The implication of an immunologic

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1 Evidence-Based Review of Biologic Therapy for Psoriasis: Infliximab, Etanercept, Adalimumab, Efalizumab, and Alefacept Jeffrey M. Weinberg, MD; Robin Buchholz, MD; Noah Scheinfeld, MD DERMATOLOGY ABSTRACT PURPOSE: To understand the efficacy and safety of novel biologic therapies for psoriasis. EPIDEMIOLOGY: Psoriasis occurs in 1% to 3% of the US population. In 20% to 25% of these individuals, the disease will be more than limited. Plaque psoriasis is more common in individuals with haplotypes HLA-B13, -B17, and -Cw6. It worsens with HIV infection, stress, other infections, and sometimes with exposure to ultraviolet light. REVIEW SUMMARY: The aim of this article is to review the progress of 5 biologic agents that are available or are under investigation for clinical use: infliximab, etanercept, adalimumab, efalizumab, and alefacept. TYPE OF AVAILABLE EVIDENCE: Double-blinded randomized trials and open-label studies. GRADE OF AVAILABLE EVIDENCE: Good. CONCLUSION: Biologic therapies for psoriasis are promising agents in the treatment of the disease. In patients treated to date, they have offered successful therapy for psoriasis with a lack of organ toxicity seen with traditional systemic therapies, such as methotrexate and cyclosporine. These agents have demonstrated varying efficacies and side-effect profiles. Issues and potential limitations inherent in the use of these agents include the expected high costs of treatment, lack of long-term follow-up, and the selective nature of subjects treated thus far. Long-term monitoring of these agents is necessary to determine the potential risks for increased infection and malignancy in patients treated with them. (Adv Stud Med. 2005;5(4): ) The implication of an immunologic phenomenon in the pathogenesis of psoriasis has led to research in new treatment options over the past few years. 1 The result has been the birth of biologic therapies, drugs that target the activity of T-lymphocytes and cytokines responsible for the inflammatory nature of this disease. Singri et al 2 recently outlined a conceptual model for immunomodulation in psoriasis. They defined 4 strategies within this model that clarify the mechanism of action for the various biologic agents. These strategies include: (1) reduction of pathogenic T-cells; (2) inhibition of T-cell activation; (3) immune deviation (deviation of a T H 1 immune response toward a greater T H 2-type response through the involvement of these T H 2-type cytokines); and (4) blocking the activity of inflammatory cytokines. 2 In this review, we present an update on the progress of Dr Weinberg is Assistant Clinical Professor of Dermatology, Columbia University, New York, NY. Dr Buchholz is Assistant Professor of Dermatology, St Luke s-roosevelt Hospital Center, New York, NY. Dr Scheinfeld is Assistant Clinical Professor of Dermatology, Columbia University; Assistant Attending, St Lukes-Roosevelt Hospital Center; and Assistant Attending, Beth Israel Medical Center, New York, NY. Conflict of Interest: Dr Weinberg is a member of the Speaker s Bureau for Amgen and Genentech, Inc. There was no industry support for preparation and publication of this manuscript. Dr Buchholz reports receiving honoraria from Amgen and Genentech, Inc. Dr Scheinfeld reports having no financial or advisory relationships with corporate organizations related to this activity. Off-label Product Discussion: The authors of this article discuss off-label/unapproved use of adalimumab and infliximab for the treatment of psoriasis. Correspondence to Jeffrey M. Weinberg, MD, Department of Dermatology, St Luke s-roosevelt Hospital Center, 1090 Amsterdam Avenue, Ste 11D, New York, NY Johns Hopkins Advanced Studies in Medicine 195

2 DERMATOLOGY Table 1. Biologic Agents Used to Treat Psoriasis Routes of Administration and Mechanism of Action Agent Mechanism of Action Administration Status Infliximab TNF-α inhibitor, IV infusion (>120 min) In Phase III trials chimeric antibody Etanercept TNF-α inhibitor, SC twice weekly for FDA approved TNF-receptor 3 months/weekly thereafter Adalimumab TNF-α inhibitor, SC once weekly/every In Phase III trials human antibody other week Efalizumab Inhibits T-cell SC once weekly FDA approved activation, migration Alefacept Reduces memory- IM once weekly FDA approved effector T-cells TNF = tumor necrosis factor; IV = intravenous; IM = intramuscular; SC = subcutaneous. Table 2. Efficacy of Biologic Agents Used in the Treatment of Psoriasis Agent Dose (Duration) PASI 50 PASI 75 PASI 90 Infliximab Phase II 3 mg/kg (week 0, 2, 6) N/A 10 weeks: 72% N/A 5 mg/kg (week 0, 2, 6) 10 weeks: 88% Etanercept Phase III 25 mg SC 2x/wk 12 weeks: 58% 12 weeks: 34% 12 weeks: 12% (24 wk) 24 weeks: 70% 24 weeks: 44% 24 weeks: 20% 50 mg SC 2x/wk 12 weeks: 74% 12 weeks: 49% 12 weeks: 22% (24 wk) 24 weeks: 77% 24 weeks: 59% 24 weeks: 30% Adalimumab Phase II 80 mg week 0 and 1, 12 weeks: 88% 12 weeks: 80% 12 weeks: 48% then 40 mg weekly 24 weeks: NA 24 weeks: 72% 24 weeks: 62% (12 wk) 80 mg week 0, 1, 12 weeks: 76% 12 weeks: 53% 12 weeks: 24% then 40 mg every 24 weeks: NA 24 weeks: 64% 24 weeks: 42% other wk (12 wk) Efalizumab Phase III 1 mg/kg/wk (12 wk) 12 weeks: 57.0% 12 weeks: 27.9% 2 mg/kg/wk (12 wk) 12 weeks: 54.5% 12 weeks: 27.6% Phase III 1 mg/kg/wk (24 wk) 12 weeks: 58.5% 12 weeks: 26.6% 24 weeks: 66.6% 24 weeks: 43.8% Alefacept IM Phase III 15 mg IM (12 wk) 14 weeks: 42% 14 weeks: 21% N/A 15 mg IM (12 wk) Any time: 57% Any time: 33% 10 mg IM (12 wk) 14 weeks: 36% 14 weeks: 12% 5 new biologic agents for psoriasis. These agents include infliximab (Strategy 4), etanercept (Strategy 4), adalimumab (Strategy 4), efalizumab (Strategy 2), and alefacept (Strategy 1) (Table 1). For the 3 tumor necrosis factor (TNF) inhibitors infliximab, etanercept, and adalimumab, the clinical experience for each drug is discussed separately, and then safety issues are discussed collectively for the class. The safety and efficacy of the T-cell-targeted therapies efalizumab and alefacept are discussed separately. The efficacy of biologic agents based on Psoriasis Area and Severity Index (PASI) score is discussed in Table 2. Table 3 reviews routes of administration, duration of therapy, dosing, and laboratory monitoring requirements of these agents. Table 4 surveys molecule type, mechanism of action, US Food and Drug Administration (FDA) status, and side effects of biologic agents used in the treatment of psoriasis. TUMOR NECROSIS FACTOR INHIBITORS INFLIXIMAB (REMICADE ) Structure and Mechanism Infliximab (Figure 1) is a chimeric (mouse-human) IgG1 monoclonal antibody that binds to TNF-α. It also inhibits production of other proinflammatory cytokines, reducing cell infiltration and, eventually, keratinocyte proliferation. Infliximab has induced apoptosis in TNF-expressing cells in vitro, which has been confirmed in vivo. The drug currently is approved for Crohn s disease, ankylosing spondylitis, and rheumatoid arthritis (RA), as an intravenous infusion. Clinical Experience In an early published trial, Chaudhari et al 3 reported the results of a double-blind, randomized trial to assess the clinical benefit and safety profile of infliximab in psoriasis. Thirty-three patients with moderate to severe plaque psoriasis were randomly assigned intravenous placebo (n = 11), infliximab 5 mg/kg (n = 11), or infliximab 10 mg/kg (n = 11) at weeks 0, 2, and 6. Patients were assessed at week 10 for the primary endpoint (score on the Physician Global Assessment [PGA]). Nine of 11 (82%) patients in the infliximab 5-mg/kg group were responders (good, excellent, or clear rating on PGA), compared with 2 of 11 (18%) in the placebo group and 10 of 11 (91%) in the infliximab 10-mg/kg group. When evaluating improvement in the 196 Vol. 5, No. 4 April 2005

3 BIOLOGIC THERAPY FOR PSORIASIS Table 3. Routes of Administration, Duration of Therapy, Dosing, and Monitoring of Biologic Agents Drug SC IV IM Frequency Duration Dose Required Monitoring Infliximab X Weeks 0, 2, 6, then Per frequency 5-10 mg/kg PPD prior to therapy every 8 weeks Alefacept X Once weekly 12-week courses, 15 mg CD4 weekly separated by 12 weeks off therapy Efalizumab X Once weekly Indefinite 1st wk 0.7 mg/kg, Recommended for then 1 mg/kg platelets Etanercept X Once or twice weekly Indefinite 50 mg biw, then None 25 mg biw Adalimumab X Every other week Indefinite 40 mg PPD prior to therapy SC = subcutaneous; IV = intravenous; IM = intramuscular; PPD = purified protein derivative; biw = twice a week. Table 4. Molecule Type, Mechanism of Action, FDA Status, and Side Effects of Biologic Agents Agent Molecule Type Mechanism FDA Approval Side effects Increased Risk of of Action Status Severe Infection Alefacept Human fusion protein Reduces memory- FDA approved Reduction of Theoretic increased effector T-cells; binds for psoriasis in CD4 T-cells risk; no demon- CD2 on CD450+ cells. January 2003 strated risk to date Efalizumab Humanized monoclonal Inhibits T-cell migration FDA approved Recurrence/ Theoretic increased antibody & activation, binds for psoriasis in rebound of risk; no demonstrated CD11 & LFA-1 October 2003 psoriasis upon risk to date discontinuation Etanercept Human fusion protein TNF-α inhibitor FDA approved Rare cases of con- Theoretic increased for psoriasis in gestive heart failure, risk; no demonstrated April 2004 neurological problems, risk to date lymphoma; causal relationship unclear Infliximab Chimeric antibody TNF-α inhibitor In Phase III trials Rare cases of con- Increased risk for psoriasis and gestive heart failure, psoriatic arthritis neurologic problems, lymphoma; causal relationship unclear Infection Neutralizing antibodies Adalimumab Fully human antibody TNF-α inhibitor In Phase III trials Rare cases of con- Theoretic increased for psoriasis and gestive heart failure, risk; no demonpsoriatic arthritis neurological problems, strated risk to date lymphoma; causal relationship unclear FDA = US Food and Drug Administration. Johns Hopkins Advanced Studies in Medicine 197

4 DERMATOLOGY PASI, the researchers found that 5 mg/kg resulted in at least 75% improvement in the PASI (PASI 75) in 82% of patients, whereas 10 mg/kg resulted in at least 75% improvement in 73% of patients. The placebo group showed only an average 15% improvement in the PASI score. The median time to response was 4 weeks for patients in both infliximab groups. There were no serious adverse events, and infliximab was well tolerated. 3 Schopf et al 4 treated 8 patients with severe psoriasis in an open-label clinical trial in which they received infliximab 5 mg/kg intravenously at weeks 0, 2, and 6. PASI score was used to monitor disease activity at weeks 0, 2, 4, 6, 8, 10, and 14. Between weeks 0 and 10, the investigators documented a nearly 85% reduction in the mean PASI score. At week 14, 2 months after the patient had received the last infliximab dose, the mean PASI score was reduced by 67% from baseline. 4 No adverse effects were reported other than fatigue during infusion on some occasions. 4 Ogilvie et al 5 described treatment with infliximab in 6 patients with both psoriasis and psoriatic arthritis. 5 All patients had long-standing disease that was refractory to several treatments with methotrexate, and each received infusions of infliximab 5 mg/kg at weeks 0, 2, and 6. They also continued to receive the same doses of methotrexate or sulfasalazine during the study period. At 10 weeks after start of therapy, all patients experienced improvement in their arthritis, as well as improvement of their skin lesions, with a decrease in PASI scores of as much as 80%. 5 Recently, Gottlieb et al 6 assessed the efficacy and safety of infliximab induction therapy for patients with severe plaque psoriasis. In this multicenter, double-blind, placebo-controlled trial, 249 patients with severe plaque psoriasis were randomly assigned to receive intravenous infusions of either 3 or 5 mg/kg of infliximab or placebo given at weeks 0, 2, and 6. The primary endpoint was the Figure 1. Illustration of the Structure of Infliximab Mouse Human proportion of patients who achieved at least 75% improvement in PASI score from baseline at week 10. At week 26, patients whose PGA indicated moderate or severe disease were eligible for a single intravenous infusion of their assigned treatment to assess the safety of retreatment after a 20-week treatment-free interval. 