Intravenous albumin infusion does not augment the response rate to a combination of exclusive enteral nutrition and intravenous steroids in acute severe ulcerative colitis: a randomized controlled trial.

INTRODUCTION: 30-40% patients with acute severe ulcerative colitis (ASUC) fail intravenous (IV) steroids requiring medical rescue therapy/colectomy. Low baseline albumin predicts steroid non-response, and exclusive enteral nutrition (EEN) has been shown to improve steroid response and albumin levels. Albumin infusion due to its anti-inflammatory and anti-oxidant properties might further improve steroid response in ASUC, which was evaluated in present study. METHODS: In this open-label randomized controlled trial, patients with ASUC were randomized in 1:1 ratio to albumin + standard of care (SOC) + EEN vs. SOC + EEN (Jan2021 - Feb2023). Both arms received 5 days of EEN with 400 mg IV hydrocortisone/day. Patients in albumin arm were administered 5 days of 20% w/v intravenous albumin (100 ml). Primary outcome was 1) steroid failure (need for rescue medical therapy or colectomy) and 2) proportion of patients with adverse events. RESULTS: Sixty-one patients (albumin-30, SOC-31)(mean age-31.6±0.4 years, male-57.4%), were included. Baseline characteristics were comparable. There was no difference in steroid failure between albumin and SOC arm(10/30(33.33 %) vs 13/31(41.94 %), p=0.49). No adverse events were reported with albumin infusions. Colectomy rate(10% vs 9.68%, P=1), response to salvage medical therapy (88.89% vs 76.92%, P=0.62) and median duration of hospitalization (10.5(7-16) vs 10(7-20), P=0.43) were also comparable. Long-term composite outcome of colectomy and re-admission rates was numerically higher in the albumin than SOC arm (37.04% vs 17.86%, p>0.05), although it did not reach statistical significance. CONCLUSION: There was no benefit of intravenous albumin infusion as an adjunct to IV steroids and EEN in patients with ASUC.

Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials.

Background: Disease extent in Ulcerative Colitis (UC) has prognostic implications for disease course. It is unclear whether the efficacy of medical therapies for moderate to severely active UC vary according to disease extent at enrollment. Methods: We analyzed patient level data from 11 Phase 2 and 3 clinical trials of advanced therapies in patients with moderate-to-severe UC to assess modifications of advanced therapy effects by disease extent. Primary outcome was clinical response and secondary outcomes were clinical remission, endoscopic response/remission and endoscopic improvement, and Mayo clinic subscore for both induction and maintenance studies. Binary and continuous outcomes were analyzed using the modified Poisson regression model and the mixed-effects model, respectively, adjusting for age, sex, disease duration, concomitant steroid use and prior anti-TNF use. Effect modifications with binary outcomes were quantified by ratios of risk ratio for left-sided to that for extensive colitis while effect modifications with the Mayo subscores were quantified by differences of the differences between mean scores of the left-sided and extensive colitis. Results were presented with point estimates and 95% confidence intervals as well as p-values. Findings: Eleven clinical trials enrolling 5450 UC patients (infliximab = 2, adalimumab = 2, golimumab = 2, vedolizumab = 2, tofacitinib = 3) were included. In induction trials, there was evidence to suggest effect modification by disease extent for clinical response with tofacitinib (the ratio of RRs 0.67, 95% CI [0.45, 0.99], p = 0.049) and clinical remission with infliximab (ratio of RRs 0.33, 95% CI [0.13, 0.85], p = 0.020) favoring patients with extensive colitis. There was no evidence to suggest effect modification for endoscopic improvement and clinical outcomes. There was evidence to suggest effect modification by disease extent for clinical remission with tofacitinib (ratio of RRs 0.44, 95% CI [0.22, 0.89], p = 0.020) favoring patients with extensive colitis. For symptom subscores from the Mayo Clinic score, tofacitinib was associated with a greater reduction in both stool frequency (difference of differences 0.37, 95% CI [0.08, 0.65], p = 0.012) and rectal bleeding scores (difference of differences 0.25, 95% CI [0.03, 0.47], p = 0.026) in patients with extensive colitis compared to left sided. Interpretation: These findings underscore the possibility of differential efficacy of medical therapies according to disease distribution. These results warrant further exploration in forthcoming trials to better inform treatment strategies and consideration of disease distribution as a baseline stratification factor in clinical trials. Funding: This study did not receive any financial support.

A phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulas (PF) affect one-third patients with Crohn's disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population. METHODS: An open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn's disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model. RESULTS: Ten patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time. CONCLUSIONS: Allogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing. TRIAL REGISTRATION: The study was prospectively registered on Clinical trials registry - India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in .

Comparative Efficacy of Advanced Therapies for Achieving Endoscopic Outcomes in Crohn's Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: We conducted a network meta-analysis to compare the efficacy of advanced therapies for achieving endoscopic outcomes in patients with moderate-to-severely active Crohn's disease. METHODS: MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to August 2, 2023 to identify phase II and III randomized controlled trials (RCTs) in adults (≥18 years) with moderate-to-severe Crohn's disease treated with tumor necrosis factor (TNF) antagonists, etrolizumab, vedolizumab, anti-interleukin (IL)12/23p40, anti-IL23p19, or Janus kinase-1 (JAK1) inhibitors, compared with placebo/active comparator, for induction and/or maintenance of remission and reported endoscopic outcomes. Primary outcome was endoscopic response after induction therapy, and endoscopic remission after maintenance therapy. We performed a random-effects network meta-analysis using a frequentist approach, and estimated relative risk (RRs), 95% confidence interval (CI) values, and P score for ranking agents. We used GRADE to ascertain certainty of evidence. RESULTS: A total of 20 RCTs (19 placebo-controlled and 1 head-to-head trial; 5592 patients) were included out of which 12 RCTs reported endoscopic outcomes for the induction phase, 5 reported for the maintenance phase, and 3 reported for both induction and maintenance phases. JAK1 inhibitors (RR, 3·49 [95% CI, 1·48-8·26]) and anti-IL23p19 (RR, 2·30 [95% CI, 1·02-5·18]) agents were more efficacious than etrolizumab (moderate certainty of evidence), and JAK1 inhibitors (RR, 2·34 [95% CI, 1·14-4·80]) were more efficacious than anti-IL12/23p40 agents for inducing endoscopic response (moderate certainty of evidence). JAK1 inhibitors and anti-IL23p19 ranked highest for induction of endoscopic response. There was paucity of RCTs of TNF antagonists reporting endoscopic outcomes with induction therapy. On network meta-analysis of 6 RCTs, all agents except vedolizumab (RR, 1.89 [95% CI, 0.61-5.92]) were effective in maintaining endoscopic remission compared with placebo. TNF antagonists, IL12/23p40, and JAK1 inhibitors were ranked highest. CONCLUSIONS: On network meta-analysis, JAK1 inhibitors and anti-IL23p19 agents may be the most effective among non-TNF-targeting advanced therapies for inducing endoscopic response. Future head-to-head trials will further inform positioning of different therapies for the management of Crohn's disease.

Coconut Water Induces Clinical Remission in Mild to Moderate Ulcerative Colitis: Double-blind Placebo-controlled Trial.

BACKGROUND & AIMS: Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative colitis (UC), and potassium possesses in vitro anti-inflammatory property. We evaluated the effect of CW as an adjunct therapy for patients with mild-moderate UC. METHODS: This single-center, double-blind, placebo-controlled trial randomized patients with mild to moderate (Simple Clinical Colitis Activity Index [SCCAI]: 3-9) endoscopically active UC (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] >1) in 1:1 ratio to CW + standard medical therapy (SMT) vs placebo + SMT. Four hundred mL of CW was administered for 8 weeks. Primary outcome measure was clinical remission (SCCAI ≤2), and secondary outcome measures were clinical response (SCCAI decline ≥3) and adverse events at 8 weeks. Microbiome was analyzed at baseline and 8 weeks. RESULTS: Of 121 patients screened, 95 were included for modified intention to treat analysis (CW, n = 49; placebo, n = 46) (mean age, 37.2 ± 11.2 years; males, 54.1%; disease duration, 48 months [interquartile range (IQR), 24-90 months]; pancolitis, 26.1%; SCCAI, 5 [IQR, 4-6]; UCEIS, 4 [IQR, 3-5]). Clinical response (57.1% vs 28.3%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.4-7.9; P = .01), remission (53.1% vs 28.3%; OR, 2.9; 95% CI, 1.2-6.7; P = .02), and proportion of patients with fecal calprotectin (FCP) <150 µg/g (30.6% vs 6.5%; OR, 6.3; 95% CI, 1.7-23.6; P = .003) were significantly higher in CW. The relative abundance of bacterial taxa that had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP increased at 8 weeks in CW, and this effect was independent of disease activity and dietary fiber. Adverse events were comparable, and no patient developed hyperkalemia. CONCLUSIONS: CW was more effective than placebo for induction of clinical remission in patients with mild to moderate UC. The trial was prospectively registered on Clinical Trials Registry of India (ctri.nic.in, Number: CTRI/2019/03/01827).

