Costimulatory blockade in patients with rheumatoid arthritis: a pilot,
dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig
and LEA29Y eighty-five days after the first infusion.
Author(s): Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, Cohen S,
Luggen M, Shergy W, Nuamah I, Becker JC.
Affiliation(s): Spain Rehabilitation Center, University of Alabama at Birmingham, 1717 6th Avenue
South, Room 068, Birmingham, AL 35294-7201, USA. larry.moreland@ccc.uab.edu
Publication date & source: 2002, Arthritis Rheum. , 46(6):1470-9
OBJECTIVE: T cells are involved in the pathogenesis of rheumatoid arthritis (RA).
In animal models of autoimmune diseases, blockade of costimulatory molecules on
antigen-presenting cells has been demonstrated to be effective in preventing or
treating this disease by preventing T cell activation. To date, the effect of
costimulatory blockade in patients with RA is unknown. The goal of this
multicenter, multinational study was to determine the safety and preliminary
efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who
have been treated unsuccessfully with at least 1 disease-modifying agent.
METHODS: CTLA-4Ig, LEA29Y (0.5, 2, or 10 mg/kg), or placebo was administered
intravenously to 214 patients with RA. Patients received 4 infusions of study
medication, on days 1, 15, 29, and 57, and were evaluated on day 85. The primary
end point was the proportion of patients meeting the American College of
Rheumatology 20% improvement criteria (ACR20). All patients were monitored for
treatment safety and tolerability.
RESULTS: CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels.
Peri-infusional adverse events were carefully monitored, and showed similar
incidence across all dose groups with the exception of headaches, which were
slightly more frequent in the 2 treatment groups. The incidence of
discontinuations due to worsening of RA was 19%, 12%, and 9% at 0.5, 2, and 10
mg/kg, respectively, in the CTLA-4Ig-treated patients and 3%, 3%, and 6% at 0.5,
2, and 10 mg/kg, respectively, in the LEA29Y-treated patients (versus 31% in the
placebo group). ACR20 responses on day 85 had increased in a dose-dependent
manner (23%, 44%, and 53% of CTLA-4Ig-treated patients and 34%, 45%, and 61% of
LEA29Y-treated patients at 0.5, 2.0, and 10 mg/kg, respectively, versus 31% of
placebo-treated patients).
CONCLUSION: Both of the costimulatory blocking molecules studied were generally
safe and well tolerated. As compared with placebo, both CTLA-4Ig and LEA29Y
demonstrated efficacy in the treatment of RA.
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