Alefacept in combination with methotrexate for treatment of active psoriatic arthritis: rationale and design of a randomized, double-blind, placebo-controlled study

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that may result in considerable joint damage if left untreated. Although the pathogenesis of PsA is uncertain, evidence suggests that T cells play an important role in this inflammatory disease. Alefacept selectively reduces memory (CD45RO+) T cells by interacting with the CD2 receptor. It is efficacious in moderate to severe plaque psoriasis—clinical improvements correlate with reductions in the memory T-cell subset. Preliminary data in active PsA showed that alefacept was well tolerated. Patients who responded with 20%, 50%, or 70% reduction in global assessments of disease activity had the greatest reductions in memory T cells, both in the circulation and synovial tissue. Based on these favorable results, a randomized, double-blind, placebo-controlled study is underway to further evaluate the efficacy and safety of alefacept when administered in combination with methotrexate in a larger population of patients with PsA. It is anticipated that the combination of alefacept and methotrexate will be used in clinical practice. Eligible patients must be 18-70 years of age, have CD4+ T-cell counts at or above the lower limit of normal, and have active PsA (at least 3 swollen joints and at least 3 tender joints) despite treatment with methotrexate (10 mg/week up to 25 mg/week) for at least 3 months before the study. The dose of methotrexate must be stable for at least 4 weeks before enrollment. Randomization will be stratified based on body surface area (BSA) involvement of chronic plaque psoriasis (3% or greater, <3%) to maintain a 2:1 ratio of alefacept versus matching placebo. Alefacept 15 mg and placebo will be administered by intramuscular injection once weekly for 12 weeks followed by a 12-week observation period. All patients will continue to receive their stable dose of methotrexate for the entire 24-week study period. Stable doses of NSAIDs and steroids (up to 10 mg/day) will be permitted. The primary efficacy endpoint will be the proportion of patients achieving ACR 20, ACR 50, and ACR 70 responses at 24 weeks and at any time during the study. Additional efficacy evaluations will include PASI and PGA for psoriasis patients with BSA involvement of at least 3%, erythrocyte sedimentation rate, and C-reactive protein. Safety will be assessed by adverse events, infections, hematology, blood chemistry, urinalysis, vital signs, physical examinations, and anti-alefacept antibodies.