Individualizing Anti-TNF Therapy in Patients With Inflammatory Bowel Disease: Pre-Treatment Prediction of Immunogenicity and Response. A Prospective Observational Study.

The introduction of anti-TNF therapy was a pivotal milestone in the treatment of inflammatory bowel diseases (IBD). Since then, additional advanced therapies with novel mechanisms of action have been introduced. The plethora of biologics and small molecule drugs increases the ability of IBD patients to achieve therapeutic goals, such as clinical, endoscopic and mucosal healing. However, primary non-response and loss of response remain a challenge and are linked to increase risks related to ongoing inflammation and disease progression.

Predicting the response rates of individual patients to therapy is the goal of a large body of research, linked to clinical characteristics, genetics, microbiome composition and pharmacokinetics. Two promising research topics are Triggering Receptor Expressed in Myeloid cells 1 (TREM1) and HLA-DQA1*05.

TREM1 is a receptor expressed on innate immune cells, known to amplify inflammatory signals triggered by Toll-like receptors, thus contributing to the pathophysiology of acute and chronic inflammatory conditions. Increased protein and mRNA levels of TREM1 in whole blood and colonic biopsies are associated with clinical and endoscopic non-response to anti-TNF. The suggested best cut-off point is 3.346 folds increase in mRNA expression in whole blood samples, with a specificity of 91.3% and sensitivity of 58.1%.

HLA class II gene HLA-DQA1 is expressed by antigen presenting cells and encodes the α-chain of the HLA-DQ heterodimer that forms part of the antigen-binding site where epitopes are presented to T-helper cells. Carriage of HLA-DQA1*05 allele confers a 2-fold risk of immunogenicity to anti-TNF therapy. This risk was mitigated using a concomitant immunomodulator.

Our goal is to evaluate the predictive power of these tests separately in a prospective observational study, and assess whether combining the tests' outcomes prior to initiation of anti-TNF therapy improve therapy outcomes, including efficacy and durability.