Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN

Gut. 2022 Feb;71(2):287-295. doi: 10.1136/gutjnl-2021-325185. Epub 2021 Aug 3.

Abstract

Objective: Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD).

Design: We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days.

Results: Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA.

Conclusion: ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.

Keywords: TNF-alpha; antibiotics; inflammatory bowel disease; infliximab; intestinal microbiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / immunology*
  • Adalimumab / therapeutic use
  • Adult
  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Antibody Formation / drug effects*
  • Female
  • Humans
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / mortality
  • Infliximab / immunology*
  • Infliximab / therapeutic use
  • Israel
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Registries
  • Survival Analysis
  • Tumor Necrosis Factor Inhibitors / immunology*
  • Tumor Necrosis Factor Inhibitors / therapeutic use
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Tumor Necrosis Factor Inhibitors
  • Infliximab
  • Adalimumab