Elsevier

The Lancet

Volume 354, Issue 9194, 4 December 1999, Pages 1932-1939
The Lancet

Articles
Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial

https://doi.org/10.1016/S0140-6736(99)05246-0Get rights and content

Summary

Background

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 α (TNF α) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.

Methods

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 ≥6 months, range 10–35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.

Findings

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.

Interpretation

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.

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.

Section snippets

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

References (23)

  • MJ Elliott et al.

    Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α.

    Arthritis Rheum

    (1993)
  • Cited by (2330)

    View all citing articles on Scopus
    View full text