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Psoriasis as a Model for T-Cell–Mediated Disease

2002; American Medical Association; Volume: 138; Issue: 5 Linguagem: Inglês

10.1001/archderm.138.5.591

1538-3652

Alice B. Gottlieb, James G. Krueger, Knut M. Wittkowski, Russell L. Dedrick, Patricia A. Walicke, Marvin R. Garovoy,

Asthma and respiratory diseases

Background Leukocyte function–associated antigen 1 (LFA-1), consisting of CD11a and CD18 subunits, plays an important role in T-cell activation and leukocyte extravasation. Objective To test whether blocking CD11a decreases immunobiologic and clinical activity in psoriatic plaques. Design Open-label, multicenter, dose escalation study. Patients Thirty-nine patients with moderate-to-severe psoriasis. Intervention Intravenous infusions of efalizumab, a humanized anti-CD11a monoclonal antibody, for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (category 1), 0.3 mg/kg weekly (category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (category 3). Skin biopsies were performed on days 0, 28, and 56. Main Outcome Measures Serum efalizumab levels, levels of total and unoccupied T-cell CD11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index (PASI) scores. Results Dose-response relationships were observed for pharmacokinetics and pharmacodynamic measures. Category 1 failed to maintain detectable serum efalizumab or T cell CD11a down-modulation between doses. Category 2 achieved both. Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses. A dose-response relationship was also observed clinically and histologically. 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 K16 expression decreased in categories 2 and 3 but not in category 1. Circulating lymphocyte counts increased in categories 2 and 3. Conclusions At doses of 0.3 mg/kg or more per week, intravenous efalizumab produced significant clinical and histologic improvement in psoriasis, which correlated with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation.