Dulai, Parambir S.

INTRODUCTION: Safety and effectiveness of treating to target mucosal healing in older patients with Crohn's disease (CD) is unknown. METHODS: We analyzed CD-related complications by 24 months in the randomized evaluation of an algorithm for Crohn's treatment—study 2-2 trial that randomized practices to an enhanced-care or step-care algorithm to determine whether patient age modifies the effect of treatment. Data were analyzed using marginal Cox regression and modified Poisson regression. RESULTS: There was no difference in treatment between younger and older patients in at 24 months. DISCUSSION: Enhanced-care was effective and not associated with increased risk compared with step-care in older patients with CD.

ABSTRACTBackgroundPatients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high‐risk orphan population.AimTo provide guidance for clinical trial design methodology in these patients.MethodsWe created a multi‐centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate–severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches.ResultsThe Truelove‐Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient‐reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS‐2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post‐discharge follow‐up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population.ConclusionWe provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.

SummaryBackgroundThe optimal ulcerative colitis biopsy protocol is unclear.AimTo evaluate the number of biopsies required to accurately assess microscopic disease activity in ulcerative colitisMethodsBiopsies from patients with ≥4 rectosigmoid samples, and clinical and endoscopic data, were retrospectively obtained from a prospective biobank. Histology and endoscopic videos were read blindly. A 4‐biopsy Robarts Histopathology Index (RHI) reference score, consisting of the worst item‐level ratings from four biopsies, was compared to 1‐, 2‐ and 3‐biopsy estimates. Agreement was determined using bivariate errors‐in‐variable regression analysis (acceptance interval: ±8.25). Endoscopic activity and disease location subgroup analyses were also performed.ResultsForty‐six patients had ≥4 rectosigmoid biopsies available (N = 287). The 2‐biopsy (tolerance interval: −7.66, 4.79) and 3‐biopsy (tolerance interval: −4.86, 3.46) RHI scores demonstrated acceptable agreement with 4‐biopsy scores. One‐biopsy scores demonstrated unacceptable agreement (tolerance interval: −13.99, 7.78). Mean RHI scores using the 2‐, 3‐ and 4‐biopsy approaches were similar (6.1 ± 9.6 P = 0.36; 6.8 ± 10.5, P = 0.7; 7.5 ± 11.2), whereas the 1‐biopsy estimate was lower (4.4 ± 8.1, P = 0.06). Histological remission rates were identical for the 2‐, 3‐ and 4‐biopsy methods (65.2%, P = 1.0). Subgroup analysis demonstrated that three biopsies were required in patients with endoscopically active disease. Sampling additional colonic locations yielded lower histological remission rates compared to rectosigmoid sampling alone (33.3% vs 61.9%, P = 0.1).ConclusionsA minimum of two — conservatively, three — biopsies are required to reliably assess disease activity in a single colonic segment using the RHI. Further studies are needed of endoscopically active patients and sampling locations. These results have implications for biopsy strategies in clinical trials and practice.

SummaryBackgroundThere is limited real‐world data on comparative effectiveness of different biologic or small molecule agents as second‐line therapies in patients with ulcerative colitis (UC) with prior exposure to a tumour necrosis factor inhibitor (TNFi).MethodsWe conducted a retrospective cohort study using TriNetX, a multi‐institutional database to assess the efficacy of tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis (UC) with prior exposure to a TNFi. Failure of medical therapy was defined as a composite outcome of intravenous steroids or colectomy within 2 years. One‐to‐one propensity score matching was performed for demographics, disease extent, mean haemoglobin, C‐reactive protein, albumin and calprotectin, prior IBD medications and steroid use between cohorts.ResultsAmong 2141 patients with UC and prior exposure to TNFi, 348 (16.2%), 716 (33.4%) and 1077 (50.3%) were switched to tofacitinib, ustekinumab and vedolizumab, respectively. After propensity‐score matching, there was no difference in the composite outcome (aOR: 0.77, 95% CI: 0.55–1.07) but higher risk of colectomy (aOR: 2.69, 95% CI: 1.31–5.50) in the tofacitinib cohort than the vedolizumab cohort. There was no difference in the risk of composite outcome (aOR: 1.29, 95% CI: 0.89–1.86) but higher risk of colectomy (aOR: 2.63, 95% CI: 1.24–5.58) in the tofacitinib cohort than the ustekinumab cohort. The vedolizumab cohort had a higher risk of composite outcome (aOR: 1.67, 95% CI: 1.29–2.16) than the ustekinumab cohort.ConclusionUstekinumab might be the preferred second‐line therapy over tofacitinib and vedolizumab in patients with UC that were previously exposed to a TNFi.

