Colon to Rectum
Gut. 2022;71(2):287–95
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
Objective: Anti-drug antibodies (ADA) to anti-tumor necrosis factor (TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. This study therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD).
Design: The authors analyzed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. They 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 (hazard ratio [HR] = 1.97, 95% confidence interval [CI]: 1.58–2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR = 1.4, 95% CI: 1.13–1.74), whereas a reduced risk was noted in patients treated with macrolides (HR = 0.38, 95% CI: 0.16–0.86) or fluoroquinolones (HR = 0.20, 95% CI: 0.12–0.35). 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: Anti-drug antibody (ADA) production is associated with the microbial composition. The risk of ADA development during anti-tumor necrosis factor therapy can possibly be reduced by avoidance of cephalosporins and penicillins with β-lactamase inhibitors, or by treatment with fluoroquinolones or macrolides.