Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two Category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. Toral Patel, M.D., and Kenneth B. Gordon, M.D., review some of the new biologic agents approved or in development for psoriasis. At the end of this article, you will find a 10-question exam. Mark your responses in the designated area and fax page 73 to HMP Communications at (610) 560-0501. Approximately 1 month after the publication date, we’ll post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. CME #118 March 2004 P soriasis is a chronic, potentially debilitating disease with a prevalence of approximately 2% worldwide; rates vary by ethnicity and geography.1 The most common form of the disease, occurring in more than 80% of cases, is plaque psoriasis, characterized by sharply demarcated, erythematous, scaling plaques. Psoriasis patients may also have psoriatic arthritis, an inflammatory arthropathy that affects 5% to 40% of psoriasis patients. Psoriatic arthritis can be significantly disabling as well as progressively destructive.2 Current psoriasis therapies include topical preparations, phototherapy and systemic medications. For those patients with extensive disease, topical therapy is not always feasible or effective, making phototherapy and/or systemic therapy indicated. Traditional systemic treatments in-clude methotrexate, cyclosporine, psoralen with ultraviolet A (PUVA) and oral retinoids. All of these medications carry with them the potential for harmful side effects. Most prominently, methotrexate is associated with hepatotoxicity and bone marrow toxicity, cyclosporine with cardiovascular changes and nephrotoxicity, PUVA with the development of skin cancer, and the retinoids with teratogenicity, hyperlipidemia, alopecia and bony abnormalities.3 While rotational strategies have been developed to minimize the toxicity of these systemic medications, there remains a need for effective drugs that can be used for the lifetime of the patient’s disease with a more acceptable side effect profile. The phenotypic expression of psoriasis is due to hyperproliferation and decreased maturation of keratinocytes. These changes are induced by an inflammatory response driven by T cells, local dendritic cells and macrophages, as well as the activated keratinocytes.4-6 The understanding of the central role of this inflammatory reaction in the pathogenesis of psoriasis has given rise to a new class of medications, known collectively as biologics; each of these biologics targets specific interactions along the T-cell activation and trafficking pathways.7 This review will discuss four of the new biologic agents approved or in development for psoriasis: alefacept (Amevive), efalizumab (Raptiva), etanercept (Enbrel) and infliximab (Remicade). Alefacept Alefacept is a fully human fusion protein consisting of a segment of lymphocyte function-associated antigen-3 (LFA-3) fused to the Fc segment of IgG1. Alefacept may work by two potential mechanisms: the LFA-3 segment binds CD2 on the T-cell surface, inhibiting T-cell activation and proliferation, and/or the IgG1 segment binds to accessory cells, triggering apoptosis of selected memory T cells expressing high levels of CD2 on the surface.8 A Phase III, randomized, double-blind, placebo-controlled trial of two 12-week treatment courses of intravenous alefacept (7.5 mg) in patients with chronic plaque psoriasis (n=553) demonstrated durable clinical improvements, as measured by changes in the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). In this study, patients were randomized to receive two 12-week courses of either once-weekly alefacept or placebo. Patients were followed for 12 weeks after each course. The primary efficacy parameter was the percentage of patients with a 75% or greater reduction in PASI (PASI 75) 2 weeks after the last dose of course one. Safety and tolerability were monitored by adverse events, laboratory tests (including CD4 and CD8 counts), vital signs, physical examinations and anti-alefacept antibodies. Two weeks after the last dose of course one, 14% of alefacept-treated patients had achieved a PASI 75 or greater, versus 4% of placebo-treated patients. The alefacept-treated patients who achieved at least a PASI 75 maintained at least a 50% reduction in their PASI score for a median duration of more than 7 months. A second course of treatment improved efficacy; 2 weeks after the last dose of course two, 26% of patients had achieved at least a PASI 75 and 55% of patients a PASI 50 or greater. Both courses were equally well tolerated. During course one, alefacept-treated patients had a higher incidence of chills than placebo-treated patients; greater than 90% of cases occurred within 24 hours of treatment after the first few doses. In course two, accidental injury and pharyngitis were observed more frequently in the alefacept group than in the placebo group. Throughout the study, no opportunistic infections and no association of infections with CD4+ T-cell counts less than 250 cells/ml were observed.8 IM Alefacept Another Phase III, multicenter, randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of intramuscular (IM) alefacept in the treatment of chronic psoriasis (n=507). Patients were randomized in a 1:1:1 ratio to receive 10 mg alefacept, 15 mg alefacept or placebo once weekly for 12 weeks followed by a 12-week observation period. Lymph-ocyte counts were obtained at all study visits during the treatment period; if a patient’s CD4+ count from the prior week was lower than 250/ml, the scheduled dose was substituted with placebo. If the CD4+ count remained below 250/ml for 4 consecutive weeks, the active drug was permanently substituted with placebo. The primary efficacy parameters were changed in PASI from baseline, percentage of patients achieving PASI 50 and PASI 75, and a PGA of “clear” or “almost clear.” PASI and PGA were evaluated throughout the treatment and observation periods. Alefacept was well tolerated during the IM study and again produced a long-lasting clinical response. Mean reductions in PASI reached a maximum of 46%, 41% and 25% in the 15 mg, 10 mg and placebo groups, respectively. Twelve weeks after treatment end, the mean PASI score in both alefacept groups had not returned to baseline values; no patient had rebound or flare of disease activity after withdrawal of therapy. The percentage of patients achieving either a PASI 50 or PASI 75 was higher in the alefacept groups than in the placebo group. The overall response rates for PGA of “clear” or “almost clear” were 24%, 22% and 8% of patients in the 15 mg, 10 mg and placebo groups, respectively. Safety of Alefacept Adverse events that occurred at an incidence of at least 5% higher in either alefacept group than placebo included headache, pruritus, infection (most frequently common cold), rhinitis and injection site reactions. No association was found between incidence of infections and decreased CD4+ cell counts.9 Treatment with alefacept does not blunt immune responses to novel and recall antigens, as shown in a multicenter, randomized, open-label, parallel-group study. Current data indicate that alefacept may not significantly affect the ability of host defenses to mount an appropriate immune response to pathogens and therefore does not increase susceptibility to infection or malignancy.10 However, the true safety profile of alefacept in regard to infection and malignancy can only be determined after long-term clinical observation. The FDA approved both the IM and IV formulations of alefacept for the treatment of psoriasis in January 2003. At this time, only the intramuscular form of alefacept is available for commercial use. Alefacept