Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group.
Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.
                In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.
                At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.
                During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate. To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression.
                Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients randomized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data.
                LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P = 0.0007 and MTX versus placebo P = 0.0196; for protocol MN301, LEF versus placebo P = 0.0004 and SSZ versus placebo P = 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ.
                These are the first 6- and 12-month randomized placebo- and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ.
Treatment with infliximab for 6 and 12 months significantly reduces RA disease activity and appeared to have an acceptable safety profile in these trials. Total radiographic scores improved, fewer patients showed radiographic progression, and more patients showed radiographic improvement with infliximab treatment at 12 months compared to controls. However, only 2 trials met the inclusion criteria, and these results are largely driven by the largest trial. The available efficacy and toxicity data is relatively short-term (6-12 months). In order to detect rare events that may be associated with infliximab, larger and longer term studies are required.