D’Haens, Geert

Abstract Background Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Methods Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1–46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. Results No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Conclusions Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

Abstract Background The operating properties of histologic indices are poorly characterized in Crohn’s disease (CD) and no validated index exists. We assessed the reliability and responsiveness of histologic indices/items, developed an exploratory index, and compared different methods of scoring. Methods Using baseline and week 12 histologic image sets from the EXTEND placebo-controlled trial, blinded central readers scored 4 histologic indices (the Global Histologic Activity Score [GHAS], Geboes Score [GS], Robarts Histopathology Index [RHI], and Nancy Index [NHI]) and 3 additional novel items identified by an expert panel (mucin depletion, basal plasmacytosis, and pyloric gland metaplasia in the ileum). Reliability and responsiveness were evaluated for a global score (4 colonic segments + ileum), colonic score (4 colonic segments) and ileal score (ileum only) using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Change was defined using treatment assignment and improvement in histologic disease activity as measured on a 100-mm visual analogue scale (VAS) in responsiveness testing. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an ICC ≥0.4 and AUC ≥0.56. The VAS served as the dependent variable. Results Paired histologic images were analysed from 55 subjects. Inter-rater reliability was substantial to almost perfect (ICC=0.73-0.85) and responsiveness was small to large (treatment assignment AUC=0.50-0.65; VAS AUC=0.71-0.94). The GHAS, GS, RHI, and NHI reached the minimum threshold for reliability (ICC ≥0.4) and responsiveness (AUC ≥0.56) regardless of whether the global and colonic scores were calculated using the worst affected segment, average of the included segments, or sum of the included segments (Table 1-3). Five items were tested as candidate predictors. Three exploratory indices were developed, each consisting of 3 items: a global index (neutrophils in the lamina propria, neutrophils in the epithelium, and erosion/ulceration), colonic index (chronic inflammatory infiltrate, neutrophils in the lamina propria, and erosion/ulceration) and ileal index (chronic inflammatory infiltrate, neutrophils in the epithelium, and erosion/ulceration). The novel indices highly correlated with the GHAS, GS, RHI, and NHI, with correlation coefficients ≥0.80 (Table 4). Conclusion The 4 existing indices were similarly reliable and responsive in measuring CD histologic activity, regardless of the method for calculating global and colonic scores and could be used in clinical trials. Attempts at novel index development did not offer benefit over current histologic indices.

Abstract Background Small bowel fibrostenotic strictures are common in patients with Crohn’s disease (CD). No global consensus recommendations on definitions, diagnosis and clinical management are available. Methods Several systematic reviews followed by a RAND/University of California Los Angeles appropriateness study on the definitions, diagnosis and clinical management of fibrostenosing CD in clinical practice were performed. A panel of 28 global experts and a patient representative were convened. They assessed a total of 152 candidate items. The items were subsequently evaluated for appropriateness. Results No accurate predictive biomarkers are available for naïve or anastomotic fibrostenosing strictures. Accurate diagnosis of fibrostenosing CD requires cross-sectional imaging which should evaluate bowel wall thickness, luminal narrowing and prestenotic dilatation. A potential inflammatory component should be assessed. Abdominal cross-sectional imaging was considered necessary prior to any treatment decision. The panel proposed an approach to medical, endoscopic, and surgical therapies (Figure 1 and Table 1). Technical characteristics for endoscopic balloon dilation and follow up strategies after successful dilation therapy were identified. Appropriateness, types and performance of different surgical approaches in various settings were evaluated. Conclusion This global consensus provides clinical guidance for the diagnostic and therapeutic management of patients with fibrostenotic CD.