6 At week 10, 72% of patients treated with infliximab 3 mg/kg and 88% of patients treated with infliximab 5 mg/kg achieved a 75% or greater improvement from baseline in PASI score compared with 6% of patients treated with placebo (P <.001). Improvement was observed in both infliximab groups in as early as 2 weeks. Overall, 63%, 78%, and 79% of patients in the placebo, 3-, and 5-mg/kg groups, respectively, reported 1 or more adverse events. The authors concluded that infliximab treatment resulted in a rapid and significant improvement in the signs and symptoms of psoriasis. In addition, infliximab generally was well tolerated. 6 Cassano et al 7 evaluated the efficacy and tolerability of infliximab monotherapy in 29 patients with moderate to severe psoriasis who were unresponsive to conventional treatments. Fourteen patients suffered from concomitant arthropathy. Patients received intravenous infliximab 5 mg/kg at weeks 0, 2, and 6. After this 3-dose induction regimen, patients were followed at monthly intervals and retreated with a single-dose infusion in case of relapse of signs and symptoms. Clinical assessment was performed using the PASI to monitor psoriasis activity; pruritus and joint pain were assessed on a scale of 0 to 3. A marked improvement in skin lesions and subjective symptoms was noted in the majority of patients; a reduction of PASI score was observed in 13.8% of cases at week 2, in 71.4% of cases at week 6, and in 78.6% of cases at week 10. During the follow-up period, some patients maintained satisfactory clinical results without requiring any additional infusions. In general, skin lesions showed a trend toward a more prolonged and sustained improvement as compared with subjective symptoms. Treatment was well tolerated and no serious adverse events occurred. 7 ETANERCEPT (ENBREL ) Structure and Mechanism Etanercept is a 100% human TNF-receptor, made from the fusion of 2 naturally occurring TNF-receptors (Figure 2). It binds to TNF with greater affinity than natural receptors, which are monomeric. The binding of etanercept to TNF renders the bound TNF biologically inactive, resulting in reduction of inflammatory activity. Etanercept is administered subcutaneously by patients at home. The drug is approved for RA, juvenile RA, ankylosing spondylitis, psoriasis, and psoriatic arthritis. Etanercept also is indicated for inhibiting the progression of structural damage in patients with RA and psoriatic arthritis and for improving physical function in patients 198 Vol. 5, No. 4 April 2005

5 BIOLOGIC THERAPY FOR PSORIASIS with RA. The approved dose in psoriasis is 50 mg subcutaneously twice weekly for 3 months, followed by 50 mg subcutaneously weekly. 8 Clinical Experience In a Phase II clinical study that assessed the efficacy and tolerability of this biologic therapy, 112 patients with moderate to severe plaque psoriasis were randomized evenly to receive 25 mg of etanercept or placebo subcutaneously twice a week for 6 months. 9 The primary endpoint of the study was the proportion of patients who achieved a PASI reduction of at least 75% after 12 weeks. At 3 months, 30% of 57 patients on etanercept achieved a 75% reduction in PASI, compared with 2% of 55 patients on placebo (P <.0001). Fifty-six percent of patients treated with etanercept achieved a 75% reduction in PASI at 6 months, compared with 5% of patients who received placebo. Additionally, at 6 months 21% of patients who received etanercept achieved a 90% reduction in PASI, compared with none of those patients who received placebo, whereas 77% of patients who received etanercept achieved a 50% reduction in PASI compared with 13% of patients who received placebo. Side effects seen were mild infections, which included mild upper respiratory infections and sinusitis, and injection site reactions. 9 Similar findings were seen in a report of 6 patients aged 33 to 57 years with severe refractory psoriasis (3 with psoriatic arthritis, as well) who had been unresponsive to systemic treatments and phototherapy. 10 The PASI scores of these patients before etanercept and, in some cases, combination therapy averaged 24, with the highest score being 29, whereas scores following treatment with etanercept had a mean of 9, with the highest score being 14. In addition, no toxicity secondary to the treatment was noted. In the patients for whom etanercept was added in combination with other systemic and topical medications, refractory disease became more responsive to treatment and permitted the use of lower doses of systemic agents. 10 The results of a Phase III study that evaluated the efficacy and tolerability of etanercept in psoriasis were recently reported. 11 Etanercept was evaluated at doses of 25 mg and 50 mg subcutaneously twice weekly. At the 25-mg dose, the percentage of patients achieving PASI 75 was 34% at 12 weeks and 49% at 24 weeks. At the 50-mg dose, the percentage of patients achieving PASI 75 was 49% at 12 weeks and 59% at 24 weeks. Therapy with etanercept generally was well tolerated. 11 ADALIMUMAB (HUMIRA ) Structure and Mechanism Adalimumab (Figure 3) is a human IgG1 monoclonal TNF-α antibody. 12 The binding of adalimumab to TNF-α results in its inactivation, thus reducing inflammatory activity. Adalimumab currently is approved for the treatment of RA and is entering Phase III clinical trials for its potential efficacy in the treatment of psoriasis and psoriatic arthritis. It can be administered in the manner of etanercept, via subcutaneous injection. Clinical Experience Gordon et al 13 recently reported preliminary efficacy and safety data from a 12-week, double-blind, placebo-controlled Phase II trial of adalimumab in psoriasis. The researchers enrolled 148 adults with diagnoses of moderate to severe chronic plaque psoriasis for at least 1 year and affected body surface areas (BSAs) of 5% or greater. The subjects were randomized to 2 active treatment groups and 1 placebo group. All subjects were naive to TNF-antagonist treatment. In the year prior to entry, about 40% of subjects had used methotrexate, cyclosporine, or an oral retinoid; 16% had used a biologic therapy approved for psoriasis; and 26% had undergone phototherapy. Figure 2. Illustration of the Structure of Etanercept Human TNF-RII Receptor Human IgG1 Fc Domain Figure 3. Illustration of the Structure of Adalimumab Adalimumab (D2E7) Characteristics Fully Human Anti-TNF-α Antibody With t1/ 2 ~2 weeks Binds only TNF-α and not other TNF family members Johns Hopkins Advanced Studies in Medicine 199

