Effect of Antibiotic Treatment on Anti-Drug Antibody Formation in Patients With IBD on Anti-TNFα Therapy
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
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.
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Additional Info
Disclosure statements are available on the authors' profiles:
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 01;71(2)287-295, Y Gorelik, S Freilich, S Gerassy-Vainberg, S Pressman, C Friss, A Blatt, G Focht, YL Weisband, S Greenfeld, R Kariv, N Lederman, I Dotan, N Geva-Zatorsky, SS Shen-Orr, Y Kashi, Y ChowersFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Anti-drug antibody (ADA) development is associated with reduction in serum drug levels, reduced treatment efficacy, and treatment failure. How to predict and mitigate the risk for ADA formation remains unknown. Combotherapy with immunosuppressant was shown to reduce the development of ADAs, even when added after anti-TNF treatment initiation, or when combined with a second anti-TNF after loss of response. However, combotherapy is associated with significant risks. Association between microbiota and clinical response to anti-TNF seems also to play a role. Studies have demonstrated the relationship between repetitive antibiotic use and modulation of immunity in IBD patients, suggesting that microbiota could be manipulated to modulate ADA formation during anti-TNF treatment. In this study, ADA production is associated with microbiota and could be reduced by specific antibiotherapy. An increased risk was noted in patients treated with cephalosporins or penicillin-BLI further supporting the validity of these associations. Moreover, drug combinations increase the immunogenicity of anti-TNF. In contrast, fluoroquinolone or macrolide use was associated with reduced immunogenicity. A recent study from the ABIRISK consortium showed that antibiotic use during therapy reduced the risk of ADA formation after multivariable adjustment.1
Modification of clinical strategy with antibiotics remains difficult. It should be interesting to prefer fluoroquinolones or macrolides in IBD patients. The future should be to analyze the microbiota and to discuss combination of treatment with anti-TNF and fecal transplantation. It would also be important to take into consideration the HLA of patients since it has been shown to be associated with the immunogenicity of biotherapies.2,3 The impact of HLA on the effect of these antibiotics should be further studied. Finally, the importance of the role of the microbiota and its manipulation with antibiotics or fecal transplantation should open the doors to new vaccine strategies in these patients.
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