is indicated for the treatment of moderate to severe plaque type psoriasis in patients who are candidates for systemic therapy or phototherapy. Alefacept is given weekly in the physician office for 12 weeks, then followed by a 12-week observation period. In the research studies, the median time to maximal improvement in psoriasis is 8 weeks after the last dose. Thus, some patients should continue to improve during the observation period.11 Efalizumab The interaction between adhesion molecules LFA-1 (lymphocyte function associated antigen-1) and ICAM-1 (intercellular adhesion molecule-1) has been implicated in the pathogenesis of psoriasis. LFA-1 is characterized by heterodimers with a common beta chain (CD18) and a unique alpha chain (CD11a), and is expressed only on leukocytes. ICAM-1, a receptor for LFA-1, is expressed on multiple cells, including T cells, endothelial cells and epidermal keratinocytes.12 The binding of these cell surface molecules plays an important role in T-cell activation, migration into the dermis and binding to keratinocytes. Previous studies have shown that the expression of ICAM-1 on keratinocytes of psoriatic lesions correlates with the clinical severity of the lesion as well as with the size of the dermal infiltrate.13 Efalizumab binds the CD11a subunit of LFA-1 and effectively blocks the physiologic function of this interaction. Efalizumab (anti-CD11a) is a humanized form of a murine antibody against CD11a, the unique alpha subunit of LFA-1.14 Phase I/II studies demonstrated that intravenous (IV) efalizumab administered as a single dose or as multiple weekly doses produced histologic and immunobiologic changes that correlated to its clinical activity, as evidenced by a dose-dependent reduction in PASI. T-cell surface CD11a expression was downmodulated; there was an inverse relationship between this downmodulation and histologic evidence of improvement.15,16 A subsequent Phase II, randomized, double-blind placebo-controlled, multi-center trial, in which patients received IV efalizumab or placebo for 8 weeks, confirmed the histologic improvement and clinical response seen in the Phase I/II studies.17 The incidence of acute adverse events (occurring within 24 hours of administration) was higher in the efalizumab group than placebo. Events included headache, fever, chills, nausea and vomiting. Incidence was highest after the first dose and decreased with subsequent infusions. SC Formulation of Efalizumab Open-label studies of a subcutaneous (SC) formulation of efalizumab demonstrated a clinical response, histologic improvement and safety profile comparable to the IV results. The SC route was chosen for the Phase III trials.14 Efalizumab was evaluated in four randomized, double-blind, placebo-controlled studies for the treatment of chronic plaque psoriasis in adult patients. Patients were randomized to receive once-weekly efalizumab 1 mg/kg, 2 mg/kg or placebo. The only allowed concomitant medication was a low-potency topical steroid. In all four studies, efalizumab-treated patients demonstrated marked clinical improvement compared to placebo-treated patients, as measured by the PASI and PGA. Of efalizumab-treated patients, 22% to 39% achieved the primary endpoint of PASI 75, compared to 2% to 5% of placebo-treated patients. Also, 19% to 32% of patients in the efalizumab group achieved a static PGA assessment of “minimal” or “clear,” compared to 3% to 4% of patients in the placebo group. Adverse events occurring at a rate of 2% or higher in the efalizumab group than in the placebo group included headache, infection, chills, nausea, pain, myalgia, flu syndrome, fever, back pain and acne.18-20 Although statistically significant improvements were seen after 12 weeks and 24 weeks of therapy, results of these trials suggest that patients would derive optimal therapeutic benefit from prolonged efalizumab therapy, especially since some patients have shown disease exacerbation at the end of the dosing period.14,18 Current Phase III studies are attempting to determine the optimal strategies for withdrawal of efalizumab therapy.14 The FDA approved subcutaneous efalizumab for the treatment of adults with moderate to severe plaque psoriasis in October 2003. Anti-TNF therapies Current evidence strongly suggests that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) plays a significant role in the pathogenesis of psoriasis and psoriatic arthritis.5,21,22 At this time, there are three agents that bind and inactivate TNF-alpha: etanercept, infliximab and adalimumab (Humira). These medications are currently approved for the treatment of rheumatoid arthritis and, in the case of etanercept, psoriatic arthritis. However, there is a significant amount of data pertaining to treatment of psoriasis with etanercept and infliximab that will be reviewed below. Adalimumab is currently in its initial clinical trials for psoriasis. Etanercept Etanercept is a fully human dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF-alpha receptor linked to the Fc portion of human IgG1. It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system.23 Etanercept is the first FDA-approved medication for the treatment of psoriatic arthritis; it is also indicated for rheumatoid arthritis (RA) and polyarticular-course juvenile rheumatoid arthritis (JRA). Etanercept has been extensively studied for rheumatoid arthritis and has been available for use in the United States since 1998. In a long-term RA treatment study, etanercept was found to be safe and well-tolerated; its clinical benefit was sustained for a median of more than 2 years and for as long as almost 5 years.24 The use of etanercept as monotherapy for psoriasis was studied in a Phase III, double-blind, placebo-controlled, crossover 24-week study. For this study, 652 patients were randomized to receive subcutaneous etanercept at a low dose (25 mg/week), medium dose (25 mg twice/week), high dose (50 mg twice/week) or placebo. At week 12, patients in the placebo group began treatment with etanercept 25 mg twice/week. The primary efficacy measure was the percentage of patients in each treatment group who achieved at least a PASI 75 at week 12. Assessments of adverse events, infections and laboratory data were performed throughout the study. This Phase III study of etanercept for psoriasis demonstrated a statistically significant improvement in the etanercept group as compared to placebo. At week 12, the percentages of patients who achieved at least a PASI 75 were 4%, 14%, 34% and 49% in the placebo, low-dose, medium-dose and high-dose groups, respectively. The percentages of patients who achieved at least a PASI 50 were 14%, 41%, 58% and 74%, respectively. At week 12, patients in the placebo group crossed over to etanercept therapy and patients in all treatment groups were followed to 24 weeks. At week 24, the percentage of patients who had achieved at least a PASI 75 were 25%, 44% and 59% in the low-dose, medium-dose and high-dose treatment groups, respectively. After 24 weeks, 58%, 70% and 77% of patients, respectively, achieved at least a PASI 50. Etanercept was well tolerated during this study, with the most commonly reported adverse events being injection-site reactions, headaches and upper respiratory infections.25 Using Etanercept Safely Although the safety of etanercept has been established in clinical trials and post-marketing surveillance, certain considerations and precautions should be taken before prescribing this medication. In post-marketing reports, serious infections and sepsis, including fatalities, have been reported. Many of the serious infections occurred in patients on concomitant immunosuppressants. Rare cases of tuberculosis