Thiopurines Have Sustained Long-term Effectiveness in Patients with Inflammatory Bowel Disease, Which is Independent of Disease Duration at Initiation: A Propensity Score Matched Analysis.

BACKGROUND AND AIMS: Thiopurines are viable option for the treatment of inflammatory bowel disease [IBD] in resource-limited countries. However, data on the effect of disease duration at thiopurines initiation on long-term effectiveness are limited. METHOD: We performed a propensity matched analysis of a retrospective cohort of patients with ulcerative colitis [UC] and Crohn's disease [CD]. Patients initiated on thiopurines early in the disease course [≤2 years] were compared with those started late [>2 years]. Effectiveness was defined as no requirement for hospitalisation, anti-tumour necrosis factor [TNF] agents, or surgery, and minimum steroid requirement [≤1 steroid course in 2 years] during follow-up. RESULTS: A total of 988 [UC: 720, CD: 268] patients were included (male: 665 [60.8%], median age: 40 [32-51] years, median follow-up: 40 [19-81] months). Overall effectiveness at 5 and 10 years was 79% and 72% in UC, and 69% and 63% in CD, respectively. After propensity score matching, there was no difference in 5- and 10-year effectiveness between early and late thiopurine initiation groups either for UC [81% and 80% vs 82% and 74%; p = 0.92] or CD [76% and 66% vs 72% and 51%, p = 0.32]. Male sex for UC (negative: hazard ratio [HR]: 0.67, 95% confidence interval [CI): 0.45-0.97; p = 0.03), and ileal involvement [positive: HR: 3.03, 95% CI: 1.32-6.71; p = 0.008], steroid-dependent disease [positive: HR: 2.70, 95% CI: 1.26-5.68; p = 0.01] and adverse events [negative: HR: 0.47, 95% CI:0.27-0.80; p = 0.005] for CD were predictors of thiopurine effectiveness. CONCLUSION: Thiopurines have sustained long-term effectiveness in both UC and CD. However, early thiopurine initiation had no better effect on long-term disease outcome compared with late initiation.

Exclusive Enteral Nutrition Mediates Beneficial Gut Microbiome Enrichment in Acute Severe Colitis.

BACKGROUND: Exclusive enteral nutrition (EEN) supplementation of the standard of care (SOC) augments steroid responsiveness in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study investigates EEN-driven gut microbial alterations in patients with ASUC and examines their correlations with clinical parameters. METHODS: Stool samples from patients with ASUC (n = 44) who received either EEN-supplemented SOC (EEN group; n = 20) or SOC alone (SOC group; n = 24) for 7 days were collected at baseline (day 0) and postintervention (day 7). Microbiome analysis was carried out using 16S ribosomal RNA gene sequencing followed by data processing using QIIME2 and R packages. RESULTS: Seven-day EEN-conjugated corticosteroid therapy in patients with ASUC enhanced the abundances of beneficial bacterial genera Faecalibacterium and Veillonella and reduced the abundance of Sphingomonas (generalized linear model fitted with Lasso regularization with robustness of 100%), while no such improvements in gut microbiota were observed in the SOC group. The EEN-associated taxa correlated with the patient's clinical parameters (serum albumin and C-reactive protein levels). Unlike the SOC group, which retained its preintervention core microbiota, EEN contributed Faecalibacterium prausnitzii, a beneficial gut bacterial taxon, to the gut microbial core. EEN responders showed enhancement of Ligilactobacillus and Veillonella and reduction in Prevotella and Granulicatella. Analysis of baseline gut microbiota showed relative enhancement of certain microbial genera being associated with corticosteroid response and baseline clinical parameters and that this signature could conceivably be used as a predictive tool. CONCLUSIONS: Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by beneficial gut microbial changes in patients with ASUC.

Exclusive enteral nutrition­supplemented corticosteroid therapy in acute severe ulcerative colitis (ASUC) is accompanied by the enrichment of beneficial gut microbial genera, which correlate negatively with the disease activity scores and objective inflammatory markers in ASUC. The baseline gut microbiota in ASUC associates with and may predict corticosteroid response.

Endoscopic and Histological Placebo Rates in Crohn's Disease Clinical Trials: A Systematic Review and Meta-analysis.

BACKGROUND: Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated. RESULTS: In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes. CONCLUSIONS: Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.

