Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies

Rheumatology (Oxford). 2014 Oct;53(10):1872-85. doi: 10.1093/rheumatology/keu172. Epub 2014 May 11.


Objective: The aim of this study was to assess the risk of active tuberculosis (TB) in patients with immune-mediated inflammatory diseases treated with biologics and tofacitinib in randomized controlled trials (RCTs) and long-term extension (LTE) studies.

Methods: A systematic review of the English-language literature by was performed by searching the Medline, Embase, Cochrane and Web of Knowledge databases. The search strategy focused on synonyms of diseases, biologics and tofacitinib. Data from RCTs were combined to assess the rate of TB using a random effects model. The incidence rate (IR) of TB and its association with disease, location and treatment were assessed in LTE studies.

Results: The search captured 11 130 articles and abstracts. One-hundred RCTs (75 000 patients) and 63 LTE studies (80 774.45 patient-years) met the inclusion criteria. There were 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib. The odds ratio for TNF inhibitors was 1.92 (95% CI 0.91, 4.03, P = 0.085). In LTE studies, the IR of TB was >40/100 000 with tofacitinib and all biologics except rituximab. IR was higher in RA patients with anti-TNF monoclonal antibodies [307.71 (95% CI 184.79, 454.93)] than in those with rituximab [20.0 (95% CI 0.10, 60)] and etanercept [67.58 (95% CI 12.1, 163.94)] or AS, PsA and psoriasis with etanercept [60.01 (95% CI 3.6, 184.79)]. The IR of TB was higher in high-background TB areas.

Conclusion: RCTs are not sensitive enough to assess the risk of reactivation of latent TB infection (LTBI). Disease, treatment and background TB rate are associated with different frequencies of active TB. The benefit/risk balance of preventing reactivation of LTBI in different backgrounds should be considered in clinical practice.

Keywords: biologic drugs; inflammatory diseases; safety; tofacitinib; tuberculosis.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Biological Products / adverse effects*
  • Biological Products / therapeutic use
  • Humans
  • Incidence
  • Latent Tuberculosis / epidemiology
  • Latent Tuberculosis / etiology*
  • Piperidines / adverse effects*
  • Piperidines / therapeutic use
  • Pyrimidines / adverse effects*
  • Pyrimidines / therapeutic use
  • Pyrroles / adverse effects*
  • Pyrroles / therapeutic use
  • Risk
  • Tuberculosis / epidemiology
  • Tuberculosis / etiology*


  • Biological Products
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • tofacitinib