have been reported in patients treated with TNF antagonists, including etanercept.23 Although the FDA does not require TB screening prior to starting etanercept, it’s recommended by physicians who have considerable experience with the medication.26 Rare cases of new onset or exacerbation of central nervous system demyelinating disorders have also been reported in post-marketing surveillance of etanercept.23 No clinical trials have evaluated etanercept therapy in patients with demyelinating diseases, but other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity.27-29 Rare reports of pancytopenia including aplastic anemia, some with a fatal outcome, have also been reported with etanercept; the causal relationship to etanercept therapy remains unclear. Prescribers should exercise caution when using etanercept in patients with CNS demyelinating disorders or hematologic abnormalities.23 Infliximab Infliximab is a chimeric IgG1 monoclonal antibody, composed of human constant and murine variable regions, that binds specifically to human TNF-alpha.30 Infliximab neutralizes the biological activity of TNF-alpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of TNF-alpha with its receptors.31,32 It is given as an intravenous infusion over 2 to 3 hours. Infliximab is an FDA-approved treatment for Crohn’s disease and rheumatoid arthritis. A placebo-controlled, double-blind, randomized study evaluated the safety and efficacy of infliximab as monotherapy for plaque psoriasis.33 In this study, 33 adult patients with a >6-month history of moderate to severe plaque psoriasis involving at least 5% of the body surface area were randomized to receive infliximab 5 mg/kg/wk, 10 mg/kg/wk or placebo at weeks 0, 2 and 6. Patients did not use any other psoriasis treatment during the study, except for non-medicated emollients and non-prescription tar or salicylic shampoos. The primary efficacy endpoint was the PGA at week 10; a positive response was defined as attaining a PGA of good, excellent or clear. A secondary endpoint was improvement in PASI; a favorable response was defined as a 75% improvement in PASI from baseline. At the week 10 evaluation, a significant clinical benefit and rapid response time was seen in the infliximab groups compared to placebo. At 10 weeks, 82% of patients in the 5 mg/kg group and 91% in the 10 mg/kg group achieved the primary endpoint of a good, excellent or clear PGA rating, compared with 18% of patients in the placebo group. The secondary efficacy endpoint, a PASI 75, was reached by 82% of patients in the 5 mg/kg group, 73% of patients in the 10 mg/kg group and 18% in the placebo group. Infliximab was well tolerated in this study — headache was the only adverse event more frequently reported in the infliximab groups (with a greater proportion of 10 mg/kg patients than 5 mg/kg patients) than the placebo group. Open-Label Infliximab Study In an open-label follow-up of this study, all patients were categorized as either responders or non-responders at the 10-week visit and the treatment assignment was unblinded. Non-responders in the placebo group were then randomized to receive open-label infliximab 5 mg/kg or 10 mg/kg at weeks 10, 12 and 16. Responders in the placebo group were followed for relapse and then offered treatment in the same manner as the placebo non-responders. Non-responders in the infliximab 5 mg/kg group were offered a single dose of infliximab 10 mg/kg and followed up for response; non-responders in the 10 mg/kg group were discontinued from the study. Patients who responded to treatment with infliximab 5 mg/kg or 10 mg/kg were followed up for relapse and offered single dose infusions of the drug upon relapse. All patients were followed to 26 weeks after the first dose of infliximab. The primary endpoint for the open-label extension study was the percent change from baseline PASI, which was used to evaluate the durability of response to infliximab. At the 26-week evaluation of all patients treated with infliximab, 57% maintained a PASI 50 and 50% maintained a PASI 75 in the absence of any further treatment after the initial three infusions of infliximab.34 A large, Phase III, multi-center, randomized, double-blind, placebo-controlled study of repeat courses of infliximab for plaque psoriasis is currently underway. Looking to the Future The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. While these medications are an addition to the therapeutic choices for this disease, physicians should consider all forms of anti-psoriasis therapy, including topical treatments, phototherapy and traditional systemic agents when considering the use of a biologic. Newer biologic agents continue to be developed (see table above). These agents can be directed against previously identified targets using new technology to improve on the medication or could be directed against entirely new targets. Thus, biologic agents are, and will likely continue to be, an important advancement in the treatment of psoriasis to improve the lives of patients with this debilitating disease.
CME #118 March 2004Biologic Immunotherapy and Psoriasis
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two Category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. Toral Patel, M.D., and Kenneth B. Gordon, M.D., review some of the new biologic agents approved or in development for psoriasis. At the end of this article, you will find a 10-question exam. Mark your responses in the designated area and fax page 73 to HMP Communications at (610) 560-0501. Approximately 1 month after the publication date, we’ll post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. CME #118 March 2004 P soriasis is a chronic, potentially debilitating disease with a prevalence of approximately 2% worldwide; rates vary by ethnicity and geography.1 The most common form of the disease, occurring in more than 80% of cases, is plaque psoriasis, characterized by sharply demarcated, erythematous, scaling plaques. Psoriasis patients may also have psoriatic arthritis, an inflammatory arthropathy that affects 5% to 40% of psoriasis patients. Psoriatic arthritis can be significantly disabling as well as progressively destructive.2 Current psoriasis therapies include topical preparations, phototherapy and systemic medications. For those patients with extensive disease, topical therapy is not always feasible or effective, making phototherapy and/or systemic therapy indicated. Traditional systemic treatments in-clude methotrexate, cyclosporine, psoralen with ultraviolet A (PUVA) and oral retinoids. All of these medications carry with them the potential for harmful side effects. Most prominently, methotrexate is associated with hepatotoxicity and bone marrow toxicity, cyclosporine with cardiovascular changes and nephrotoxicity, PUVA with the development of skin cancer, and the retinoids with teratogenicity, hyperlipidemia, alopecia and bony abnormalities.3 While rotational strategies have been developed to minimize the toxicity of these systemic medications, there remains a need for effective drugs that can be used for the lifetime of the patient’s disease with a more acceptable side effect profile. The phenotypic expression of psoriasis is due to hyperproliferation and decreased maturation of keratinocytes. These changes are induced by an inflammatory response driven by T cells, local dendritic cells and macrophages, as well as the activated keratinocytes.4-6 The understanding of the central role of this inflammatory reaction in the pathogenesis of psoriasis has given rise to a new class of medications, known collectively as biologics; each of these biologics targets specific interactions along the T-cell activation and trafficking