6 DERMATOLOGY One group of subjects received 80 mg adalimumab at week 0, followed by 40 mg every other week from week 1 onward. The second active treatment group received 80 mg at weeks 0 and 1, then 40 mg weekly beginning at week 2. A placebo was administered weekly to the third group. Ninety-five percent of the subjects completed the study. The primary endpoint was the percentage of subjects achieving at least a 75% reduction in the PASI at week 12. Adalimumab 40 mg every other week achieved a mean PASI of 75 at a 53% rate, compared with a 4% rate for placebo, and 40 mg weekly achieved a mean PASI of 75 at an 80% rate. 13 The results for this trial at 24 weeks also were recently reported. 14 Upon completion of 12 weeks of therapy, patients in the treatment group were eligible to continue their assigned blinded dose, adalimumab 40 mg either weekly or ever other week, whereas the placebo group was switched to an 80-mg loading dose of adalimumab at week 12 and then 40 mg every other week, starting at week 13. By week 24, 72% of the 40-mg-weekly group (n = 47) and 64% of the 40-mg-every-other-week group (n = 43) had achieved a PASI 75 response. The placebo group, having been switched to every-other-week active therapy for 12 weeks, achieved a PASI 75 reduction in 55% (n = 47), a response comparable to that of the everyother-week group at week 12. In addition to the PASI 75, the investigators measured PASI 90 responses in the 3 groups. At week 12, none of the placebo group had achieved a PASI 90 response, whereas 24% of the 40-mgevery-other-week group (n = 45) and 48% of the 40-mgweekly group did. By week 24, the percentage of patients showing a PASI 90 reduction response was 32% of the placebo/40-mg-every-other-week group, 42% of the 40- mg-every-other-week group (n = 43), and 62% of the 40- mg-weekly group (n = 43). Dermatology Life Quality Index (DLQI), a complementary measure of disease severity, was assessed as well. The percentage of patients with a DLQI of 0 (patients not at all affected by their psoriasis) at 12 weeks was 1.9% (placebo), 33.3% (40 mg every other week), and 42% (40 mg weekly). These results correlate well with the PASI 90 response rates in all 3 groups at both time points. 14 SAFETY OF TNF INHIBITORS The TNF inhibitors share a number of common safety issues and concerns. These include infection, risk of lymphoma, demyelinating disease, heart failure, and drug-induced lupus. It should be noted that once screening for tuberculosis was done in patients who were going to receive these medications, the incidence of tuberculosis was almost eliminated during their use. It also should be noted that the incidence of lymphoma is increased 2- to 3-fold in patients with psoriasis and RA (perhaps as much as 4 to 26 times this correlated to disease activity in the latter), so data that relates TNF-α to use must account for this. Almost all data relating to TNF-α blockers and safety relates to their use for the treatment of RA and Crohn s disease. The intrinsic qualities of these disease states differ from the intrinsic qualities of psoriasis; therefore, extrapolation and comparison of side-effect profiles between disease states need further investigation before a true disease profile for the use of TNF-α inhibitors in patients with psoriasis can be defined. INFECTION Infection is an issue of major concern, and there have been multiple reports of reactivation of latent tuberculosis with use of infliximab The available in vitro and epidemiologic evidence for the TNF inhibitors infliximab and etanercept shows that the risk of development of active tuberculosis is higher with infliximab. 18 In controlled trials, however, an increased risk of serious infection in infliximab-treated patients has not been observed. 15 Hamilton 19 recently reviewed the infectious complications of biologic therapy. His review described the most important pathogen-specific infections and their relative frequency. Tuberculosis has continued to be the most common pathogen-specific infection reported in association with infliximab, but it is less commonly reported with etanercept and adalimumab. Determining treated-population case rates depends on having an accurate denominator and reflects the local population s latent infection rate. The same is true for histoplasmosis. Other pathogens that require intact cellular immunity for control of latent infection also have been reported. Specific recommendations for preventive therapy are being made, but prospective clinical trials are needed to assess the risk-benefit ratio of any particular approach. Hamilton concluded that microorganisms responsible for the infectious complications associated with anticytokine therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic latent state and are normally held in check by cell-mediated immunity. Diagnosis requires a high index of suspicion and prompt acquisition of appropriate tissue for microscopic examination and microbiologic culture. 19 LYMPHOMA One of the major concerns with the use of TNF inhibitors is the potential risk for development of lymphomas. Brown et al 20 investigated the occurrence of lymphoproliferative disorders in patients treated with these agents. They reviewed relevant data in the MedWatch postmarket adverse-event surveillance system run by the US FDA and identified 26 cases of lymphoproliferative disorders that followed treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-hodgkin s lymphomas. The inter- 200 Vol. 5, No. 4 April 2005

