ReviewOptimizing anti-TNF treatments in inflammatory bowel disease☆
Introduction
The anti-TNF monoclonal antibodies (infliximab, adalimumab and certolizumab) are efficacious agents for the treatment of inflammatory bowel disease (IBD) and several other immune-driven disorders [1], [2]. However, treatment failures do occur in the form of primary non-response, secondary loss of response or secondary–primary non response (i.e. failure of re-induction in a patient previously exposed to the drug). In addition, although not strictly a failure of the drug, unnecessary continuation of anti-TNF may be considered a specific type of treatment shortcoming in the broad sense as it may severely impede patients' quality of life and impose adverse effects' risk without clinical justification. Diverse and probably distinct mechanisms underlie the different forms of anti-TNF treatment failures in both IBD and in other immune-driven disorders [3], [4]. Although it probably has little role in mediating primary non-response, immunogenicity has emerged as an important mechanism driving secondary loss of response in a subset of patients. Nonetheless, other mechanisms also play a role in propagating uncontrolled IBD inflammation despite anti-TNF treatment, thereby dictating an individualized approach in diagnosing and identifying the pathogenesis of loss of response in individual patients.
The aim of this review is to provide an overview of the incidence, predisposing factors and causes of primary, secondary and secondary–primary non-response to anti-TNF treatments in IBD, with a specific focus on immunogenicity role in this respect. It also aims to elucidate management strategies to prevent and to treat the diverse forms of non-response to anti-TNFs.
Section snippets
Definition and incidence
There is no unanimous definition of primary non-response. Indeed, even the time-points at which to gage primary non-response are not consensual, being different between clinical trials evaluating the same drug. This, in turn, makes the discussion about the incidence and impact of this phenomenon to be fraught with inherent inconsistencies. For instance, primary non-response to infliximab in ACCENT I study of Crohn's disease (CD) was defined as lack of response at 2 weeks after a single first
Conclusions
Optimization of anti TNF treatments necessitates considerations of different clinical scenarios in which therapy failure may occur. Prediction, prevention and interventions may need to be tailored separately to primary non-response, secondary loss of response or failure of re-induction. Moreover, individual factors may play an important role in the variability of failure mechanisms such as immunogenicity between different patients, necessitating a personalized approach to the optimization of
Take-home messages
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Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms.
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Primary non-response is probably not a class-effect phenomenon.
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Secondary loss of response is reported in 23–46% of patients at 12 months after anti-TNF initiation.
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Measuring anti-TNF trough levels and anti-drug antibodies may clarify the underlying mechanism in individual patients although there are still limited and conflicting data regarding the role of these measurements in guiding the
Acknowledgments
This work was supported in part by the ‘Talpiot’ medical leadership grant from the Sheba Medical Center (to SBH) and the Legacy Heritage Foundation from the Rambam Health Care Campus (to YC).
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Financial disclosure: Shomron Ben-Horin and Yehuda Chowers have received consultancy fees from Abbot and Schering-Plough.