. When a 50% increase of this index appears after a period of improvement, the disease is considered recurrent (32). There are currently five available biologic agents recognized for treating moderate-to-severe psoriasis and/ or psoriatic arthritis: alefacept, efalizumab, etanercept, infliximab and adalimumab. These agents comprise two main groups: agents that target pathogenic activated T cells and APCs (alefacept and efalizumab), and agents that target cytokine TNF-α (etanercept, infliximab and adalimumab) (Table 1, Figure 1) (33). 57

3 Prohić et al. Psoriasis new therapies Table 1 Biologic therapies for psoriasis Agents targeting T-cells or APCs DRUG Molecule Type Mechanism of Action Dose / Duration Side effects Reduces memory-effector T cells; 15 mg IM once weekly 12 Alefacept Human fusion protein Decrease in CD + count binds CD2 on CD45RO + cells weeks 0.7 mg/kg one dose, then I Fly-like symptoms Humanized monoclonal Inhibits T-cell migration and Efalizumab mg/kg weekly (maximum Thrombocytopenia Rebound antibody activation; binds CD11 and LFA-1 single dose 200 mg) upon discontinuation Agents targeting cytokines 50 mg SC twice weekly 3 Injection site reaction Aplastic Etanercept Human fusion protein TNF-a inhibitor Infliximab Adalimumab Chimeric monoclonal antibody Fully human monoclonal antibody TNF-a inhibitor TNF-a inhibitor months then 50 or 25 mg weekly 3 mg/kg, 5 mg/kg or 10 mg/kg IV at week 0,2,5 than every 8 weeks 40 mg SC once a week or 40 mg every other week anemia Demyielinating disorders ANA seroconversion Infusion reactions Reactivation of tuberculosis Neutralizing antibodies Congestive heart failure Injection site reactions Reactivation of tuberculosis Development of antibody formation disorders Demyelinating Biologic agents targeting T cells or antigen presenting cells Alefacept is a human fusion protein that is composed of the 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. (34). Alefacept also induces selective apoptosis of memory-effector T-cells by binding to the FcγRIII receptor on natural killer cells and macrophages (35). Alefacept was the first biological agent approved for the treatment of moderate-to severe psoriasis. There is not, however, a similar approval in EU. The recommended regimen of alefacept is once-weekly 15 mg intramuscular (IM) injections, given for 12 weeks (Biogen Idec Inc, Amevive ; alefacept package insert; Cambridge, MA, USA, 2005). In an international, randomized, double-blind, placebocontrolled, parallel-group trial with total of 507 patients with chronic plaque psoriasis, patients were administered either 10 mg of alefacept or 15 mg of alefacept once weekly for 12 weeks, followed by 12 weeks of observation. In the 15 mg group, 33% patients achieved 75% reduction in PASI, 2 weeks after the last dose and 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up. Comparatively, 28% patients achieved 75% reduction in PASI in the 10 mg group (36). Adverse events reported from clinical trials appear minimal include headache, pruritus, infection, rhinitis, injection site pain and injection site inflammation. Alefacept reduces total lymphocyte count and CD4+ and CD8+cell counts, but there is no evidence that this significantly affects overall immune function (37). To date, no clinically significant signs of immunosuppression or opportunistic infections and no increase of malignancy have been observed (38). However, alefacept has been studied for a few years and long-term safety data are needed. Figure 1. Sites of action of biologic agents Efalizumab is a humanized monoclonal antibody directed against the CD11a molecule. CD11a and CD18 comprise subunits of LFA-1, which plays a critical role 58

