Efficacy and Safety of Antiintegrin Antibody for Inflammatory Bowel Disease

We sought to evaluate the safety and efficacy of available biologics that inhibit T-cell migration by blocking a4b7 integrins in inflammatory bowel diseases. The aim of this study is to evaluate whether Crohn disease (CD) patients receiving either vedolizumab or natalizumab have any different effect in CD Activity Index (CDAI). Using Medline, Excerpta Medica dataBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar until October 31, 2013, we identified 10 studies examining the safety and efficacy of specific integrin inhibitors—vedolizumab, which targets an epitope comprising thea4b7 heterodimer; natalizumab, which recognizes thea4 integrin subunit; etrolizumab, which is specific for theb7 subunit— in the treatment of CD and ulcerative colitis (UC). CD patients receiving either vedolizumab or natalizumab demonstrated a modest increase in remission rate, when compared with that of the placebo group. Further, although both treatments reduced the CDAI slightly, the observed clinical response was less robust than that of the remission rate. UC patients treated with vedolizumab and natalizumab were found to show more prominent increases in both remission and clinical response, compared with placebo, than patients with CD. Etrolizumab, however, was not found to significantly affect either response or remission rates in UC patients. Biologics targeting integrins show promise as therapeutics in the treatment of inflammatory bowel disease in patients who are either nonresponsive or intolerant to traditional approaches, though further research is necessary to optimize treatment efficacies. (Medicine 94(10):e556) Abbreviations: CD = Crohn disease, CDAI = CD activity index, CI = confidence interval, IBD = inflammatory bowel disease, u Wang, MD, and Changqing Zheng, MD, PhD INTRODUCTION C rohn disease (CD) and ulcerative colitis (UC), the 2 most prevalent forms of inflammatory bowel disease (IBD), affect more than 2.5 million people of European ancestry, whereas increasing frequencies are being reported in the developing world. Currently, approved therapies for IBD have considerable limitations, as they frequently display only moderate efficacy and are often associated with unacceptable risk of serious adverse events (SAEs), constituting a clear need to develop new treatment options. Indeed, it was recently reported that 20% to 40% of CD and 40% of UC patients will ultimately prove refractive to conventional approaches using antitumor necrosis factor (anti-TNF)-a, illustrating the clear need for new treatment strategies. CD and UC are both characterized by persistent inflammation, which is mediated by the migration of proinflammatory T cells into the gastrointestinal tract. The repertoire of receptors expressed on the T-cell surface plays a critical role in maintaining this chronic inflammatory state. Naı̈ve T cells encounter antigen in peripheral lymphoid organs, driving clonal expansion of effector T cells, which then migrate from the blood to affected tissues and back to the blood, creating the perpetual state of activation observed in chronic inflammatory disorders. Activated effector T cells home from the blood to affected tissues via tightly regulated cell–cell interactions. T-cell infiltration in the gut is dependent upon interactions between surface-expressed a4b7 integrins and mucosal addressin cell adhesion molecule (MAdCAM-1), present on endothelial cells. The critical role of this interaction in extravasation of T cells into the GI tract makes a4b7 integrins a good target for therapy. Several monoclonal antibodies that function to block a4b7 integrins have been developed: natalizumab is specific for the a4 integrin subunit (Tysabri; Biogen Idec and Elan Pharmaceuticals, Cambridge, Massachusetts, USA), vedolizumab (Entyvio, Millennium Pharmaceuticals, Cambridge, Massachusetts, USA, MLN02, LDP02, MLN0002; Millennium Pharmaceuticals) is directed against an epitope comprising the a4b7 heterodimer, and etrolizumab (Genentech, South San Francisco, California, USA) recognizes the b7 subunit (rhuMAb b7, anti-b7, PRO145223; Genentech). Though the potential application of these molecules for the treatment of IBD is still emerging, preliminary studies suggest that they may provide efficacy for patients who are either intolerant or refractive to conventional treatment with anti-TNF-a. To gain a better overview of these agents in the treatment of CD and UC, we have conducted a systematic review of randomized controlled trials to assess their relative safety and efficacy. Here, using a meta-analytical approach, we summarize and ata regarding the inducement of remisnses by natalizumab, vedolizumab, and tients. www.md-journal.com | 1 