Abstract Background Network meta-analysis (NMA) using randomised controlled trial (RCT) data can provide indirect evidence on comparative efficacy of various treatments.1 The NMA reported herein was conducted to evaluate infliximab (IFX) and vedolizumab (VDZ) comparative efficacy during maintenance treatment of moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC), covering various dosing regimens and administration routes for each biologic. Methods Studies were identified by literature searches that included publications up to 1 November 2022. Parallel-group RCTs evaluating IFX or VDZ (intravenous [IV] or subcutaneous [SC]) for maintenance treatment of adult patients with moderate-to-severe CD or UC that reported clinical remission rates were included. Eligible studies treated patients for a minimum of 22 weeks, with follow-up of 30–60 weeks for maintenance. Clinical remission rates in tumour necrosis factor inhibitor (TNFi)-naïve patients from each study were analysed in a Bayesian NMA fixed-effect model. Results Overall, 13 RCTs were identified and included in the analysis (Table 1 for CD and Table 2 for UC). The difference in study design between IFX (treat-through) and VDZ (re-randomisation of induction responders only) was noted. A connected network of evidence could be generated using CD and UC studies (Figures 1A and 1B, respectively). In both CD and UC, IFX SC 120 mg had the highest odds ratio (95% confidence interval [CI]) vs. placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90–18.2]; UC: 5.45 [1.94–15.3]), albeit with the CIs overlapping with the CIs of the other tested regimens (Figures 2A and 2B). In both CD and UC, IFX SC 120 mg ranked highest for clinical remission among the biological agents, dosing regimens, and routes of administration tested. Conclusion In both CD and UC, IFX SC showed a favourable efficacy profile for achieving clinical remission during maintenance treatment of TNFi-naïve adult patients, when compared with the other IFX IV or VDZ IV/SC regimens tested. References: 1 Rouse B et al., Intern Emerg Med 2017;12(1):103-111.

Abstract Background Corticosteroids (CS) may be used for induction of remission in Crohn’s disease (CD); however, side effects, toxicities, and low rates of mucosal healing may limit their long-term use. Safety and efficacy of upadacitinib (UPA), an oral selective Janus kinase inhibitor, were evaluated among patients with CD receiving UPA with CS at baseline in phase 3 clinical trials. Methods In 2 phase 3 studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were rerandomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline or week 0 of maintenance (end of induction) were included. A CS taper began at induction week 4 and continued during maintenance. Endpoints included the proportion of patients who discontinued CS use (CS-free) at week 12 or for ≥ 90 days prior to week 52, and achieved clinical remission by stool frequency/abdominal pain score or by Crohn’s Disease Activity Index (CDAI), enhanced clinical response, decrease of at least 100 points in CDAI from baseline, endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone equivalent doses) was recorded. Safety was assessed through induction and maintenance. Results Of 1021 patients evaluated, 358 (35.1%) were taking CS at baseline (mean daily prednisone equivalent dose, 23.0 mg). Greater changes from baseline in mean CS daily dose were observed with UPA vs PBO at induction week 12 (−17.3 mg vs −10.7 mg); these changes were sustained at maintenance week 52 (UPA 30 mg, −16.4 mg; UPA 15 mg, −17.4 mg; PBO, −14.7 mg). The proportion of patients who achieved a ≥ 50% reduction in CS daily dose was higher with UPA vs PBO at induction week 12 among patients taking CS at baseline (72.6% vs 48.4%) and at week 52 among patients taking CS at baseline or week 0 of maintenance (UPA 30 mg, 49.2%; UPA 15 mg, 44.4%; PBO, 11.1%). A significantly higher proportion of patients taking UPA vs PBO were CS-free and achieved clinical remission, clinical response, endoscopic response, and endoscopic remission at week 12 (Fig 1A) and week 52 (Fig 1B). Rates of adverse events (AEs), serious AEs, and discontinuation were comparable between groups (Table 1). Serious infections, opportunistic infections, and herpes zoster events were numerically higher with UPA vs PBO (Table 1). Conclusion Patients with CD taking CS were able to taper and discontinue their CS regimen and experience clinical and endoscopic improvements with UPA treatment during the induction and maintenance periods.