Clinical experiences and predictors of success of treatment with vedolizumab in IBD patients: a cohort study.

BACKGROUND: Vedolizumab has become a standard treatment for the inflammatory bowel diseases ulcerative colitis (UC) and Crohn's disease (CD). However, there is an ongoing debate on the ideal individual treatment algorithms and means to predict treatment response are not routinely established. AIMS: We aimed to describe our experiences with vedolizumab at a large German tertiary referral center and to identify clinical predictors of success of vedolizumab treatment. METHODS: We performed a retrospective single-center cohort study employing univariable and multivariable analyses as well as Kaplan-Meier analyses of persistence on treatment. RESULTS: 36% and 35% of the patients with UC and CD, respectively, reached clinical remission after 17 weeks. Patients with lower clinical disease activity were more likely to achieve remission. The median persistence on treatment was 33 months for UC and 29 months for CD. CONCLUSION: Our study confirms that vedolizumab is an efficient option for the treatment of UC and CD. Clinical parameters of disease activity may help to predict the success of treatment.

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study.

BACKGROUND: While the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4ß7 integrin antibody vedolizumab are currently lacking. METHODS: We performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4+ T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4ß1 integrin on peripheral blood CD4+ T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab. RESULTS: Dynamic adhesion of peripheral blood CD4+ T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4ß1 expression on CD4+ T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value. CONCLUSIONS: Determining dynamic adhesion of CD4+ T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.

Expression and function of α4ß7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.

Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need. We had previously suggested that the expression and function of α4ß7 integrin on T cells in the peripheral blood correlate to outcomes of therapy with the anti-α4ß7 integrin antibody vedolizumab. Here, we conducted a translational multicenter trial to prospectively evaluate this hypothesis. In a cohort of 89 patients with inflammatory bowel disease undergoing regular therapy with vedolizumab, lower baseline expression of α4ß7 was associated with short-term clinical response. Consistently, low α4ß7 expression in patients achieving remission predicted sustained remission in week 30. Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission. These data substantiate the potential of α4ß7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.

Vedolizumab blocks α4ß7 integrin-mediated T cell adhesion to MAdCAM-1 in microscopic colitis.

Background: In Crohn's disease and ulcerative colitis, the anti-α4ß7 integrin antibody vedolizumab has demonstrated efficacy in phase III trials and has been successfully used under real-world conditions. Occasionally, it has also been used in other forms of inflammatory bowel disease (IBD) such as microscopic colitis (MC). However, the mechanisms of vedolizumab in MC have not been studied to date. Therefore, we aimed to investigate the expression and functional role of gut-homing integrins and in particular α4ß7 integrin in a cohort study in MC. Methods: We studied the expression of gut homing integrins on T cells from patients with MC and healthy controls by flow cytometry. To investigate the function of α4ß7 integrin in MC and the potential of vedolizumab to block it, we used dynamic adhesion assays and transmigrations assays. Moreover, we describe two clinical cases of MC patients treated with vedolizumab. Results: A specific profile of gut homing markers can be found on T cells from patients with MC. α4ß7 integrin functionally leads to firm adhesion to MAdCAM-1 and supports transmigration. Vedolizumab is able to block both processes. In two cases of MC, we observed reduced clinical symptoms and histologic improvement upon therapy with vedolizumab. Conclusion: Our data suggest that α4ß7 mediates gut homing of T cells also in MC and that, on single cell level, vedolizumab blocks the function of α4ß7 in MC. Thus, we provide mechanistic evidence supporting vedolizumab as promising therapeutic option for MC.

α4ß7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis.

BACKGROUND: The anti-α4ß7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far. METHODS: We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis. RESULTS: T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4ß7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1. CONCLUSION: Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.