7 BIOLOGIC THERAPY FOR PSORIASIS val between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short: median 8 weeks. The authors concluded that, although data from a case series such as theirs cannot establish a clear causal relationship between exposure to these medications and risk of lymphoproliferative disease, the known predisposition of patients with diseases such as RA and Crohn s disease to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti-tnf drugs provide a biologic basis for concern and a justification for the initiation of additional epidemiologic studies to formally evaluate a possible association. 20 The risk of lymphoma increases in patients with RA, and spontaneous reporting suggests that methotrexate and anti-tnf therapy might be independently associated with an increased risk of lymphoma. Wolfe and Michaud 21 conducted a study to determine the rate of and Standardized Incidence Ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, they sought to determine predictors of lymphoma in RA. They prospectively studied patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma cases received detailed follow-up. The Survey, Epidemiology, and End Results (SEER) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort. 21 The overall SIR for lymphoma was 1.9 (95% confidence interval [CI], ). The SIR for biologic use was 2.9 (95% CI, ) and for the use of infliximab (with or without etanercept) it was 2.6 (95% CI, ). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI, ). The SIR for methotrexate was 1.7 (95% CI, ), and for those not receiving methotrexate or biologics it was 1.0 (95% CI, ). Lymphoma was associated with increasing age, male sex, and education. The authors concluded that lymphoma rates are increased in RA. Although SIR values are greatest for anti-tnf therapies, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with anti-tnf therapy may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive anti-tnf therapy. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma. 21 Adams et al 22 described 2 cases of cutaneous and systemic T-cell lymphoma that progressed rapidly in the setting of TNF-α blockade, 1 with etanercept and 1 with infliximab. Both cases were characterized by rapid onset, a fulminant clinical course with extensive cutaneous and systemic involvement, and death within months of diagnosis. A warning was recently added to the Remicade (infliximab) package insert. 23,24 Data from studies showed a 6-fold lymphoma increase among RA and Crohn s disease patients taking the drug. The studies showed a 3-fold increase among RA patients alone. The studies suggest that the combined population of patients with RA and Crohn s disease taking infliximab will have 12 cases of lymphoma for every patients taking the drug for 1 year. Among arthritis patients alone, there would be 7 lymphoma cases for every patients taking infliximab for 1 year. 23 The incidence of lymphomas in patients who received adalimumab is similar to that in the general RA population. Among 2468 RA patients treated in clinical trials with the drug for a median of 24 months, lymphoma was observed in 10 patients. The SIR (ratio of observed rate to age-adjusted expected frequency in the general population) for lymphomas was 5.4 (95% CI, ). 25 DEMYELINATING DISEASE There have been infrequent reports of central nervous system demyelinating disorders during treatment with anti-tnf agents. Several of these cases have been temporally related to anti-tnf therapy and have resolved when treatment was withdrawn. Mohan et al 25 reviewed the occurrence of neurologic events suggestive of demyelination during anti-tnf-α therapy for inflammatory arthritides. The Adverse Events Reporting System of the FDA was queried following a report of a patient with refractory RA who developed confusion and difficulty with walking after receiving etanercept for 4 months. Nineteen patients with similar neurologic events were identified from the FDA database, 17 whose events followed etanercept administration and 2 whose events followed infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti-tnf therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon. The authors concluded that further surveillance and studies are required to better define risk factors for demyelination and the frequency of adverse events and their relationship to anti-tnf therapies. Until more long-term safety data are available, consideration should be given to avoiding anti- TNF therapy in patients with preexisting multiple sclerosis and to discontinuation of anti-tnf therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation. Given these data, etanercept, infliximab, or adalimumab should be avoided in patients with a personal history of any central nervous system demyelinating disorder, and they should be used with caution in patients with a family history of these disorders. 26 Johns Hopkins Advanced Studies in Medicine 201

8 DERMATOLOGY HEART FAILURE There have been rare reports of heart failure in patients receiving anti-tnf therapy, but the relationship to therapy is unclear because the background rate of heart failure may be elevated in the patient populations receiving these drugs. Kwon et al, 27 utilizing the US FDA s MedWatch program, documented 47 patients who developed new or worsening heart failure during TNF antagonist therapy. After TNF antagonist therapy, 38 patients (26 etanercept, 12 infliximab) developed new-onset heart failure and 9 patients (3 etanercept, 6 infliximab) experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%; 12 etanercept, 7 infliximab) had no identifiable risk factors. The authors concluded that, in a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease. However, they also noted that these spontaneous reports alone are not sufficient to allow them to make causal inferences. 27 DRUG-INDUCED LUPUS Induction of antinuclear and anti-dna antibodies is observed in some patients treated with infliximab and etanercept. 28 Few if any cases of lupus have been related to adalimumab, although the risk of the induction of lupus is contained in the Humira package insert. 29 Recently, the induction of true lupus erythematosus by TNF-inhibitors has been observed. Few cases without major organ involvement that resolved after anti-tnf discontinuation were reported to be associated with infliximab treatment, 28,30-32 and only 4 cases have been described with the use of etanercept. 33 Etanercept-induced systemic lupus erythematosus has been noted even in the context of psoriasis. 34 DRUG-SPECIFIC ISSUES Infliximab has been associated with a number of Figure 4. Illustration of the Structure of Efalizumab adverse events. 