Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?

Abstract

The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.

Role of the IL23/IL17 Pathway in Crohn’s Disease

“…Clinical practice will also answer the important question whether patients will still benefit from anti-IL23p19 antagonism if they have previously failed to benefit from anti-IL12p40 antibody therapy, and vice versa ( 114 ). Even with the upcoming availability of p19 inhibitors in addition to the already available anti-p40 antibody, there is still the currently unmet clinical need to establish predictive markers of response to identify the subgroup of IBD patients that have a heightened probability of response to respective treatments ( 115 ). In IL23p19 inhibitors, there has so far been only a report that indicated that higher serum IL22 concentrations were associated with a greater likelihood of response to brazikumab ( 14 ).…”

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data

“…This is a new concept in our field, but many new findings associated to the ability to predict response, relapse and even adverse events by using clinical data and biomarkers will allow us to choose the best drug, for an individual patient at the right time ( 15 , 16 ). Several factors have been linked to the response to TNF blockade in IBD, including clinical factors, pharmacokinetics, biochemical markers, pharmacogenomics, microbiome signatures, metabolic compounds and mucosal markers ( 17 , 18 ). While there are significant advances allowing a better identification of patients more likely to respond to anti-TNFs, including also a more profound understanding of its pharmacokinetics, few studies have investigated predictive factors of therapeutic efficacy to UST that may improve the probability of response and long-term benefit.…”

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers

“…In addition, laboratory biomarkers provide a reproducibly quantifiable tool for the evaluation of disease status and therapeutic efficacy in IBD patients. Therefore, the discovery of reliable biomarkers would be extremely useful in the clinical practice and adds a great help to assess therapeutic efficacy, minimize side-effects, and optimize personalized medicine and strategy for identifying IBD patients who will benefit from anti-TNF therapy [ 7 , 8 ].…”