CTLA4Ig Shows Promise in the Treatment of RA

After lackluster success with T-cell oriented therapies (such as anti-CD4 antibodies, cyclosporine, tacrolimus, and vaccination strategies), the past decade of interest in drug development of RA therapies has centered on selective cytokine inhibition and more recently, on targeted B-cell therapies. Resurrecting interest in T-cell oriented therapies, Kremer et al (NEJM 349;20:1907, 2003) investigate CTLA4Ig in RA patients with an inadequate response to methotrexate. CTLA4Ig, a fully human fusion protein consisting of the binding domain of human cytotoxic T-lymphocyte-associated antigen 4 to human IgG1, works by binding CD80 and CD86 on antigen presenting cells. Preventing this binding blocks the engagement of CD28, a sequence of co-stimulatory events required for optimal activation of T cells, a process important for the maintenance of the inflammatory response in RA.

Methods: Patients with active RA and at least six months of treatment with methotrexate were randomized into one of three groups: CTLA4Ig 2mg/kg, CTLA4Ig 10 mg/kg, or placebo. Methotrexate, stable for the 28 days before enrollment, was continued while all other DMARDs were discontinued 1-2 months prior to enrollment. Stable low-dose prednisone and NSAIDs were allowed. Study drug was administered as an IV infusion at baseline, at 15 days, 30 days, and monthly thereafter for a total of 6 months. Blinded efficacy and safety measurements were taken at each infusion. The primary efficacy variable was ACR 20 response at 6 months. Safety was assessed via adverse event reporting and the development of drug-specific antibodies.

Results: Baseline characteristics were similar between the three groups and were typical for this type of therapeutic RA trial (i.e. mean age 55 years, 63-75% female, 87% Caucasian) except for the presence of rheumatoid factor, which was 90-99% present. The groups were evenly matched for methotrexate dose (approx 15mg/week). Baseline disease activity would be considered high, despite concurrent methotrexate. Eighty patients discontinued the study prior to completion, half of whom were from the placebo group. Most discontinued because of lack of efficacy. The number of patient discontinuations due to lack of efficacy was more than two fold higher in the placebo group than in either of the treatment groups. Analysis by last observation carried forward was performed. When intention-to-treat analysis was performed, results were essentially the same.

Approximately sixty percent of patients in the CTLA4Ig 10mg/kg group achieved an ACR 20 response by 2 months. This degree of ACR 20 response was sustained to study conclusion in this group (6 months) and was significant compared with placebo, in which only 35.3% of patients had achieved an ACR 20 response at 6 months.

Other efficacy endpoints, measured through the SF-36 questionnaire, showed clinically meaningful and significant differences between the CTLA4Ig 10mg/kg group compared with placebo in all eight subscales at six months. Smaller improvements were observed in the CTLA4Ig 2mg/kg group, but these were only significant compared to placebo in terms of pain.

No deaths, malignancies, or opportunistic infections were noted. One serious infection (cellulitis) occurred in a patient in the CTLA4Ig 2mg/kg group. No serious adverse events related to the study drug were observed in the CTLA4Ig 10mg/kg group. The development of antibodies to CTLA4Ig was observed in two patients, one in each of the two active treatment groups. No clinical significance was ascribed to these.

Conclusions: CTLA4Ig given at a dose of 10mg/kg as a monthly infusion with concurrent methotrexate is safe and effective in improving quality of life and reducing the signs and symptoms of active RA.

Editorial Comments: This is the first report of a successful intervention in RA that targets T-B cell interactions. Extension trials and further investigation are required to establish the durability of the observed effects, the risk of serious infections or malignancies after prolonged exposure, effect on radiographic progression, and the clinical significance of drug-specific antibody formation. Further, the potential for combination therapies with TNF inhibitors is intriguing.