15 Infusion reactions, reported in 19% of patients in clinical trials, consist of fever or chills or, more rarely, chest pain, hypotension, hypertension, and dyspnea. Neutralizing antibodies are formed, and patients can develop a serum sickness reaction days after administration of the drug. 15 Recently, live toxicity and decreased blood counts have been added to the warnings contained in the package insert of Remicade. 24 Etanercept has been used safely over the past few years. Injection-site reactions are the main adverse events noted. 15 There have been infrequent observations of allergic reactions and aplastic anemia. 15 There have been no reports of aplastic anemia occurring in patients with psoriasis, and it must be recalled that RA can be related intrinsically to Felty s syndrome that involves neutropenia; this implies that the blood dyscrasias are more common in patients with RA. Adalimumab has been associated with injectionsite reactions, erythema, pain, swelling, and itching seen in 20% of patients. 12 The incidence of less serious reactions like rash and pneumonia was significantly lower at 0.3% for both. 12 T-CELL TARGETED THERAPIES EFALIZUMAB (RAPTIVA ) Structure and Mechanism Efalizumab (Figure 4) is a humanized monoclonal antibody against the CD11a molecule. CD11a and CD18 are subunits of leukocyte function-associated antigen-1 (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell migration into skin, and cytotoxic T-cell function. Binding of this drug to CD11a on T-cells blocks the interaction between LFA-1 and intercellular adhesion molecule 1 (ICAM-1), its partner molecule for adhesion. The blockade is reversible and does not deplete T-cells. The drug currently is delivered as a weekly subcutaneous injection. CLINICAL EXPERIENCE Papp et al 35 reported the results of a double-blind, placebo-controlled, Phase II, multicenter study with anti-cd11a, in which 145 patients with minimum PASI scores of 12 and affected BSAs of 10% or more were enrolled sequentially into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. The patients were then randomized to treatment or placebo (n = 48) in a 2:1 ratio. Intravenous infusions were administered at weekly intervals for 8 weeks. Fifteen percent of placebo patients and 48% of those receiving the high dose of the drug achieved a >50% improvement in PGA after 1 week of receipt of the final dose. The PGA of excellent improvement (>75%) was 25% in the 0.3-mg/kg group (25%) compared with 2% in the placebo group. PASI scores also were lower in the group that received the drug (10.9 ( 8.4) than in the 202 Vol. 5, No. 4 April 2005

9 BIOLOGIC THERAPY FOR PSORIASIS placebo group (13.9 ± 7.5). The overall treatment was well tolerated and the most frequently observed adverse events were mild to moderate flulike symptoms. 35 Gottlieb et al 36 examined the immunobiologic and clinical effects of treatment with multiple doses of efalizumab. In an open-label, multiple-dose, dose-escalation study, 39 patients with stable, moderate to severe plaque psoriasis (>15% BSA involvement and a PASI score of >15) were treated with efalizumab. The subjects received infusions of the following dose levels for 7 weeks in an ascending-dose escalation paradigm: 0.1 mg/kg every other week or 0.1 mg/kg weekly (Category 1); 0.3 mg/kg weekly (Category 2); or 0.3, 0.4, then 0.6 mg/kg or 0.3, 0.4, 0.6, then 1.0 mg/kg for the remaining weeks (Category 3). The median baseline PASI score was 23, ranging from 15 to 42. Because of early discontinuations or damage to some biopsy samples during transit, histologic analyses were conducted for only 32 subjects. Skin biopsies were performed on days 0, 28, and The main outcome measures included serum efalizumab levels, levels of total and unoccupied T-cell CD11a, T-cell counts, epidermal thickness, cutaneous ICAM-1 and keratin 16 expression, as well as PASI scores. Results showed that Category 1 failed to maintain detectable serum efalizumab or T-cell CD11a downmodulation between doses. Category 2 achieved both, as did Category 3, which also maintained sustained T-cell CD11a saturation between doses. Clinically, the mean decrease in the PASI score was 47% in Category 3, 45% in Category 2, and 10% in Category 1 (P <.001). Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and keratin 16 expression decreased in Categories 2 and 3, but not in Category 1. Circulating lymphocyte counts also increased in Categories 2 and 3, which showed that intravenous efalizumab at a dose of 0.3 mg/kg or more per week produced clinical and histologic improvement in psoriasis, correlating with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation. 36 Recently, a Phase III trial with subcutaneous efalizumab showed promising results in treatment of moderate to severe plaque psoriasis. 37 In this multicenter, randomized, placebo-controlled, double-blind study, 597 subjects with psoriasis were assigned to receive subcutaneous efalizumab (1 or 2 mg/kg of body weight per week) or placebo for 12 weeks. Depending on the response after 12 weeks, subjects received an additional 12 weeks of treatment with efalizumab or placebo. Study treatments were discontinued at week 24, and subjects were followed for an additional 12 weeks. 37 At week 12, there was an improvement of 75% or more in the PASI in 22% of the subjects who had received 1 mg/kg of efalizumab per week and in 28% of those who had received 2 mg/kg of efalizumab per week, as compared with 5% of the subjects in the placebo group (P <.001 for both comparisons). Efalizumab-treated subjects had greater improvement than those in the placebo group as early as week 4 (P <.001). Among the efalizumab-treated subjects who had an improvement of 75% or more at week 12, improvement was maintained through week 24 in 77% of those who continued to receive efalizumab, compared with 20% of those who were switched to placebo (P <.001 for both comparisons). After the discontinuation of efalizumab at week 24, an improvement of 50% or more in the PASI was maintained in approximately 30% of subjects during the 12 weeks of follow-up. Efalizumab was well tolerated, and adverse events, such as skin rash, itch, and flulike symptoms, were mild to moderate in severity. The authors concluded that efalizumab therapy resulted in significant improvements in moderate to severe plaque psoriasis. Extending treatment from 12 to 24 weeks resulted in both maintenance and improvement of responses. 