LAUSR

In the past decades, biological agents (engineered monoclonal antibodies [mAbs]) have emerged as essential therapy for moderate-to-severe inflammatory bowel disease (IBD). More recently, the mAb tumor necrosis factor-α antagonists (anti-TNFα), infliximab, adalimumab, golimumab, and certolizumab pegol have been supplemented by newer clinically approved biological agents that target different inflammatory pathways. Vedolizumab is a humanized mAb and the first in class of selective anti-α4β7 integrin that has gained approval for the treatment of moderate-to-severe IBD in adult patients who fail to respond to, lose response to, or are intolerant to conventional therapies (corticosteroids and immunomodulators) or to TNFα mAbs [1]. Natalizumab is another anti-α4 mAb that in contrast to vedolizumab binds both the α4β7 and-α4β1 heterodimers and is therefore less selective. The α4β7 integrin an adhesion molecule expressed on a variety of circulating leukocytes, including cluster of differentiation (CD)4+ and CD8+ naive T cells, CD4+ and CD8+ memory T cells, B cells, eosinophils, natural killer (NK) cells, that is essential for the migration these cells from the systemic circulation to the inflamed intestine. The counterpart of α4β7 integrin is primarily, but not exclusively, represented by the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), whose expression is abundant in intestinal endothelial cells (Fig. 1a, b). Because the α4β7–MAdCAM-1 interaction is highly restricted to the intestine, vedolizumab appears to selectively target recruitment of inflammatory cells to the gastrointestinal tract. The success of vedolizumab in treating IBD has facilitated the development of additional treatments that target the β7 integrin (etrolizumab) or MAdCAM-1 (PF-00547659). In preclinical models, vedolizumab effectively reduced leukocyte trafficking toward the intestine, thus reducing inflammation and immune dysfunction. These findings were confirmed by results of Phase III trials, in which the anti-α4β7 antagonist successfully induced and maintained remission in patients with Crohn’s disease (CD) and ulcerative colitis (UC) [2–4]. Nevertheless, similar to anti-TNFα agents, a significant proportion of patients (≈ 40%) failed to reach or to maintain remission in response to vedolizumab. In real-word cohorts, the primary response rate to vedolizumab is effectively similar in UC and CD patients, 40–60% of patients [5, 6]. Lack of response or need for dose optimization occurs in 40–60% of IBD patients during the maintenance phase [7, 8]. Due to the above factors, the place of vedolizumab in the management of IBD remains unclear, particularly taking into account the utility of anti-integrin therapy in the context of currently available biological therapies. In patients with less severe disease, as assessed by clinical and biochemical markers and naïve to anti-TNFα therapy, those with higher circulating concentrations of vedolizumab at induction are more likely to respond to treatment. The severity of disease at baseline is a robust predictor of response to vedolizumab in both UC and CD patients. Thus, while a higher response rate was observed in patients with a baseline Mayo score < 9 and Crohn’s disease activity index (CDAI) score ≤ 330 at 6 and 54 weeks [2, 3], others have reported a less favorable outcome in patients with Harvey–Bradshaw index (HBI) score > 10 and/or a Mayo score > 9 at 54 weeks [7]. Additionally, a history of smoking and active perianal disease were inverse predictors for clinical remission during maintenance therapy [8]. Further on, patients with severe systemic and bowel inflammation, as measured by higher concentrations of the nonspecific inflammatory biomarkers C-reactive protein (C-RP), leukocytosis, and fecal calprotectin are less likely to reach a * Stefano Fiorucci [email protected]