Scoring Indices for Perianal Fistulising Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: In this systematic review we summarise existing scoring indices for assessing disease activity and quality of life in perianal fistulising Crohn's disease [PFCD], and highlight gaps in the literature. METHODS: MEDLINE, EMBASE, and CENTRAL were searched from August 24, 2022, to identify studies evaluating clinical, radiological, or patient-reported outcome measures [PROMS] in PFCD. The primary objective was to identify all available scoring indices and describe the operating properties of these indices. RESULTS: A total of 53 studies reported on the use of one clinical index [Perianal Disease Activity Index: PDAI], three PROMs, and 10 radiological indices; 25 studies evaluated the operating properties of these indices. The PDAI demonstrated content validity, construct validity, and responsiveness but criterion validity or reliability were not assessed. The Van Assche Index [VAI], modified VAI, and the Magnetic Resonance Index for Assessing Fistulas in Patients with CD [MAGNIFI-CD] were the most studied radiological indices. These indices demonstrated responsiveness and reliability. The VAI and MAGNIFI-CD demonstrated construct validity; criterion and content validity and feasibility have not been assessed. Among the three PROMs, the Crohn's Anal Fistula Quality of Life index demonstrated content and construct validity, inter-observer reliability, and responsiveness; criterion validity, intra-observer reliability, and feasibility have not been assessed for this index. CONCLUSIONS: There are no fully valid, reliable, and responsive clinical disease or radiological indices for PFCD. Although the radiological indices demonstrated responsiveness and reliability, well-defined cut-offs for response and remission are lacking. Future research should focus on establishing standardised definitions and thresholds for outcomes.

"Prevalence, Predictors, and Impact of Hepatic Steatosis in Patients With Ulcerative Colitis: A Prospective Observational Cohort Study".

Background and Aims: There are no prospective studies evaluating effect of non-alcoholic fatty liver disease (NAFLD) in patients with ulcerative colitis (UC). This prospective observational study assessed the prevalence of NAFLD, its predictors, and its effect on long-term outcomes in UC. Methods: Consecutive UC patients underwent transient elastography, body composition analysis, bone densitometry, anthropometry, and baseline demographic and subjective global assessment. NAFLD was diagnosed by controlled attenuation parameter of >260 dB/m. To evaluate predictors and outcomes, patients of UC with NAFLD (n = 29) were compared with age- and sex-matched patients of UC without NAFLD (n = 27). Results: Among 107 patients of UC (mean age-29 ± 10.6 years; males = 56%, median disease duration-48 [interquartile range: 24-84] months, left sided/pancolitis = 84%), 27% (n = 29) had NAFLD. Patients with body mass index (BMI) > 23 kg/m2 had higher proportion of NAFLD than with normal or low BMI (54.7% [23/42] vs 10% [5/50] vs 6.7% [1/15]). Patients with NAFLD had high BMI (P < 0.001), waist circumference, and fat mass (P < 0.001) but similar fat-free mass (P = 0.798) compared to patients without NAFLD. There was no difference in immunosuppressant and cumulative steroid exposure between two groups. Dietary parameters including daily energy, protein, fat, and carbohydrate intake were similar between the two groups. On multivariate analysis, high BMI was found to be predictive and low socioeconomic status as a protective factor of NAFLD. On long-term follow-up of three years, there was no difference in steroid, or biologic requirement, disease-related hospitalization, or composite of all three outcomes between two groups. Conclusion: The prevalence of NAFLD was found in nearly a quarter of patients of UC and was affected by metabolic parameters rather than disease activity.

Characteristics of Interventional Trials for Patients Living With Intestinal Stoma Registered in ClinicalTrials.gov With a Focus on Inflammatory Bowel Disease.

