The use fluoroquinolones or macrolides reduced immunogenicity risk in inflammatory bowel disease (IBD) patients on anti–tumor necrosis factor (anti-TNF) therapy, according to data from nearly 2,000 individuals.
Anti-TNF therapy with monoclonal antibodies is an established treatment for Crohn’s disease and ulcerative colitis, but approximately 40% of patients fail to respond initially and even more fail to achieve complete remission, wrote Yuri Gorelik, MD, of Rambam Health Care Campus, Haifa, Israel, and colleagues.
“Immunogenicity, which refers to the development of antidrug antibodies [ADA] is considered as the main factor driving secondary loss of response and is likely involved in primary nonresponse as well,” but data on how to predict the risk for ADA formation are limited, they said.
In a study published in Gut, the researchers identified data from 1,946 IBD patients using the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all IBD patients in Israel.
A total of 363 patients had positive ADA after a median follow-up period of 651 days after starting therapy. Overall, the risk of ADA development was significantly higher in patients on cephalosporins (adjusted hazard ratio, 1.97; 95% confidence interval, 1.58-2.44) or penicillin with beta-lactamase inhibitors (BLIs) (aHR, 1.38; 95% CI, 1.13-1.74) during anti-TNF therapy, and it was higher still for patients using both. By contrast, the risk was lower in patients on macrolides (aHR, 0.36; 95% CI, 0.16-0.82) or fluoroquinolones (aHR, 0.20; 95% CI; 95% CI, 0.12-0.35). All P values were less than .05 when compared with nontreated groups.
In the same study, the researchers reported data on mice treated with antibiotics and challenged with infliximab to evaluate the causative effect of antibiotics and the associated disruption to the gut microbiome on the formation of ADA. After 14 days, the researchers found significantly increased ADA production in mice treated with cephalosporins, compared with those treated with macrolides, but germ-free mice produced no ADA, which supports the role of microbial composition on ADA production.
The investigators cited previous research into the microbiome as a biomarker for prediction response to anti-TNF therapy; past results have also suggested that the effect of cephalosporins and penicillin-BLIs could be explained by the particular dysbiosis induced by those agents.
The study findings were limited by several factors including the retrospective design and potential for selection bias, as well as the inability to adjust antibiotic exposure according to type and severity of infection, they noted. However, “this is the first large scale study that extensively evaluated the effect of different antibiotic classes on immunogenicity of anti-TNF therapy,” and the results suggest that ADA development during anti-TNF therapy may to reduced by the use of fluoroquinolones and macrolides.
“Specific microbial manipulation may serve as a tool to modify immunogenicity which is preferably turned on for protective immunizations and off for biological therapy,” they noted. “Further studies involving detailed analysis of the antibiotic effects on the human microbiome and immune milieu are needed, as well as comparative experiments with other medications used to reduce immunogenicity.”
Unexpected Findings May Drive Future Drug Choices
“Development of antidrug antibodies in patients on biologics for inflammatory bowel disease is an important mechanism for loss of response to a therapeutic agent,” Kim L. Isaacs, MD, AGAF, of the University of North Carolina at Chapel Hill, said in an interview. “To date the causes of development of ADAs is relatively understudied. Our approach to prevent ADA includes increasing immunosuppression in patients most commonly with combination therapy with thiopurines. If factors that provoke or prevent antibody formation are elucidated, therapy can be tailored to prevent ADAs and maximize the duration of response of many of our biologic therapies.”
Dr Kim Isaacs
A prior study performed by the ABIRISK European consortium demonstrated associations with antibiotics. “In the current study, there was a differential effect of cephalosporins/penicillins (increased immunogenicity) and macrolides (decreased immunogenicity),” she said. “These studies suggest that the microbiome may be important in ADA formation to biologics – this is a concept that is novel and unexpected.
“The rationale for the choice of antibiotics in the population studied is not known, and it is possible that different infections may have led to different antibiotic choices, which in turn may have affected immunogenicity,” said Isaacs. However, clinicians might be able to tailor antibiotic choice in the future if the microbiome is playing a major role in risk for development of ADA.
“Further research is needed to further correlate microbiome changes with immunogenicity, to look at other classes of antibiotics and their role in immunogenicity, and to clarify the infections or reasons that these patients are receiving antibiotics,” Isaacs concluded.
Understanding the Microbiome
Recent observations have shown associations between clinical response to anti-TNF and gut microbiota composition, noted Jatin Roper, MD, of Duke University, Durham, N.C. “More broadly, a growing body of evidence suggests that the gut microbiota modulates the metabolism of many therapeutic agents, as well as immune responses to infections.”
That said, Roper was surprised that “clinical use of different antibiotics, often short term, had such distinct effects on ADA levels.” Furthermore, “these findings suggest that distinct microbiota or microbial metabolic products impact antibody development to common immunomodulatory therapies in opposite ways,” which is itself a surprising finding.
Such antibodies to anti-TNF therapy are common in IBD, he said, but one implication of the study is how antibiotics could be carefully used “to reduce risk of ADAs and enhance efficacy of anti-TNF therapy.”
However, because any antibiotic therapy will modify the gut microbiome and lead to unwanted effects, “further research is needed on how these agents impact the gut microbiome, with the ultimate goal of identifying specific microbiota or microbial metabolic products that can reproduce the intriguing findings of this paper.”
The study was supported in part by the Leona M. and Harry B. Helmsley Charitable Trust and the Israeli Ministry of Science and Technology. Gorelik had no financial conflicts to disclose. Several coauthors disclosed relationships with multiple pharmaceutical companies including AbbVie, CytoReason, Takeda, and Pfizer. Isaacs had no financial conflicts to disclose, but serves on the GI&Hepatology News board of editors. Roper had no relevant disclosures.
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This article originally appeared on GI & Hepatology News, the official newspaper of the AGA Institute.