Background: There is limited data on Vedolizumab utilization in elderly patients. Our study aims to assess the effectiveness and safety of Vedolizumab in this subset population. Materials and Methods: Databases including Cochrane Central, Embase, Medline (via Ovid), Scopus, and Web of Science were searched in August 2022 to identify studies that assessed Vedolizumab therapy in elderly patients. Pooled proportion and risk ratios (RR) were calculated. Results: Total 11 studies with 3546 IBD patients (1314 elderly and 2232 young) were included in the final analysis. Pooled rate of overall and serious infections in the elderly cohort was 8.45% (95% CI=6.27-11.29; I223%) and 2.59% (95% CI=0.78-8.29; I276%), respectively. However, there was no difference in overall infection rates between elderly and young patients. Pooled rate of endoscopic, clinical, and steroid-free remission for elderly IBD patients was 38.45% (95% CI=20.74-59.56; I293%), 37.95% (95% CI=33.08-43.06; I213%), and 38.8% (95% CI=31.6-46.4; I277%), respectively. Elderly patients had lower steroid-free remission rates [RR 0.85, 95% CI=0.74-0.99; I20%, P=0.03]; however, there was no difference in rates of clinical (RR 0.86, 95% CI=0.72-1.03; I20%, P=0.10) or endoscopic remission (RR 1.06, 95% CI=0.83-1.35; I20%, P=0.63) compared with younger patients. Pooled rate of IBD-related surgery and IBD-related hospitalizations was 9.76% (95% CI=5.81-15.92; I278%) and 10.54% (95% CI=8.37-13.2; I20%), respectively for the elderly cohort. There was no statistical difference in IBD-related surgeries between elderly and young IBD patients, RR 1.20 (95% CI=0.79-1.84; I216%), P=0.4. Conclusions: Vedolizumab is equally safe and effective for clinical and endoscopic remission in elderly and younger populations.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49–0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48–0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

INTRODUCTION: Limited guidance exists for the postdischarge care of patients with ulcerative colitis hospitalized for moderate-severe flares. METHODS: RAND methodology was used to establish appropriateness of inpatient and postdischarge steroid dosing, discharge criteria, follow-up, and postdischarge biologic or small molecule initiation. A literature review informed on the panel's voting, which occurred anonymously during 2 rounds before and after a moderated virtual session. RESULTS: Methylprednisolone 40–60 mg intravenous every 24 hours or hydrocortisone 100 mg intravenous 3 times daily is appropriate for inpatient management, with methylprednisolone 40 mg being appropriate if intolerant of higher doses. It is appropriate to discharge patients once rectal bleeding has resolved (Mayo subscore 0–1) and/or stool frequency has returned to baseline frequency and form (Mayo subscore 0–1). It is appropriate to discharge patients on 40 mg of prednisone after observing patients for 24 hours in hospital to ensure stability before discharge. For patients being discharged on steroids without in-hospital biologic or small molecule therapy initiation, it is appropriate to start antitumor necrosis factor (TNF) therapy after discharge for anti-TNF-naive patients. For anti-TNF-exposed patients, it is appropriate to start vedolizumab or ustekinumab for all patients and tofacitinib for those with a low risk of adverse events. It is appropriate to follow up patients clinically within 2 weeks and with lower endoscopy within 4–6 months after discharge. DISCUSSION: We provide recommendations on the inpatient and postdischarge management of patients with ulcerative colitis hospitalized for moderate-severe flares.