BACKGROUND: This systematic review was performed to characterize the landscape of research conducted in patients with intestinal stoma (IS) and highlight unmet needs for clinical research in Crohn's disease (CD) and IS. METHODS: We searched ClinicalTrials.gov from inception to May 25, 2022, to identify clinical trials assessing interventions in patients with an IS, as well as those with an IS and CD. Studies were grouped according to type of intervention. We excluded observational studies with no treatment arm. RESULTS: A total of 253 studies were included in the final analysis. Most studies investigated devices (n = 122 [48.2%]), or surgical procedures (n = 63 [24.9%]), followed by behavioral interventions (n = 30 [11.8%]), drugs (n = 20 [7.9%]), dietary interventions (n = 2 [0.8%]), skin care products (n = 2 0.8%]), and others (n = 14 [5.5%]). A total of 50.9% (n = 129) of studies had completed recruitment, enrolling 11 116 participants. Only 6 studies (surgery: n = 3; physiological studies: n = 2; drugs: n = 1) exclusively included patients with inflammatory bowel disease (IBD), and 16 studies commented that patients with IBD were excluded in their eligibility criteria. No study assessed efficacy of drugs in patients with CD and IS. Approximately one-quarter of studies (n = 65 of 253) included quality of life as an outcome measure. CONCLUSION: There is a paucity of research in IBD patients with IS, with the majority focusing on devices and surgical procedures. There have been no drug trials evaluating efficacy in patients with CD and IS. There is an urgent need to identify barriers to enrollment and develop eligibility and outcome measures that enable the inclusion of patients with CD with stoma into clinical trials.

We analyzed registered trials for patients with intestinal stoma with special focus on Crohn's disease patients to explore research and unmet needs. Our results indicate a scarcity of studies in this area with most studies limited to surgical procedures and devices.

Pharmacological therapies for the management of fistulising Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: Fistulas are a debilitating complication of Crohn's disease (CD). We conducted a systematic review to assess the efficacy of medical therapies for fistulising CD. METHODS: MEDLINE, Embase, and CENTRAL were searched on May 26, 2022, for randomised controlled trials (RCTs) of pharmacologic therapy in adults with fistulising CD. The primary outcome was induction and maintenance of fistula response. Pooled risk ratios (RRs) and 95% confidence intervals (CI) were calculated. GRADE was used to assess certainty of evidence. RESULTS: Thirty-eight RCTs were included. Nineteen trials (50%) exclusively involved perianal fistula. The remaining studies included some participants with non-perianal fistula. Pooled RRs for anti-tumor necrosis factor (TNF) agents were not statistically significant for induction (RR 1.36, 95% CI 0.97-1.91) or maintenance of fistula response (RR 1.48, 95% CI 0.97-2.27). However, in a sensitivity analysis of studies with fistula response as the primary outcome, anti-TNFs were superior to placebo for induction (RR 1.94, 95% CI 1.10-3.41) and maintenance (RR 1.88, 95% CI 1.23-2.88) of fistula response. Oral small molecules (RR 2.56, 95% CI 1.18-5.53) and mesenchymal stem cell (MSC) therapy (RR 1.26, 95% CI 1.01-1.57) were effective for induction of fistula response. Ustekinumab was associated with maintenance of fistula response (RR 1.80, 95% CI1.04-3.11). Vedolizumab was not superior to placebo. The certainty of evidence ranged from very low to moderate. CONCLUSION: Very low-to-moderate certainty evidence suggests that anti-TNF therapy, oral small molecules, ustekinumab, and MSCs are effective for perianal fistulising CD. Dedicated fistula studies evaluating biologics and small molecules are needed.

Systematic review with meta-analysis: Medical therapies for treatment of ulcerative proctitis.

BACKGROUND: Ulcerative proctitis (UP) is a common highly symptomatic form of ulcerative colitis that can be difficult to treat. AIM: To assess the efficacy of medical treatments for UP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL on 23 November 2022 for randomised controlled trials (RCTs) of medical therapy for adults with UP. Primary outcomes included induction and maintenance of clinical remission. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each outcome. RESULTS: We included 53 RCTs (n = 4096) including 46 induction studies (n = 3731) and seven maintenance studies (n = 365). First-line therapies included topical 5-aminosalicylic acid (5-ASA), conventional corticosteroids, budesonide, and oral 5-ASA. Therapy for refractory UP included topical tacrolimus and small molecules. Topical 5-ASA was superior to placebo for induction (RR 2.72, 95% CI 1.94-3.82) and maintenance of remission (RR 2.09, 95% CI 1.26-3.46). Topical corticosteroids were superior to placebo for induction of remission (RR 2.83, 95% CI 1.62-4.92). Topical budesonide was superior to placebo for induction of remission (RR 2.34, 95% CI 1.44-3.81). Combination therapy with topical 5-ASA and topical corticosteroids was superior to topical monotherapy with either agent. Topical tacrolimus was superior to placebo. Etrasimod was superior to placebo for induction (RR 4.71, 95% CI 1.2-18.49) and maintenance of remission (RR 2.08, 95% CI 1.31-3.32). CONCLUSIONS: Topical 5-ASA and corticosteroids are effective for active UP. Topical 5-ASA may be effective for maintenance of remission. Tacrolimus may be effective for induction of remission. Etrasimod may be effective for induction and for maintenance of remission. Trials should include UP to expand the evidence base for this under-represented population.