pathways.7 This review will discuss four of the new biologic agents approved or in development for psoriasis: alefacept (Amevive), efalizumab (Raptiva), etanercept (Enbrel) and infliximab (Remicade). Alefacept Alefacept is a fully human fusion protein consisting of a segment of lymphocyte function-associated antigen-3 (LFA-3) fused to the Fc segment of IgG1. Alefacept may work by two potential mechanisms: the LFA-3 segment binds CD2 on the T-cell surface, inhibiting T-cell activation and proliferation, and/or the IgG1 segment binds to accessory cells, triggering apoptosis of selected memory T cells expressing high levels of CD2 on the surface.8 A Phase III, randomized, double-blind, placebo-controlled trial of two 12-week treatment courses of intravenous alefacept (7.5 mg) in patients with chronic plaque psoriasis (n=553) demonstrated durable clinical improvements, as measured by changes in the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). In this study, patients were randomized to receive two 12-week courses of either once-weekly alefacept or placebo. Patients were followed for 12 weeks after each course. The primary efficacy parameter was the percentage of patients with a 75% or greater reduction in PASI (PASI 75) 2 weeks after the last dose of course one. Safety and tolerability were monitored by adverse events, laboratory tests (including CD4 and CD8 counts), vital signs, physical examinations and anti-alefacept antibodies. Two weeks after the last dose of course one, 14% of alefacept-treated patients had achieved a PASI 75 or greater, versus 4% of placebo-treated patients. The alefacept-treated patients who achieved at least a PASI 75 maintained at least a 50% reduction in their PASI score for a median duration of more than 7 months. A second course of treatment improved efficacy; 2 weeks after the last dose of course two, 26% of patients had achieved at least a PASI 75 and 55% of patients a PASI 50 or greater. Both courses were equally well tolerated. During course one, alefacept-treated patients had a higher incidence of chills than placebo-treated patients; greater than 90% of cases occurred within 24 hours of treatment after the first few doses. In course two, accidental injury and pharyngitis were observed more frequently in the alefacept group than in the placebo group. Throughout the study, no opportunistic infections and no association of infections with CD4+ T-cell counts less than 250 cells/ml were observed.8 IM Alefacept Another Phase III, multicenter, randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of intramuscular (IM) alefacept in the treatment of chronic psoriasis (n=507). Patients were randomized in a 1:1:1 ratio to receive 10 mg alefacept, 15 mg alefacept or placebo once weekly for 12 weeks followed by a 12-week observation period. Lymph-ocyte counts were obtained at all study visits during the treatment period; if a patient’s CD4+ count from the prior week was lower than 250/ml, the scheduled dose was substituted with placebo. If the CD4+ count remained below 250/ml for 4 consecutive weeks, the active drug was permanently substituted with placebo. The primary efficacy parameters were changed in PASI from baseline, percentage of patients achieving PASI 50 and PASI 75, and a PGA of “clear” or “almost clear.” PASI and PGA were evaluated throughout the treatment and observation periods. Alefacept was well tolerated during the IM study and again produced a long-lasting clinical response. Mean reductions in PASI reached a maximum of 46%, 41% and 25% in the 15 mg, 10 mg and placebo groups, respectively. Twelve weeks after treatment end, the mean PASI score in both alefacept groups had not returned to baseline values; no patient had rebound or flare of disease activity after withdrawal of therapy. The percentage of patients achieving either a PASI 50 or PASI 75 was higher in the alefacept groups than in the placebo group. The overall response rates for PGA of “clear” or “almost clear” were 24%, 22% and 8% of patients in the 15 mg, 10 mg and placebo groups, respectively. Safety of Alefacept Adverse events that occurred at an incidence of at least 5% higher in either alefacept group than placebo included headache, pruritus, infection (most frequently common cold), rhinitis and injection site reactions. No association was found between incidence of infections and decreased CD4+ cell counts.9 Treatment with alefacept does not blunt immune responses to novel and recall antigens, as shown in a multicenter, randomized, open-label, parallel-group study. Current data indicate that alefacept may not significantly affect the ability of host defenses to mount an appropriate immune response to pathogens and therefore does not increase susceptibility to infection or malignancy.10 However, the true safety profile of alefacept in regard to infection and malignancy can only be determined after long-term clinical observation. The FDA approved both the IM and IV formulations of alefacept for the treatment of psoriasis in January 2003. At this time, only the intramuscular form of alefacept is available for commercial use. Alefacept is indicated for the treatment of moderate to severe plaque type psoriasis in patients who are candidates for systemic therapy or phototherapy. Alefacept is given weekly in the physician office for 12 weeks, then followed by a 12-week observation period. In the research studies, the median time to maximal improvement in psoriasis is 8 weeks after the last dose. Thus, some patients should continue to improve during the observation period.11 Efalizumab The interaction between adhesion molecules LFA-1 (lymphocyte function associated antigen-1) and ICAM-1 (intercellular adhesion molecule-1) has been implicated in the pathogenesis of psoriasis. LFA-1 is characterized by heterodimers with a common beta chain (CD18) and a unique alpha chain (CD11a), and is expressed only on leukocytes. ICAM-1, a receptor for LFA-1, is expressed on multiple cells, including T cells, endothelial cells and epidermal keratinocytes.12 The binding of these cell surface molecules plays an important role in T-cell activation, migration into the dermis and binding to keratinocytes. Previous studies have shown that the expression of ICAM-1 on keratinocytes of psoriatic lesions correlates with the clinical severity of the lesion as well as with the size of the dermal infiltrate.13 Efalizumab binds the CD11a subunit of LFA-1 and effectively blocks the physiologic function of this interaction. Efalizumab (anti-CD11a) is a humanized form of a murine antibody against CD11a, the unique alpha subunit of LFA-1.14 Phase I/II studies demonstrated that intravenous (IV) efalizumab administered as a single dose or as multiple weekly doses produced histologic and immunobiologic changes that correlated to its clinical activity, as evidenced by a dose-dependent reduction in PASI. T-cell surface CD11a expression was downmodulated; there was an inverse relationship between this downmodulation and histologic evidence of improvement.15,16 A subsequent Phase II, randomized, double-blind placebo-controlled, multi-center trial, in which patients received IV efalizumab or placebo for 8 weeks, confirmed the histologic improvement and clinical response seen in the Phase I/II studies.17 The incidence of acute adverse events (occurring within 24 hours of administration) was higher in the efalizumab group than placebo. Events included headache, fever, chills, nausea and vomiting. Incidence was highest after the first dose and decreased with subsequent infusions. SC Formulation of Efalizumab Open-label studies of a subcutaneous (SC) formulation of efalizumab demonstrated a clinical response, histologic improvement and