ArticlesInfliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial
Introduction
Disease modifying antirheumatic drugs (DMARDS) are useful in the treatment of rheumatoid arthritis. By current consensus, weekly methotrexate has become the standard DMARD in clinical practice,1, 2 either singly or in combination with other DMARDS.3, 4 However, not all patients tolerate these drugs or show an acceptable therapeutic response to them;5 this has led to the development of treatment based on a better knowledge of the pathogenesis of rheumatoid arthritis.
There is mounting evidence for a central role of tumour necrosis factor α in the pathogenesis of rheumatoid arthritis, and tumour necrosis factor α has emerged as a molecular target for treatment of rheumatoid arthritis.6, 7 The first such agent to be assessed in rheumatoid arthritis was a chimeric human-murine monoclonal antibody, a specific inhibitor of tumour necrosis factor α (infliximab, cA2, Remicade, Centocor Inc).8, 9 Several trials have established the efficacy of various anti-tumour necrosis factor agents in relieving symptoms and signs of the disease.10, 11, 12, 13, 14 In a recent trial in a small number of patients, infliximab in combination with a fixed low-dose (7·5 mg per week) of methotrexate in rheumatoid arthritis patients with active disease despite methotrexate treatment, showed enhanced degree and duration of efficacy.15 The combination of methotrexate and a tumour necrosis factor-receptor-IgG1 fusion protein (etanercept, Enbrel) is also effective in rheumatoid arthritis patients unresponsive to methotrexate alone.16
This placebo-controlled, double-blind, randomised trial of anti-tumour necrosis factor therapy in patients who were inadequately controlled on methotrexate was undertaken to determine whether infliximab, at two doses every 4 or 8 weeks, added to therapeutic doses of methotrexate, is safe and effective in relief of signs and symptoms of disease.
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Patients
Patients were eligible if they had been diagnosed with rheumatoid arthritis according to the 1987 American College of Rheumatology criteria and had evidence of active disease despite treatment with methotrexate (six or more swollen and tender joints plus two of: morning stiffness greater than or equal to 45 min, erythrocyte sedimentation rate greater than 28 mm/h, C-reactive protein greater than 2 mg/dL. The patients were classified into a functional class (American College of Rheumatology
Characteristics of randomised population
The baseline characteristics of the five treatment groups were well matched (table 1), and consisted of a predominantly white, female, rheumatoid factor-positive population, with a median age range of 51–56 years, and disease duration of 7·2 to 9·0 years. About half the patients were in functional class III and three of 428 in functional class IV. In the treatment groups a mean of 2·5–2·8 DMARDS (excluding methotrexate) had been used and included drugs such as gold (237 patients, 63%),
Safety
The eight infliximab infusions were generally well tolerated. Adverse experiences (table 4) were common in all groups, including placebo, and were reported at least once in over 80% of patients. Upper respiratory tract infections and headache were the most commonly seen adverse events. 14–16 patients (16–20%) receiving infliximab, compared with nine (10%) treated with placebo (p=0·477) developed an infusion reaction, defined as any adverse experience occurring during, or up to 1 h after
Discussion
This placebo-controlled trial provides evidence for a rapid reduction in disease activity measurements in response to infliximab at 3 mg/kg and 10 mg/kg in patients inadequately controlled with therapeutic doses of methotrexate, with a significant improvement in over half the treated patients. Maintenance treatment with infliximab 3 mg/kg every 8 weeks (the lowest dose used) shows that the response is sustained for up to 30 weeks with equivalent efficacy to 3 mg/kg every 4 weeks and 10 mg/kg
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