Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Systematic review and meta-analysis

Joint Bone Spine. 2014 May;81(3):215-21. doi: 10.1016/j.jbspin.2013.07.009. Epub 2013 Aug 7.


Background: TNF blockers have demonstrated efficacy in inflammatory rheumatic diseases (IRDs). The drugs are associated with a moderate but definite risk of bacterial infection, but risk of viral infection is not clearly known.

Objective: To assess the risk of herpes zoster (HZ) reactivation in patients with rheumatoid arthritis (RA) receiving TNF blockers as compared with DMARDs.

Methods: A systematic search of literature up to March 2013 was performed, in MEDLINE, EMBASE, the Cochrane library and abstracts from the ACR and EULAR congresses from 2008 to 2011. Studies were included if they reported the incidence of HZ, respectively, in patients receiving anti-TNF and conventional DMARDs.

Results: The literature search identified 3446 articles and 88 congress abstracts; a manual search retrieved seven articles. Finally, 26 articles and nine abstracts were included; six articles and one abstract were of meta-analyses estimating the relative risk of HZ in patients with RA with a total follow-up of 163,077 patient-years. From the meta-analyses of data for seven registries, the pooled risk ratio for HZ with TNF blockers was 1.61 [95% CI 1.16-2.23] (P = 0.004). Proportions of severe HZ ranged from 4.9% to 20.9% with TNF-blockers and from 2.0% to 5.5% with conventional DMARDs, in the different registries.

Conclusions: This meta-analysis revealed a significantly increased risk of HZ, up to 61%, in patients with IRD receiving TNF blockers. These data raise the issue of systematic prophylactic treatment with known history of HZ or vaccination without this history.

Keywords: Herpes zoster; Meta-analysis; Rheumatoid arthritis; TNF inhibitors.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Herpes Zoster / etiology
  • Herpesviridae Infections / etiology*
  • Humans
  • Risk
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors


  • Antirheumatic Agents
  • Tumor Necrosis Factor-alpha