safety profile comparable to the IV results. The SC route was chosen for the Phase III trials.14 Efalizumab was evaluated in four randomized, double-blind, placebo-controlled studies for the treatment of chronic plaque psoriasis in adult patients. Patients were randomized to receive once-weekly efalizumab 1 mg/kg, 2 mg/kg or placebo. The only allowed concomitant medication was a low-potency topical steroid. In all four studies, efalizumab-treated patients demonstrated marked clinical improvement compared to placebo-treated patients, as measured by the PASI and PGA. Of efalizumab-treated patients, 22% to 39% achieved the primary endpoint of PASI 75, compared to 2% to 5% of placebo-treated patients. Also, 19% to 32% of patients in the efalizumab group achieved a static PGA assessment of “minimal” or “clear,” compared to 3% to 4% of patients in the placebo group. Adverse events occurring at a rate of 2% or higher in the efalizumab group than in the placebo group included headache, infection, chills, nausea, pain, myalgia, flu syndrome, fever, back pain and acne.18-20 Although statistically significant improvements were seen after 12 weeks and 24 weeks of therapy, results of these trials suggest that patients would derive optimal therapeutic benefit from prolonged efalizumab therapy, especially since some patients have shown disease exacerbation at the end of the dosing period.14,18 Current Phase III studies are attempting to determine the optimal strategies for withdrawal of efalizumab therapy.14 The FDA approved subcutaneous efalizumab for the treatment of adults with moderate to severe plaque psoriasis in October 2003. Anti-TNF therapies Current evidence strongly suggests that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) plays a significant role in the pathogenesis of psoriasis and psoriatic arthritis.5,21,22 At this time, there are three agents that bind and inactivate TNF-alpha: etanercept, infliximab and adalimumab (Humira). These medications are currently approved for the treatment of rheumatoid arthritis and, in the case of etanercept, psoriatic arthritis. However, there is a significant amount of data pertaining to treatment of psoriasis with etanercept and infliximab that will be reviewed below. Adalimumab is currently in its initial clinical trials for psoriasis. Etanercept Etanercept is a fully human dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF-alpha receptor linked to the Fc portion of human IgG1. It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system.23 Etanercept is the first FDA-approved medication for the treatment of psoriatic arthritis; it is also indicated for rheumatoid arthritis (RA) and polyarticular-course juvenile rheumatoid arthritis (JRA). Etanercept has been extensively studied for rheumatoid arthritis and has been available for use in the United States since 1998. In a long-term RA treatment study, etanercept was found to be safe and well-tolerated; its clinical benefit was sustained for a median of more than 2 years and for as long as almost 5 years.24 The use of etanercept as monotherapy for psoriasis was studied in a Phase III, double-blind, placebo-controlled, crossover 24-week study. For this study, 652 patients were randomized to receive subcutaneous etanercept at a low dose (25 mg/week), medium dose (25 mg twice/week), high dose (50 mg twice/week) or placebo. At week 12, patients in the placebo group began treatment with etanercept 25 mg twice/week. The primary efficacy measure was the percentage of patients in each treatment group who achieved at least a PASI 75 at week 12. Assessments of adverse events, infections and laboratory data were performed throughout the study. This Phase III study of etanercept for psoriasis demonstrated a statistically significant improvement in the etanercept group as compared to placebo. At week 12, the percentages of patients who achieved at least a PASI 75 were 4%, 14%, 34% and 49% in the placebo, low-dose, medium-dose and high-dose groups, respectively. The percentages of patients who achieved at least a PASI 50 were 14%, 41%, 58% and 74%, respectively. At week 12, patients in the placebo group crossed over to etanercept therapy and patients in all treatment groups were followed to 24 weeks. At week 24, the percentage of patients who had achieved at least a PASI 75 were 25%, 44% and 59% in the low-dose, medium-dose and high-dose treatment groups, respectively. After 24 weeks, 58%, 70% and 77% of patients, respectively, achieved at least a PASI 50. Etanercept was well tolerated during this study, with the most commonly reported adverse events being injection-site reactions, headaches and upper respiratory infections.25 Using Etanercept Safely Although the safety of etanercept has been established in clinical trials and post-marketing surveillance, certain considerations and precautions should be taken before prescribing this medication. In post-marketing reports, serious infections and sepsis, including fatalities, have been reported. Many of the serious infections occurred in patients on concomitant immunosuppressants. Rare cases of tuberculosis have been reported in patients treated with TNF antagonists, including etanercept.23 Although the FDA does not require TB screening prior to starting etanercept, it’s recommended by physicians who have considerable experience with the medication.26 Rare cases of new onset or exacerbation of central nervous system demyelinating disorders have also been reported in post-marketing surveillance of etanercept.23 No clinical trials have evaluated etanercept therapy in patients with demyelinating diseases, but other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity.27-29 Rare reports of pancytopenia including aplastic anemia, some with a fatal outcome, have also been reported with etanercept; the causal relationship to etanercept therapy remains unclear. Prescribers should exercise caution when using etanercept in patients with CNS demyelinating disorders or hematologic abnormalities.23 Infliximab Infliximab is a chimeric IgG1 monoclonal antibody, composed of human constant and murine variable regions, that binds specifically to human TNF-alpha.30 Infliximab neutralizes the biological activity of TNF-alpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of TNF-alpha with its receptors.31,32 It is given as an intravenous infusion over 2 to 3 hours. Infliximab is an FDA-approved treatment for Crohn’s disease and rheumatoid arthritis. A placebo-controlled, double-blind, randomized study evaluated the safety and efficacy of infliximab as monotherapy for plaque psoriasis.33 In this study, 33 adult patients with a >6-month history of moderate to severe plaque psoriasis involving at least 5% of the body surface area were randomized to receive infliximab 5 mg/kg/wk, 10 mg/kg/wk or placebo at weeks 0, 2 and 6. Patients did not use any other psoriasis treatment during the study, except for non-medicated emollients and non-prescription tar or salicylic shampoos. The primary efficacy endpoint was the PGA at week 10; a positive response was defined as attaining a PGA of good, excellent or clear. A secondary endpoint was improvement in PASI; a favorable response was defined as a 75% improvement in PASI from baseline. At the week 10 evaluation, a significant clinical benefit and rapid response time was seen in the infliximab groups compared to placebo. At 10 weeks, 82% of patients in the 5 mg/kg group and 91% in the 10 mg/kg group achieved the primary endpoint of a good, excellent or clear PGA rating, compared with 18% of patients in the placebo group. The secondary efficacy endpoint, a PASI 75, was reached by 82% of patients in the 5 mg/kg group, 73% of patients in the 10 