Elsevier

Autoimmunity Reviews

Volume 13, Issue 1, January 2014, Pages 24-30
Autoimmunity Reviews

Review
Optimizing anti-TNF treatments in inflammatory bowel disease

https://doi.org/10.1016/j.autrev.2013.06.002Get rights and content

Abstract

Background

Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms, each posing distinct etio-pathogenic considerations and management dilemmas.

Aim

The aim of this study is to review the mechanisms responsible for the various forms of anti-TNF failures in IBD and to elucidate strategies for optimizing clinical efficacy.

Results

Primary failures of anti-TNF induction therapy occur in up to 40% of patients in clinical trials and in 10–20% in clinical series. Longer disease duration, smoking and several genetic mutations are predisposing factors for primary failures. Curiously, primary non-response is probably not a class-effect phenomenon since switching to another anti-TNF is effective in over 50% of such patients. Secondary loss of response is also a common clinical problem with incidence ranging between 23 and 46% at 12 months after anti-TNF initiation. Underlying mechanisms are often related to increased anti-TNF clearance by anti-drug antibodies, but may also include other causes for recalcitrant IBD activity as well as disorders that are unrelated to IBD itself. Astute management begins with verifying the presence of uncontrolled inflammatory IBD activity as a cause for patient's symptoms. Next, it is prudent to consider a trial of wait-and-see approach, since in some patients with mild-moderate symptoms, loss of response may resolve without alteration of therapy. If it does not, 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 choice between dose-intensification, switch to another anti-TNF or to another immuno-modulator, and the addition of an immuno-modulator as a combination therapy with the failing anti-TNF. Anti-TNF re-induction after prior drug-holiday is a distinct clinical scenario and scarce evidence suggests re-induction outcome to be dependent on the circumstances when drug-holiday was commenced. Finally, discontinuation of anti-TNF in patients with stable deep clinico-biologic and mucosal remission may be a viable option, as in these carefully selected patients the majority may enjoy long-term remission without the need for continued anti-TNF treatment.

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

  • Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms.

  • Primary non-response is probably not a class-effect phenomenon.

  • Secondary loss of response is reported in 23–46% of patients at 12 months after anti-TNF initiation.

  • 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.

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