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

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.

Figure 1

Kaplan-Meier curves of cumulative risk of ADA development for prior use of different antibiotic classes. Tick marks represent censoring and shaded area represent 95% CI. Plot is limited to first 2000 days of follow-up. A p value for the log-rank test is presented in each plot. ADA, anti-drug antibodies; BLI, β-lactamase inhibitors.

Figure 2

Multivariable-adjusted HRs (represented by blue points) for anti-drug antibodies development for use of various antibiotic classes during anti-tumour necrosis factor therapy. HRs are presented on a log₁₀ scale. Black lines represent 95% CIs. BLI, β-lactamase inhibitors.

Figure 3

Estimated adjusted regression coefficients for a range of number of dispensations for cephalosporins (A); penicillin-BLIs (B); macrolides (C); and fluoroquinolones (D). Shaded areas represent 95% CIs. BLIs, β-lactamase inhibitors.

Figure 4

Kaplan-Meier curves with risk tables of cumulative risk of ADA development for prior use of combinations of pairs from cephalosporins, penicillin-BLIs, macrolides and fluoroquinolones. Tick marks represent censoring and shaded areas represent the 95% CI. The plot is limited to the first 2000 days of follow-up. A p value for the log-rank test is presented in each plot. ADA, anti-drug antibodies; BLI, β-lactamase inhibitors.

Figure 5

Mean anti-drug antibodies levels in mice treated with anti-tumour necrosis factor and prior cefuroxime (n=20), azithromycin (n=21) or no antibiotic (regular control, n=25, or germ-free, n=5). ADA, anti-drug antibodies.