mg/kg group and 18% in the placebo group. Infliximab was well tolerated in this study — headache was the only adverse event more frequently reported in the infliximab groups (with a greater proportion of 10 mg/kg patients than 5 mg/kg patients) than the placebo group. Open-Label Infliximab Study In an open-label follow-up of this study, all patients were categorized as either responders or non-responders at the 10-week visit and the treatment assignment was unblinded. Non-responders in the placebo group were then randomized to receive open-label infliximab 5 mg/kg or 10 mg/kg at weeks 10, 12 and 16. Responders in the placebo group were followed for relapse and then offered treatment in the same manner as the placebo non-responders. Non-responders in the infliximab 5 mg/kg group were offered a single dose of infliximab 10 mg/kg and followed up for response; non-responders in the 10 mg/kg group were discontinued from the study. Patients who responded to treatment with infliximab 5 mg/kg or 10 mg/kg were followed up for relapse and offered single dose infusions of the drug upon relapse. All patients were followed to 26 weeks after the first dose of infliximab. The primary endpoint for the open-label extension study was the percent change from baseline PASI, which was used to evaluate the durability of response to infliximab. At the 26-week evaluation of all patients treated with infliximab, 57% maintained a PASI 50 and 50% maintained a PASI 75 in the absence of any further treatment after the initial three infusions of infliximab.34 A large, Phase III, multi-center, randomized, double-blind, placebo-controlled study of repeat courses of infliximab for plaque psoriasis is currently underway. Looking to the Future The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. While these medications are an addition to the therapeutic choices for this disease, physicians should consider all forms of anti-psoriasis therapy, including topical treatments, phototherapy and traditional systemic agents when considering the use of a biologic. Newer biologic agents continue to be developed (see table above). These agents can be directed against previously identified targets using new technology to improve on the medication or could be directed against entirely new targets. Thus, biologic agents are, and will likely continue to be, an important advancement in the treatment of psoriasis to improve the lives of patients with this debilitating disease.
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two Category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. Toral Patel, M.D., and Kenneth B. Gordon, M.D., review some of the new biologic agents approved or in development for psoriasis. At the end of this article, you will find a 10-question exam. Mark your responses in the designated area and fax page 73 to HMP Communications at (610) 560-0501. Approximately 1 month after the publication date, we’ll post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. CME #118 March 2004 P soriasis is a chronic, potentially debilitating disease with a prevalence of approximately 2% worldwide; rates vary by ethnicity and geography.1 The most common form of the disease, occurring in more than 80% of cases, is plaque psoriasis, characterized by sharply demarcated, erythematous, scaling plaques. Psoriasis patients may also have psoriatic arthritis, an inflammatory arthropathy that affects 5% to 40% of psoriasis patients. Psoriatic arthritis can be significantly disabling as well as progressively destructive.2 Current psoriasis therapies include topical preparations, phototherapy and systemic medications. For those patients with extensive disease, topical therapy is not always feasible or effective, making phototherapy and/or systemic therapy indicated. Traditional systemic treatments in-clude methotrexate, cyclosporine, psoralen with ultraviolet A (PUVA) and oral retinoids. All of these medications carry with them the potential for harmful side effects. Most prominently, methotrexate is associated with hepatotoxicity and bone marrow toxicity, cyclosporine with cardiovascular changes and nephrotoxicity, PUVA with the development of skin cancer, and the retinoids with teratogenicity, hyperlipidemia, alopecia and bony abnormalities.3 While rotational strategies have been developed to minimize the toxicity of these systemic medications, there remains a need for effective drugs that can be used for the lifetime of the patient’s disease with a more acceptable side effect profile. The phenotypic expression of psoriasis is due to hyperproliferation and decreased maturation of keratinocytes. These changes are induced by an inflammatory response driven by T cells, local dendritic cells and macrophages, as well as the activated keratinocytes.4-6 The understanding of the central role of this inflammatory reaction in the pathogenesis of psoriasis has given rise to a new class of medications, known collectively as biologics; each of these biologics targets specific interactions along the T-cell activation and trafficking pathways.7 This review will discuss four of the new biologic agents approved or in development for psoriasis: alefacept (Amevive), efalizumab (Raptiva), etanercept (Enbrel) and infliximab (Remicade). Alefacept Alefacept is a fully human fusion protein consisting of a segment of lymphocyte function-associated antigen-3 (LFA-3) fused to the Fc segment of IgG1. Alefacept may work by two potential mechanisms: the LFA-3 segment binds CD2 on the T-cell surface, inhibiting T-cell activation and proliferation, and/or the IgG1 segment binds to accessory cells, triggering apoptosis of selected memory T cells expressing high levels of CD2 on the surface.8 A Phase III, randomized, double-blind, placebo-controlled trial of two 12-week treatment courses of intravenous alefacept (7.5 mg) in patients with chronic plaque psoriasis (n=553) demonstrated durable clinical improvements, as measured by changes in the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). In this study, patients were randomized to receive two 12-week courses of either once-weekly alefacept or placebo. Patients were followed for 12 weeks after each course. The primary efficacy parameter was the percentage of patients with a 75% or greater reduction in PASI (PASI 75) 2 weeks after the last dose of course one. Safety and tolerability were monitored by adverse events, laboratory tests (including CD4 and CD8 counts), vital signs, physical examinations and anti-alefacept antibodies. Two weeks after the last dose of course one, 14% of alefacept-treated patients had achieved a PASI 75 or greater, versus 4% of placebo-treated patients. The alefacept-treated patients who achieved at least a PASI 75 maintained at least a 50% reduction in their PASI score for a median duration of more than 7 months. A second course of treatment improved efficacy; 2 weeks after the last dose of course two, 26% of patients had achieved at least a PASI 75 and 55% of patients a PASI 50 or greater. Both courses were equally well tolerated. During course one, alefacept-treated patients had a higher incidence of chills than placebo-treated patients; greater than 90% of cases occurred within 24 hours of treatment after the first few doses. In course two, accidental injury and pharyngitis were observed more frequently in the alefacept group than in the placebo group. Throughout the study, no opportunistic infections and no association of infections with CD4+ T-cell counts less than 250 cells/ml were observed.8 IM Alefacept Another Phase III, multicenter, randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of intramuscular (IM) alefacept in the treatment of chronic psoriasis (n=507). Patients