The efficacy of inhibiting tumour necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons

Rheumatology (Oxford). 2007 Jul;46(7):1140-7. doi: 10.1093/rheumatology/kem072. Epub 2007 May 3.


Objective: New treatments that inhibit the cytokines tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1) in the treatment of rheumatoid arthritis have proven clinical effect against placebo and methotrexate (MTX) in several clinical trials in early and late-stage disease and different severity groups. Since there are no head-to-head randomized controlled trials directly comparing the currently available treatments, etanercept, adalimumab, infliximab or anakinra, we perform a meta-analysis that adjusts for differences between study characteristics, and allows indirect comparisons between treatments.

Methods: Thirteen trials of cytokine antagonists were included from a systematic review of the literature. They reported the primary outcome of American College of Rheumatology (ACR) response criteria at 6 months or beyond. Meta-analytical methods are used to quantify relative treatment effects, using the log odds ratio of an ACR20 or ACR50 response at 6 months, whilst adjusting for study-level variables.

Results: In each of the trials, cytokine treatment was efficacious in comparison with placebo or MTX. For each treatment, the inclusion of MTX in combination improved the response. After adjustment for study-level variables, we found TNFalpha antagonists to be more efficacious compared with anakinra (P < 0.05). Indirect comparisons between the three TNFalpha antagonists indicated no difference in efficacy. Sensitivity analysis using a different statistical model structure confirmed these results.

Conclusion: When the outcome of interest is the probability of an ACR20 or ACR50 response at 6 months we found: (i) treatment with the IL-1 antagonist anakinra is better than placebo; (ii) for each treatment, the use of combination MTX improves the probability of response; (iii) treatment with any of the TNFalpha antagonists is better than with the IL-1 antagonist anakinra; and (iv) all drugs in the TNFalpha antagonist class are no different from each other.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Systematic Review

MeSH terms

  • Adalimumab
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Arthritis, Rheumatoid / drug therapy*
  • Drug Therapy, Combination
  • Etanercept
  • Humans
  • Immunoglobulin G / therapeutic use
  • Immunosuppressive Agents / therapeutic use*
  • Infliximab
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-1 / antagonists & inhibitors*
  • Methotrexate / therapeutic use
  • Randomized Controlled Trials as Topic
  • Receptors, Tumor Necrosis Factor / therapeutic use
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Adalimumab
  • Etanercept
  • Methotrexate