35 Gordon et al 38 assessed the efficacy and safety of efalizumab, a T-cell modulator, in patients with plaque psoriasis. In a Phase III randomized, double-blind, parallel-group, placebo-controlled trial that involved 556 adult patients with stable, moderate to severe plaque psoriasis and conducted at 30 study centers in the United States and Canada between January and July 2002, patients were randomly assigned in a 2:1 ratio to receive 12 weekly doses of subcutaneous efalizumab 1 mg/kg (n = 369) or placebo equivalent (n = 187). The following were assessed: at least 75% improvement on the PASI; improvement on the overall DLQI, itching visual analog scale, and Psoriasis Symptom Assessment (PSA) at week 12 vs baseline. 38 Efalizumab-treated patients experienced significantly greater improvement on all endpoints than did placebo-treated patients. Twenty-seven percent of efalizumab-treated patients achieved PASI 75 vs 4% of the placebo group (P <.001). Efalizumab-treated patients exhibited significantly greater mean percentage improvement than placebo-treated patients on the overall DLQI (47% vs 14%; P <.001), itching visual analog scale (38% vs -0.2%; P <.001), and PSA frequency and severity subscales (48% vs 18% and 47% vs 17%, respectively; P <.001 for both) at the first assessment point. Efalizumab was safe and well tolerated and was associated with primarily mild to moderate adverse events, such as skin rash, itch, and flulike symptoms. 38 SAFETY To date, no serious adverse events have been reported in association with the T-cell agents. The product labeling for efalizumab includes cautions about a potential increased risk of infection and malignancy, but an increase in the risk of either of these conditions has not been clearly demonstrated in either clinical tri- Johns Hopkins Advanced Studies in Medicine 203

10 DERMATOLOGY Figure 5. Illustration of the Structure of Alefacept Human LFA-3 Human IgG1 Fc Domain als or postmarketing surveillance. 39 There have been no opportunistic infections, no clinical signs of immunosuppression, and no hepatotoxicity or nephrotoxicity associated with the use of efalizumab. 15 In the Phase III trial, there was no evidence of T-cell depletion, nor of increased risk of end-organ toxicity or infection. Efalizumab is very well tolerated, and the only significant safety concern is the risk of psoriasis worsening during or after discontinuation of therapy. In clinical trials, 14% of efalizumab-treated subjects abruptly withdrawn from treatment experienced an increase in the severity of their psoriasis to a level worse than it had been at baseline (rebound). 39 Rebound following efalizumab discontinuation was much more likely to occur in patients who did not respond well to efalizumab, but it also can occur in treatment responders. A further minor safety concern during efalizumab therapy is thrombocytopenia. During clinical trials for efalizumab, a small number of patients (8/2762; 0.3%) experienced reversible thrombocytopenia. 39 The causal relationship between efalizumab therapy and thrombocytopenia is unknown, but Raptiva product labeling recommends obtaining platelet counts monthly for the first 3 months of efalizumab treatment, and every 3 months thereafter. 39 Generalized pustular psoriasis following withdrawal of efalizumab has been reported. 40 Headache was the most common dose-limiting toxicity observed at a single dose of 0.6 mg/kg or higher. The package insert of efalizumab (Raptiva) discusses the induction of malignancy involved with its use. 39 Among the 2762 psoriasis patients who received efalizumab at any dose (median duration of 8 months), 31 patients were diagnosed with 37 malignancies. The overall incidence of malignancies of any kind was 1.8 per 100 patient-years for efalizumab-treated patients compared with 1.6 per 100 patient-years for placebotreated patients. Malignancies observed in the efalizumab-treated patients included nonmelanoma skin cancer, non-cutaneous solid tumors, Hodgkin s and non-hodgkin s lymphoma, and malignant melanoma. The incidence of noncutaneous solid tumors (8 in 1790 patient-years) and of malignant melanoma were within the range expected for the general population. The majority of the malignancies were nonmelanoma skin cancers; 26 cases (13 basal, 13 squamous) in 20 patients (0.7% of 2762 efalizumab-treated patients). The incidence of malignancies in efalizumab-treated patients was comparable with that in placebo-treated patients. ALEFACEPT (AMEVIVE ) Structure and Mechanism Psoriatic plaques are characterized by infiltration with CD4+, CD45RO+, CD8+, and CD45RO+ memory-effector T-lymphocytes. The recombinant protein alefacept binds to CD2 on memory-effector T-lymphocytes, inhibiting their activation and reducing the number of these cells. Alefacept is a fusion protein composed of leukocyte function-associated antigen type 3 (LFA-3) protein and human IgG1 Fc domains (Figure 5). The method of action of alefacept in the treatment of psoriasis is also affected by granzyme-dependent T-cell apoptosis via an alefacept-mediated bridge to selectively target natural killer cells. The drug is administered weekly by intramuscular injection. The intravenous form of this medication is no longer available. CLINICAL EXPERIENCE In a multicenter, randomized, placebo-controlled, double-blind study, Ellis et al 41 evaluated alefacept as a treatment for psoriasis. Two hundred twenty-nine patients with chronic psoriasis received intravenous alefacept (0.025, 0.075, or mg/kg of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks. Before treatment, the median PASI scores were between 14 and 20 in all groups (0 denotes no psoriasis and 72 the most severe disease possible). In the study, alefacept was well tolerated and nonimmunogenic. The mean reduction in the PASI score 2 weeks after treatment was greater in the alefacept groups (38%, 53%, and 53% in the groups that received 0.025, 0.075, and mg/kg, respectively) than in the placebo group (21%; P <.001). Twelve weeks after treatment, 28 patients who had received alefacept alone were clear or almost clear of psoriasis. Three patients in the placebo group were clear or almost clear; all 3 had received additional systemic therapy for psoriasis. Alefacept reduced peripheral blood memory-effector T- lymphocyte (CD45RO+) counts, which correlated with the improvement in psoriasis. Similar responses were seen in a retreatment study in which one half of the patients achieved more than 50% improvement and one fifth improved by 75% Vol. 5, No. 4 April 2005