were randomized in a 1:1:1 ratio to receive 10 mg alefacept, 15 mg alefacept or placebo once weekly for 12 weeks followed by a 12-week observation period. Lymph-ocyte counts were obtained at all study visits during the treatment period; if a patient’s CD4+ count from the prior week was lower than 250/ml, the scheduled dose was substituted with placebo. If the CD4+ count remained below 250/ml for 4 consecutive weeks, the active drug was permanently substituted with placebo. The primary efficacy parameters were changed in PASI from baseline, percentage of patients achieving PASI 50 and PASI 75, and a PGA of “clear” or “almost clear.” PASI and PGA were evaluated throughout the treatment and observation periods. Alefacept was well tolerated during the IM study and again produced a long-lasting clinical response. Mean reductions in PASI reached a maximum of 46%, 41% and 25% in the 15 mg, 10 mg and placebo groups, respectively. Twelve weeks after treatment end, the mean PASI score in both alefacept groups had not returned to baseline values; no patient had rebound or flare of disease activity after withdrawal of therapy. The percentage of patients achieving either a PASI 50 or PASI 75 was higher in the alefacept groups than in the placebo group. The overall response rates for PGA of “clear” or “almost clear” were 24%, 22% and 8% of patients in the 15 mg, 10 mg and placebo groups, respectively. Safety of Alefacept Adverse events that occurred at an incidence of at least 5% higher in either alefacept group than placebo included headache, pruritus, infection (most frequently common cold), rhinitis and injection site reactions. No association was found between incidence of infections and decreased CD4+ cell counts.9 Treatment with alefacept does not blunt immune responses to novel and recall antigens, as shown in a multicenter, randomized, open-label, parallel-group study. Current data indicate that alefacept may not significantly affect the ability of host defenses to mount an appropriate immune response to pathogens and therefore does not increase susceptibility to infection or malignancy.10 However, the true safety profile of alefacept in regard to infection and malignancy can only be determined after long-term clinical observation. The FDA approved both the IM and IV formulations of alefacept for the treatment of psoriasis in January 2003. At this time, only the intramuscular form of alefacept is available for commercial use. Alefacept is indicated for the treatment of moderate to severe plaque type psoriasis in patients who are candidates for systemic therapy or phototherapy. Alefacept is given weekly in the physician office for 12 weeks, then followed by a 12-week observation period. In the research studies, the median time to maximal improvement in psoriasis is 8 weeks after the last dose. Thus, some patients should continue to improve during the observation period.11 Efalizumab The interaction between adhesion molecules LFA-1 (lymphocyte function associated antigen-1) and ICAM-1 (intercellular adhesion molecule-1) has been implicated in the pathogenesis of psoriasis. LFA-1 is characterized by heterodimers with a common beta chain (CD18) and a unique alpha chain (CD11a), and is expressed only on leukocytes. ICAM-1, a receptor for LFA-1, is expressed on multiple cells, including T cells, endothelial cells and epidermal keratinocytes.12 The binding of these cell surface molecules plays an important role in T-cell activation, migration into the dermis and binding to keratinocytes. Previous studies have shown that the expression of ICAM-1 on keratinocytes of psoriatic lesions correlates with the clinical severity of the lesion as well as with the size of the dermal infiltrate.13 Efalizumab binds the CD11a subunit of LFA-1 and effectively blocks the physiologic function of this interaction. Efalizumab (anti-CD11a) is a humanized form of a murine antibody against CD11a, the unique alpha subunit of LFA-1.14 Phase I/II studies demonstrated that intravenous (IV) efalizumab administered as a single dose or as multiple weekly doses produced histologic and immunobiologic changes that correlated to its clinical activity, as evidenced by a dose-dependent reduction in PASI. T-cell surface CD11a expression was downmodulated; there was an inverse relationship between this downmodulation and histologic evidence of improvement.15,16 A subsequent Phase II, randomized, double-blind placebo-controlled, multi-center trial, in which patients received IV efalizumab or placebo for 8 weeks, confirmed the histologic improvement and clinical response seen in the Phase I/II studies.17 The incidence of acute adverse events (occurring within 24 hours of administration) was higher in the efalizumab group than placebo. Events included headache, fever, chills, nausea and vomiting. Incidence was highest after the first dose and decreased with subsequent infusions. SC Formulation of Efalizumab Open-label studies of a subcutaneous (SC) formulation of efalizumab demonstrated a clinical response, histologic improvement and safety profile comparable to the IV results. The SC route was chosen for the Phase III trials.14 Efalizumab was evaluated in four randomized, double-blind, placebo-controlled studies for the treatment of chronic plaque psoriasis in adult patients. Patients were randomized to receive once-weekly efalizumab 1 mg/kg, 2 mg/kg or placebo. The only allowed concomitant medication was a low-potency topical steroid. In all four studies, efalizumab-treated patients demonstrated marked clinical improvement compared to placebo-treated patients, as measured by the PASI and PGA. Of efalizumab-treated patients, 22% to 39% achieved the primary endpoint of PASI 75, compared to 2% to 5% of placebo-treated patients. Also, 19% to 32% of patients in the efalizumab group achieved a static PGA assessment of “minimal” or “clear,” compared to 3% to 4% of patients in the placebo group. Adverse events occurring at a rate of 2% or higher in the efalizumab group than in the placebo group included headache, infection, chills, nausea, pain, myalgia, flu syndrome, fever, back pain and acne.18-20 Although statistically significant improvements were seen after 12 weeks and 24 weeks of therapy, results of these trials suggest that patients would derive optimal therapeutic benefit from prolonged efalizumab therapy, especially since some patients have shown disease exacerbation at the end of the dosing period.14,18 Current Phase III studies are attempting to determine the optimal strategies for withdrawal of efalizumab therapy.14 The FDA approved subcutaneous efalizumab for the treatment of adults with moderate to severe plaque psoriasis in October 2003. Anti-TNF therapies Current evidence strongly suggests that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) plays a significant role in the pathogenesis of psoriasis and psoriatic arthritis.5,21,22 At this time, there are three agents that bind and inactivate TNF-alpha: etanercept, infliximab and adalimumab (Humira). These medications are currently approved for the treatment of rheumatoid arthritis and, in the case of etanercept, psoriatic arthritis. However, there is a significant amount of data pertaining to treatment of psoriasis with etanercept and infliximab that will be reviewed below. Adalimumab is currently in its initial clinical trials for psoriasis. Etanercept Etanercept is a fully human dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF-alpha receptor linked to the Fc portion of human IgG1. It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system.23 Etanercept is the first FDA-approved medication for the treatment of psoriatic arthritis; it is also indicated for rheumatoid