TY - JOUR T1 - Deciphering the vedolizumab dosing conundrum in IBD: when less is more JF - Gut JO - Gut DO - 10.1136/gutjnl-2021-325893 SP - gutjnl-2021-325893 AU - Timon Erik Adolph AU - Britta Siegmund Y1 - 2021/09/08 UR - http://gut.bmj.com/content/early/2021/09/07/gutjnl-2021-325893.abstract N2 - Already in the 1990s, the integrin α4β7, expressed on innate and adaptive immune cells, has been implicated in the control of lymphocyte recruitment to the intestinal mucosa.1 Pharmacological blockade of α4β7 with a monoclonal antibody, later termed vedolizumab, protected against spontaneous chronic colitis in the cotton-top tamarin model.2 Almost two decades later, phase III clinical trials in patients with IBDs proved vedolizumab efficacious for induction and maintenance of remission in UC3 as well as Crohn’s disease (CD),4 which led to the drug approval by the European Medicines Agency in 2014. Only recently, the VARSITY trial indicated superiority of vedolizumab compared with adalimumab in UC with respect to clinical remission and endoscopic improvement,5 6 while at the same time displaying a favourable safety profile7 and the potential to predict treatment response (in CD) by a clinical scoring system.8 Notably, the initial reasoning for this therapeutic concept appeared rather clear; however, we are only beginning to appreciate its mechanisms of action. For example, characterisation of the mucosal and systemic immune cell compartment before and during vedolizumab treatment of 18 patients with IBD did reveal neither alterations in the abundance nor the receptor repertoire of mucosal T cells. Unexpectedly, vedolizumab rather resulted in profound effects on the innate immune system.9 A second study corroborated this notion by demonstrating that vedolizumab affected mucosal homing of non-classical monocytes,10 indicating that the immunomodulatory actions of vedolizumab are more diverse than previously anticipated. These findings were paralleled by the observation that vedolizumab efficacy is counterintuitively affected by dosing, in that higher trough concentrations appear to confer an unfavourable clinical response.11 12 More specifically, these studies reported worse clinical outcomes in … ER -