11 BIOLOGIC THERAPY FOR PSORIASIS An international multicenter trial randomized more than 500 patients to 1 of 3 arms: intramuscular alefacept 15 mg once a week for 12 weeks, intramuscular alefacept 10 mg once a week for 12 weeks, or placebo. 42 Two weeks after the last dose was given, 21% of patients treated with the 15-mg dose achieved at least a 75% reduction from baseline in their PASI score, compared with 5% of patients receiving placebo (P <.001). 42 Another multicenter Phase III study evaluated the efficacy and tolerability of once-weekly alefacept 7.5 mg administered by 30-second intravenous bolus in patients with moderate to severe chronic plaque psoriasis. 43 This study consisted of 2 treatment courses, each with a 12- week treatment and 12-week follow-up phase. Patients (n = 553) were randomized to 1 of 3 cohorts: Cohort 1 received alefacept during both courses; Cohort 2 received alefacept followed by placebo; and Cohort 3 received placebo followed by alefacept. Clinical response was measured by change in PASI from baseline and by PGA. During the first course of treatment, 14% and 4% of patients who received alefacept and placebo, respectively, achieved 75% improvement in PASI at week 14 (primary endpoint; P <.001). PASI improvement of 50% was achieved by 38% of alefacept-treated patients and by 10% of placebo patients at week 14 after the first course (P <.001). At any time after the first dose of alefacept during the first course of treatment, 28% and 56% of patients achieved 75% and 50% PASI improvement, respectively (P <.001 vs placebo). Patients in Cohort 1 who were randomized to receive 2 courses of alefacept showed additional improvement at the end of the second course of therapy, with 40% and 71% of subjects achieving 75% and 50% PASI improvement at any time point. The percentages of these patients who achieved clear or almost clear on PGA at any time after the first dose were 23% after the first course of alefacept and 32% after the second course of therapy. There was no increased risk of infection (placebo, 11%; alefacept, 10%) and no complicated or opportunistic infections associated with alefacept therapy. 43 Krueger and Ellis 44 recently reported that alefacept therapy produces remission for patients with chronic plaque psoriasis. In the previously published, randomized, placebo-controlled Phase II study of intravenous alefacept in 229 patients with chronic plaque psoriasis, clinical improvement was observed during dosing as well as in the postdosing follow-up period. 41 The investigators objective was to assess the remission period that followed alefacept therapy in this population. 44 The time before retreatment was required was measured in patients who were clear or almost clear of disease, according to a PGA at the end of the follow-up phase. In these patients, responses were sustained for a median of 10 months and for up to 18 months. No patient reported disease rebound after cessation of alefacept. 44 In the evaluation of alefacept it must be noted that Phase III studies did not show a correlation between peripheral T-cell drop and clinical response. SAFETY In terms of adverse events, patients treated with alefacept have a reduction in CD45RO+ memory T-cells, which correlates with improvement in psoriasis. To date, no clinically significant signs of immunosuppression or opportunistic infections, and no increase in malignancy, have been observed. 15 In the United States, weekly monitoring of T-cells is recommended in patients treated with alefacept. The product labeling for Amevive includes cautions about a potential increased risk of infection and malignancy, but an increase in the risk of either of these conditions has not been clearly demonstrated in either clinical trials or postmarketing surveillance. 45 There seem to be no serious safety concerns that are specific for alefacept. Alefacept does cause transient decreases in CD4+ and CD8+ cell counts, but there is no evidence that this significantly affects overall immune function. The product labeling for Amevive states that CD4+ and CD8+ cell counts must be monitored weekly and that alefacept therapy should be withheld if counts are below normal (250) and suspended if counts stay below normal for 1 month or more, or if counts come up and then decrease again. 43 PREGNANCY CATEGORY Biologic medications should be used during pregnancy only when clearly indicated. Infliximab, alefacept, etanercept, and adalimumab are pregnancy category B. Efalizumab is pregnancy category C; this labeling is justified by animal experiments that focused on antibody responses, which have not been conducted for any of the biologic agents that are categorized as pregnancy category B. 8,24,29,39,45 CONCLUSION Biologic therapy research continues to make great strides in the treatment of psoriasis. With continued progress at this rate, it is possible that one or more of these biologic agents will become major therapeutic options for psoriasis. The data from clinical trials are very encouraging (Table 2), but we await further data on many of these medications, as well as on those treatments that will follow. These therapies offer successful therapy for psoriasis, with a lack of organ toxicity seen with traditional systemic therapies such as methotrexate and cyclosporine. Limitations of the current data include the lack of direct head-to-head comparisons with traditional agents, and the absence of pharmacoeconomic evaluations of these agents, especially given the expected high costs of treatment. Long-term monitoring of these agents is necessary Johns Hopkins Advanced Studies in Medicine 205