arthritis (RA) and polyarticular-course juvenile rheumatoid arthritis (JRA). Etanercept has been extensively studied for rheumatoid arthritis and has been available for use in the United States since 1998. In a long-term RA treatment study, etanercept was found to be safe and well-tolerated; its clinical benefit was sustained for a median of more than 2 years and for as long as almost 5 years.24 The use of etanercept as monotherapy for psoriasis was studied in a Phase III, double-blind, placebo-controlled, crossover 24-week study. For this study, 652 patients were randomized to receive subcutaneous etanercept at a low dose (25 mg/week), medium dose (25 mg twice/week), high dose (50 mg twice/week) or placebo. At week 12, patients in the placebo group began treatment with etanercept 25 mg twice/week. The primary efficacy measure was the percentage of patients in each treatment group who achieved at least a PASI 75 at week 12. Assessments of adverse events, infections and laboratory data were performed throughout the study. This Phase III study of etanercept for psoriasis demonstrated a statistically significant improvement in the etanercept group as compared to placebo. At week 12, the percentages of patients who achieved at least a PASI 75 were 4%, 14%, 34% and 49% in the placebo, low-dose, medium-dose and high-dose groups, respectively. The percentages of patients who achieved at least a PASI 50 were 14%, 41%, 58% and 74%, respectively. At week 12, patients in the placebo group crossed over to etanercept therapy and patients in all treatment groups were followed to 24 weeks. At week 24, the percentage of patients who had achieved at least a PASI 75 were 25%, 44% and 59% in the low-dose, medium-dose and high-dose treatment groups, respectively. After 24 weeks, 58%, 70% and 77% of patients, respectively, achieved at least a PASI 50. Etanercept was well tolerated during this study, with the most commonly reported adverse events being injection-site reactions, headaches and upper respiratory infections.25 Using Etanercept Safely Although the safety of etanercept has been established in clinical trials and post-marketing surveillance, certain considerations and precautions should be taken before prescribing this medication. In post-marketing reports, serious infections and sepsis, including fatalities, have been reported. Many of the serious infections occurred in patients on concomitant immunosuppressants. Rare cases of tuberculosis have been reported in patients treated with TNF antagonists, including etanercept.23 Although the FDA does not require TB screening prior to starting etanercept, it’s recommended by physicians who have considerable experience with the medication.26 Rare cases of new onset or exacerbation of central nervous system demyelinating disorders have also been reported in post-marketing surveillance of etanercept.23 No clinical trials have evaluated etanercept therapy in patients with demyelinating diseases, but other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity.27-29 Rare reports of pancytopenia including aplastic anemia, some with a fatal outcome, have also been reported with etanercept; the causal relationship to etanercept therapy remains unclear. Prescribers should exercise caution when using etanercept in patients with CNS demyelinating disorders or hematologic abnormalities.23 Infliximab Infliximab is a chimeric IgG1 monoclonal antibody, composed of human constant and murine variable regions, that binds specifically to human TNF-alpha.30 Infliximab neutralizes the biological activity of TNF-alpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of TNF-alpha with its receptors.31,32 It is given as an intravenous infusion over 2 to 3 hours. Infliximab is an FDA-approved treatment for Crohn’s disease and rheumatoid arthritis. A placebo-controlled, double-blind, randomized study evaluated the safety and efficacy of infliximab as monotherapy for plaque psoriasis.33 In this study, 33 adult patients with a >6-month history of moderate to severe plaque psoriasis involving at least 5% of the body surface area were randomized to receive infliximab 5 mg/kg/wk, 10 mg/kg/wk or placebo at weeks 0, 2 and 6. Patients did not use any other psoriasis treatment during the study, except for non-medicated emollients and non-prescription tar or salicylic shampoos. The primary efficacy endpoint was the PGA at week 10; a positive response was defined as attaining a PGA of good, excellent or clear. A secondary endpoint was improvement in PASI; a favorable response was defined as a 75% improvement in PASI from baseline. At the week 10 evaluation, a significant clinical benefit and rapid response time was seen in the infliximab groups compared to placebo. At 10 weeks, 82% of patients in the 5 mg/kg group and 91% in the 10 mg/kg group achieved the primary endpoint of a good, excellent or clear PGA rating, compared with 18% of patients in the placebo group. The secondary efficacy endpoint, a PASI 75, was reached by 82% of patients in the 5 mg/kg group, 73% of patients in the 10 mg/kg group and 18% in the placebo group. Infliximab was well tolerated in this study — headache was the only adverse event more frequently reported in the infliximab groups (with a greater proportion of 10 mg/kg patients than 5 mg/kg patients) than the placebo group. Open-Label Infliximab Study In an open-label follow-up of this study, all patients were categorized as either responders or non-responders at the 10-week visit and the treatment assignment was unblinded. Non-responders in the placebo group were then randomized to receive open-label infliximab 5 mg/kg or 10 mg/kg at weeks 10, 12 and 16. Responders in the placebo group were followed for relapse and then offered treatment in the same manner as the placebo non-responders. Non-responders in the infliximab 5 mg/kg group were offered a single dose of infliximab 10 mg/kg and followed up for response; non-responders in the 10 mg/kg group were discontinued from the study. Patients who responded to treatment with infliximab 5 mg/kg or 10 mg/kg were followed up for relapse and offered single dose infusions of the drug upon relapse. All patients were followed to 26 weeks after the first dose of infliximab. The primary endpoint for the open-label extension study was the percent change from baseline PASI, which was used to evaluate the durability of response to infliximab. At the 26-week evaluation of all patients treated with infliximab, 57% maintained a PASI 50 and 50% maintained a PASI 75 in the absence of any further treatment after the initial three infusions of infliximab.34 A large, Phase III, multi-center, randomized, double-blind, placebo-controlled study of repeat courses of infliximab for plaque psoriasis is currently underway. Looking to the Future The recognition of psoriasis as a disease mediated by T cells and other inflammatory cells and mediators has allowed for the development of new biologic medications that are effective in the treatment of the disease with fewer potential risks. While these medications are an addition to the therapeutic choices for this disease, physicians should consider all forms of anti-psoriasis therapy, including topical treatments, phototherapy and traditional systemic agents when considering the use of a biologic. Newer biologic agents continue to be developed (see table above). These agents can be directed against previously identified targets using new technology to improve on the medication or could be directed against entirely new targets. Thus, biologic agents are, and will likely continue to be, an important advancement in the treatment of psoriasis to improve the lives of patients with this debilitating disease.
