T Cell Blockade Appears to be Efficacious in the Treatment of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease. T cells play a significant role in adaptive immunity and are therefore relevant in the pathogenesis RA. Recent studies of Cytotoxic T Lymphocyte-associated Antigen 4 ImmunoGlobulin (CTLA-4Ig) in animal models have shown that inhibition of T cell activation by blockade of costimulatory molecules on antigen presenting cells displayed clinical efficacy and improvement in autoimmune disease. The purpose of this study by Moreland et al. (Arthritis and Rheum. 46;1470-1479;2002) was to assess the safety and efficacy of costimulatory blockade of CD80 and CD86 using CTLA-4Ig and LEA29Y in patients with refractory rheumatoid arthritis (RA). LEA29Y is a second-generation molecule of CTLA-4Ig with two amino acid mutations.
Methods: 214 patients with active RA were randomized into a multicenter, multinational, double-blinded placebo controlled trial and randomized to placebo, 0.5, 2, or 10 mg/kg of CTLA-4Ig or LEA29Y. All disease modifying anti-rheumatic drug (DMARDS) were discontinued 28 days prior to baseline, but stable doses of corticosteroids (< 10 mg/day) and non-steroidal anti-inflammatory drugs (NSAIDS) were maintained. Study treatment was administered intravenously on day 1, 15, 29, and 57. Additionally, specific antibody formation against CTLA-4Ig and LEA29Y with and without the immunoglobulin constant regions was evaluated in serum and compared to pre-dose serum for each subject. The primary outcome measure of 20 % improvement in clinical response (ACR20) was evaluated on day 85. Assessments of safety and tolerability were monitored throughout the duration of the study. Also, subject follow-up continued through day 169.
Results: The patient population was 75% female and 91% white with mean duration of RA of 3.4 + 2 years. Of the 214 patients who received study medication, 90 received CTLA-4Ig, 92 received LEA29Y, and 32 received placebo. At baseline, the mean number of tender and swollen joints for all subjects was 30.3 + 13.9 and 21.9 + 10 respectively. On day 85 the observed ACR20 responses increased in a dose dependent manner and were 23%, 44%, 53% for CTLA-4Ig and 34%, 45%, 61% for LEA29Y dosed at 0.5, 2, and 10mg/kg respectively, in comparison to 31% placebo. 81% of the patients completed follow up through day 85, and 160 patients completed follow up through day 169. The most common reason for discontinuation of the protocol was worsening arthritis; discontinuation frequencies were 31% for placebo, 13% for CTLA-4Ig, and 4% for LEA29Y.
The incidence of adverse events was similar across all treatment groups with no observed significant renal, hepatic, or hematologic adverse events. 117 peri-infusional events occurred with similar frequencies of 29%, 34%, and 31% in CTLA4Ig, LEA29Y, and placebo dose groups respectively. The most common peri-infusional events were nausea/vomiting in CTLA-4Ig treated patients (7%) versus placebo (3%) and headache in LEA29Y treated patients (8%) versus placebo (3%). Also, the frequency of serious adverse events was greater in the placebo treated group (13%) in comparison to the active treatment groups (4%) due to worsening of RA and was unrelated to study treatment. However, one case of septic arthritis was assessed as possibly related to study drug.
Conclusion: The results suggest that both CTLA-4Ig and LEA29Y at 2mg/kg and 10 mg/kg were effective in decreasing the signs and symptoms of RA were also generally safe for the short duration of the study.
Editorial Comment: This is an important study because it is the first clinical trial in RA aimed at inhibiting (or depleting) T cells that suggests efficacy. Prior T cell directed therapies such as anti-CD4 and anti-IL2 monoclonal antibodies were not efficacious, at least in Phase I trials. No statistics are provided, so that it is unclear whether the modest ACR 20/50/70 responses in the treated groups are significantly higher than placebo. Additional studies with background methotrexate, however, are showing the same trends. (see EULAR 2002 highlights)Further work with these compounds may shed light on the role of T cells in the pathogenesis of RA.