MATERIALS AND METHODS Search Strategy and Selection Criteria In conducting this meta-analysis, we followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically searched Medline, Embase, the Cochrane Library, and Google Scholar through October 31, 2013 for various combinations of the following keywords: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, integrin, vedolizumab, natalizumab, etrolizumab, and monoclonal antibody. Furthermore, the reference lists of all relevant publications were searched by hand. This study did not involve human subjects, so informed consent was not required. In addition, no approval was required from any institutional review board. Inclusion criteria for this meta-analysis required that the study be: original, excluding review articles and meta-analyses; a randomized controlled trial of an anti-a4b7 antibody as monotherapy; participants demonstrate active IBD. NonEnglish publications, studies employing a single arm, and those comprising retrospective data were excluded from this analysis. The following information was extracted from studies that met the inclusion criteria: the name of the first author, year of publication, study design, demographic data of subjects, regimen (dose and frequency) of anti-a4b7 integrin antibody, clinical remission rate, clinical response rate, adverse events, and SAEs. Data Extraction and Quality Assurance Studies in this meta-analysis were identified by 2 independent reviewers using the above search strategy. Uncertainties regarding eligibility were resolved by consensus. The following information was extracted from studies that met the inclusion criteria: first author name, year of publication, study design, subject demographics (ie, age and gender), number of participants in each study, antibody and dosage for respective study groups, primary and secondary endpoints, and adverse events. Lin et al Quality assessment of all included studies was carried out using a Delphi list (Table 1). This list employed 8 conditions: randomization; baseline characteristics; eligibility criteria; TABLE 1. Quality Assessment of Included Studies Using the Delp First Author (Year) Was a Method of Randomization Used? Were the Groups Similar at Baseline Regarding the Most Important Prognostic Indicators? Were the Eligibility Criteria Specified? CD Sandborn (2013) Y Y Y Feagan (2008) Y Y Y Targan (2007) Y Y Y Sandborn (2005) Y Y Y Ghosh (2003) Y Y Y Gordon (2001) Y Y Y UC Rutgeerts (2013) Y Y Y Feagan (2013) Y Y Y Parikh (2012) Y Y Y Feagan (2005) Y Y Y CD1⁄4Crohn disease, UC1⁄4 ulcerative colitis. 2 | www.md-journal.com blinding of outcome assessor, physician, and patient; use of point estimates and variability; intention-to-treat analysis. Outcome Measures The primary outcome measurement was the percent of patients achieving remission, as defined by the parameters laid out by each individual study. The secondary outcomes were clinical response rates, also as defined by the primary study, and adverse events. Briefly, for the CD studies, remission was universally defined as a CD Activity Index (CDAI) score <150, whereas defined clinical response corresponded to a decrease of 70 points in CDAI in all studies, except for Sandborn et al, which required a decrease of 100 points in CDAI. For UC studies, the threshold for remission was universally defined as a Mayo Clinic score <2, with individual subscores <1. A decrease in the Mayo Clinic score >3 points, >30% from baseline, accompanied by >1 point reduction in the rectal bleeding subscore, or an absolute rectal bleeding subscore of 0–1, generally constituted clinical response. In 1 study, however, clinical response was defined by a Mayo Clinic score reduction >2 points and 25% from baseline measurements. Statistical Analysis The relative effect of treatment and placebo on clinical remission, response rates, and SAEs were compared and expressed as odds ratios (ORs), with 95% confidence intervals (CIs). ORs, calculated for binary outcomes, were compared between treatment and control groups. For the rate of clinical remission and response, an OR >1 indicates that the treatment group is favored, whereas for SAEs, an OR <1 indicates that the treatment group is favored (ie, associated with fewer adverse events). Study heterogeneity was identified by x, using Cochran Q statistic, and quantified by I, which determines the percent of the total variability that cannot be ascribed to chance. For analyses in which heterogeneity (I> 50%) was detected, a random-effects model was used. A fixed-effects Medicine Volume 94, Number 10, March 2015 model was employed in the absence of significant heterogeneity. Pooled ORs resulting in a 2-sided P value <0.05 were considered statistically significant. Sensitivity analysis, for both