The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials

Am J Med. 2014 Dec;127(12):1208-32. doi: 10.1016/j.amjmed.2014.06.012. Epub 2014 Jun 17.


Objective: The study objective was to evaluate and update the safety data from randomized controlled trials of tumor necrosis factor inhibitors in patients treated for rheumatoid arthritis.

Methods: A systematic literature search was conducted from 1990 to May 2013. All studies included were randomized, double-blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs).

Results: Forty-four randomized controlled trials involving 11,700 subjects receiving tumor necrosis factor inhibitors and 5901 subjects receiving placebo or traditional disease-modifying antirheumatic drugs were included. Tumor necrosis factor inhibitor treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% confidence interval [CI], 1.13-1.78) and treatment discontinuation due to adverse events (OR, 1.23; 95% CI, 1.06-1.43) compared with placebo and traditional disease-modifying antirheumatic drug treatments. Specifically, patients taking adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63, respectively) and showed an increased risk of discontinuation due to adverse events (OR, 1.38, 1.67, and 2.04, respectively). In contrast, patients taking etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for malignancy varied across the different tumor necrosis factor inhibitors, none reached statistical significance.

Conclusions: These meta-analysis updates of the comparative safety of tumor necrosis factor inhibitors suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis.

Keywords: Adverse events; Meta-analysis; Rheumatoid arthritis; Safety; Tumor necrosis factor inhibitors.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adalimumab
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Certolizumab Pegol
  • Etanercept
  • Humans
  • Immunoglobulin Fab Fragments / adverse effects
  • Immunoglobulin G / adverse effects
  • Infliximab
  • Polyethylene Glycols / adverse effects
  • Randomized Controlled Trials as Topic
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents
  • Immunoglobulin Fab Fragments
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Polyethylene Glycols
  • golimumab
  • Infliximab
  • Adalimumab
  • Etanercept
  • Certolizumab Pegol