Putative biomarkers of vedolizumab resistance and underlying inflammatory pathways involved in IBD

Abstract

ObjectivesCharacterise the circulating inflammatory cytokine pattern among patients failing consecutive anti-tumour necrosis factor (anti-TNF) and anti-integrin treatments to identify predictors of response.MethodsA retrospective single-centre cohort study of 28 patients with inflammatory bowel disease (IBD) receiving anti-integrin therapy (vedolizumab) subsequent to the failure of anti-TNF treatment was conducted. Blood samples were obtained immediately prior to initiation of vedolizumab therapy, and the response to treatment was evaluated after completion of the 14-week induction regimen. Multiplex ELISA was applied to quantify 47 preselected plasma proteins based on their putative involvement in the inflammatory process in IBD.ResultsAnti-TNF and vedolizumab non-responders (n=20) had significantly higher levels of circulating interleukin (IL)-6 than anti-TNF non-responders with subsequent response to vedolizumab (n=8): median 9.5 pg/mL versus 5.9 pg/mL, p<0.05. Following stratification by diagnosis, patients with Crohn’s disease who failed vedolizumab therapy (n=7) had higher soluble CD40 ligand (sCD40L) than responders (n=4): 153.0 pg/mL versus 45.5 pg/mL, p<0.01; sensitivity 100% (95% CI 59% to 100%), specificity 100% (95% CI 40% to 100%). Osteocalcin was higher among patients with ulcerative colitis responding to vedolizumab (n=4) compared with those not responding (n=13): 4219 pg/mL versus 2823 pg/mL, p=0.01; sensitivity 85% (95% CI 55% to 98%), specificity 100% (95% CI 40% to 100%).ConclusionsPatients with IBD failing vedolizumab induction and anti-TNF therapy have persistent IL-6 pathway activity, which could be a potential alternative treatment target. sCD40L, osteocalcin and the IL-6 pathway activity might be predictors for response to vedolizumab.

Can molecular stratification improve the treatment of inflammatory bowel disease?

“…Other studies have examined whether other cytokines and cytokine receptors could be useful markers of anti-TNF responses [[96], [97], [98]]. West and colleagues demonstrated that the expression of OSM can be used to predict response to anti-TNF therapy [96].…”

“…Interestingly, α 4 β 7 expression on CD4 + T cells and Natural Killer (NK) cells prior to treatment was found to be higher in responders than non-responders [110]. A separate study of 11 CD and 17 UC patients found that vedolizumab non-responders had higher baseline levels of circulating IL-6 [97], and that CD40 Ligand (100% specificity/sensitivity) and osteocalcin (100% specificity, 85% sensitivity) could predict response in CD or UC patients, respectively. These observations are encouraging, but the cohort size was small in both of these studies and further validation is required.…”

Predictors of response and disease course in patients with inflammatory bowel disease treated with biological therapy—the Danish IBD Biobank Project: protocol for a multicentre prospective cohort study

“…Previous studies have primarily focused on linking genetic polymorphisms associated with IBD to the response to biological treatment, however, associations are vague and suggest that other omics profiles are also implicated 17 18. Recent findings indicate that mucosal inflammatory patterns and serum cytokine profiles differ between responders and non-responders to biological treatment 19–22. Furthermore, interactions between host and gut microbiota play a pivotal role in IBD pathogenesis and should be taken into consideration when predicting treatment response 23 24.…”

Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases

“…In contrast, vedolizumab-specific biomarkers are even more limited, with studies focusing only on prediction of clinical response. 8,9 As targets in IBD are evolving from clinical to endoscopic remission, 10 biomarker development should focus on the prediction of endoscopic remission.…”