4 Medicinski glasnik, Volume 4, Number 2, August 2007 in allowing T-cells to adhere to other cell types. Binding of efalizumab to CD11a blocks the interaction between LFA-1 and ACAM-1, its partner molecule for the adhesion (39). Psoriasis-inducing T-cells are thereby prevented from being activated by the APCs and from binding to the blood vessel wall migrating into skin (40). Efalizmab is approved for the treatment of moderate to severe psoriasis but not for psoriatic arthritis. The licensed dose of efalizumab is 1 mg/kg weekly as a subcutaneous (SC), self administered injection for 12 weeks, following a first conditioning dose of 0.7 mg/ kg, with the recommendation that treatment should be continued only in those who respond (Genentech Inc, Raptiva ; efalizumab package insert; South San Francisco, CA, USA, 2005). The safety and efficacy of efalizumab has been evaluated in four large studies in 2000 patients with moderate-to-severe chronic plaque psoriasis, most of whom had received previous systemic therapy for psoriasis (41-44). Efalizumab appears to be effective, with 27% of patients receiving a dose of 1 mg/kg weekly, achieving PASI 75 compared to 4% in placebo group by week 12. Continuation of therapy beyond 12 weeks increases the response rate further: after 24 weeks 43.8% of patients achieved PASI-75. The relapse of psoriasis is usually evident about 2 months of discontinuation of therapy and rebound in approximately 5% of the patients, as defined by flaring>125% of baseline. The commonest side effects were headache, chills, fever, nausea, vomiting, or myalgia occurring on the day of injection or in the following two days during the initial three weeks of therapy (41-44). Adverse effects associated with this drug are a rebound phenomenon post discontinuation of therapy and a worsening of disease in unresponsive patients during therapy (45). Biologic agents targeting cytokine TNF-α Etanercept is a recombinant fusion protein consisting of two TNF receptors fused to the Fc portion of human IgG antibody. This construct creates an exogenous TNF receptor and prevents excess TNF from binding to cell-bound receptors. The end result is a reduction of active TNF (46). Etanercept is the only biologic agent approved for both psoriasis and psoriatic arthritis. 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 (Immunex Corporation, Enbrel ; etanercept package insert; Thousand Oaks, CA, USA, 2005). Two randomized controlled trials involving about 1000 patients with moderate to severe chronic plaque psoriasis indicate that etanercept is an effective treatment for chronic plaque psoriasis (47,48). In a 24-week, double blind study, efficacy of etanercept at different doses was compared with placebo. At week 12, there was an improvement from a base line of 75 percent or more in the PASI, in 4% of the patients in the placebo group, 14% in the low-dose etanercept group (25 mg once weekly), 34% in the medium-dose group (25 mg twice weekly) and 49 % in the high-dose group (50 mg twice weekly). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75% improvement in PASI in 25% of the patients in the low-dose group, 44% in the medium-dose group and 59% in the high-dose group. Of patients achieving PASI 75 response at 24 weeks of therapy, 11% remained in remission for 1 year. In clinical trials etanercept was generally well tolerated. The most commonly reported adverse was reaction at the site of injection, characterized by erythema and edema at injection sites and are usually mild. Rare cases of aplasic anemia and central nervous system demyelinating diseases such as optic neuritis and multiple sclerosis have also been described as potential adverse events (49). Infliximab is a chimeric (mouse-human) IgG1 monoclonal antibody that binds to TNF-α. It also inhibits production of other pro-inflammatory cytokines, reducing cell infiltration and eventually keratinocyte proliferation (50). Infliximab has been approved for the treatment of moderate to severe psoriasis and for the treatment of PsA. 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 maintenance dosing every eight weeks (Centocor Inc., Remicade ; infliximab package insert; Malvern, PA, USA, 2005). In two randomized placebo-controlled trials (51,52) in patients with moderate to severe stable chronic plaque psoriasis, 75% improvement in PASI scores at week 10 has been noted in 72% of patients treated with infliximab (3 mg/kg) and 88% of patients treated with infliximab (5 mg/kg) compared with 6% of patients treated with placebo. Improvement was observed in both infliximab groups as early as 2 weeks. The authors concluded that infliximab treatment resulted in a rapid and significant improvement in the signs and symptoms of psoriasis. 59

5 Prohić et al. Psoriasis new therapies Commonly reported side effects include headaches and infusion reactions, the vast majority of which were classified as mild (52); however, a severe adverse event such as anaphylactic reactions have been described, although in less than 1% of patients (53). Another concern is increased risk of reactivating latent tuberculosis (54) and invasive fungal infections, such as histoplasmosis (55). The risk of lymphoma appears to be slightly increased (54), but this may be to a higher risk of lymphoma in the patient population in which this drug has been used (56). Adalimumab is a human IgG1 monoclonal antibody specific for TNF-a, binding both soluble and membrane-bound forms of this cytokine (57). This drug is approved for the treatment of both psoriatic arthritis and is currently undergoing clinical trials for psoriasis. 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 (58). In the recent clinical trial, adalimumab is demonstrated to be also effective for the treatment of psoriasis. At week 12, 53% of patients taking adalimumab every other week, 80% of patients taking adalimumab weekly, and 4% of patients taking placebo achieved 75% improvement in PASI score. Responses were sustained for 60 weeks (58). From the clinical trials for rheumatoid arthritis, the most common adverse events reported were headache, injection site reactions, nausea, abdominal pain and respiratory infections (59). 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 adalimumab and autoantiobodies. 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 (60). Table 2 summarizes the efficacies of the biologic agents determined by PASI score. The biologic agents have revolutionized the management of chronic disease such as rheumatoid arthritis and Crohn s disease, and more recently have started to impact significantly the management of psoriasis. Currently they comprise two main groups: agents that target T cells or APCs (alefacept and efalizumab) and agents that target the cytokine TNF-alpha (etanercept, infliximab and adlimumab). Each currently available biologic agent is unique and offers different benefits and challenges to physicians who chose to incorporate them into their practice. The clear advantage of biologic agents is that they may be less toxic than the traditional systemic therapies when administrated over the long period. Biologic therapies for moderate to severe psoriasis provide dermatologist new options for the long-term management of this disease, more prolonged remission and improved quality of life. Although these agents do not have known organ toxicity as with long-term use of traditional systemic therapy, the patient must be carefully selected and monitored to avoid or identify and manage potential adverse reactions. However, the long term safety profile of biologics still needs to be established. Biologic treatments significantly improve the quality of life of psoriasis patients; however, they are significantly more expensive than traditional therapies. The costs and benefits of biologic therapies should be compared to those of traditional treatments when considered for treatment of psoriasis patients. Table 2. Efficacy of biologic agents DRUG Alefacept Efalizumab Etanercept Infliximab Adalimumab Dosage 10 mg IM once weekly 15 mg IM once weekly 1mg/kg SC weekly 1mg/kg SC weekly 25 mg SC once weekly 25 mg SC twice weekly 50 mg SC twice weekly 3 mg/kg IV at weeks 0, 2, 6 5 mg/kg IV at weeks 0, 2, 6 40 mg SC every other week 40 mg SC weekly Percent of patients achieving PASI 75 at week 12 28% 33% (25) 22% 28% (31-34) 14% 34% 49% (38,39) 72% 88% (43,44) 53% 80% (50) 60

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