Long Washout Periods Between Biologics for Inflammatory Bowel Disease Clinical Trials Are Unnecessary: A Canadian Retrospective Cohort Study.

INTRODUCTION: To assess the safety of early vs late biologic switch in patients with inflammatory bowel disease. METHODS: In this retrospective study, we included patients with inflammatory bowel disease who underwent biologic switch between January 2014 and July 2022 at a tertiary center. The primary outcome was any infection by 6 months. RESULTS: There was no statistically significant difference between patients who had early biologic switch (≤30 days, n = 51) and late switch (>30 days, n = 77) in either infectious or noninfectious adverse events by 6 and 12 months. DISCUSSION: Early biologic switch is safe. A prolonged washout period between 2 biologics is unnecessary.

Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). AIMS: This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD. METHODS: MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively. RESULTS: Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I2 = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I2 = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence). CONCLUSION: Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.

Efficacy and Safety of Advanced Oral Small Molecules for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Oral small-molecule drugs [SMDs] are expanding the therapeutic landscape for inflammatory bowel disease [IBD]. This systematic review and meta-analysis summarizes the efficacy and safety of JAK inhibitor [JAKi] and sphingosine-1-phosphate [S1P] receptor modulator treatments for ulcerative colitis [UC] and Crohn's disease [CD]. METHODS: MEDLINE, Embase, and CENTRAL were searched from inception to May 30, 2022. Randomized controlled trials [RCTs] of JAKi and S1P receptor modulators in adults with UC or CD were eligible. Clinical, endoscopic, histological, and safety data were pooled and analysed using a random-effects model. RESULTS: Thirty-five RCTs [26 UC, nine CD] were included. In UC, JAKi therapy was associated with induction of clinical (risk ratio [RR] 3.16, 95% confidence interval [CI] 2.03-4.92; I2 = 65%) and endoscopic [RR 3.99, 95% CI 2.36-6.75; I2 = 36%] remission compared to placebo. Upadacitinib was associated with histological response [RR 2.63, 95% CI 1.97-3.53]. S1P modulator therapy was associated with induction of clinical [RR 2.52, 95% CI 1.88-3.39; I2 = 1%] and endoscopic [RR 2.39, 95% CI 1.07-5.33; I2 = 0%] remission relative to placebo. Ozanimod was superior to placebo for inducing histological remission in UC [RR 2.20, 95% CI 1.43-3.37; I2 = 0%], while etrasimod was not [RR 2.36, 95% CI 0.71-7.88; I2 = 0%]. In CD, JAKi therapy was superior to placebo for induction of clinical remission [RR 1.53, 95% CI 1.19-1.98; I2 = 31%], and endoscopic remission [RR 4.78, 95% CI 1.63-14.06; I2 = 43%] compared to placebo. The risk of serious infections was similar for oral SMDs and placebo. CONCLUSION: JAKi and S1P receptor modulator therapies are effective in IBD for inducing clinical and endoscopic remission and, in some circumstances, histological response.

Targeting IL-23 for IBD: Rationale and Progress to Date.

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, comprises multiple complex immune-mediated disorders. Early diagnosis and prompt disease control may prevent long-term complications and hospitalization. The therapeutic options have expanded in the last two decades, with the development of biologics and small molecules targeting specific pathways implicated in inflammatory bowel disease pathogenesis. The interleukin (IL)-23/Th-17 axis is one such example. Targeting IL-12/23 is effective for the treatment of both moderate-to-severe Crohn's disease and ulcerative colitis, and ustekinumab (an IL-12/23p40 antagonist) is approved for both indications. In patients with psoriasis, improved clinical outcomes were observed with agents that more selectively targeted IL-23 (IL-23p19 antagonists) compared with those that target both IL-12 and IL-23. Many specific IL-23p19 antagonists are currently being investigated in Crohn's disease and ulcerative colitis, and risankizumab has been recently approved for moderate-to-severely active Crohn's disease. In this review, we summarize the mechanisms of action and the evidence from clinical trials supporting the efficacy and safety of IL-23p19 antagonists for the treatment of inflammatory bowel disease.

Disorders of gut-brain interaction in post-acute COVID-19 syndrome.

The novel coronavirus SARS-CoV-2 is responsible for the devastating pandemic which has caused more than 5 million deaths across the world until today. Apart from causing acute respiratory illness and multiorgan dysfunction, there can be long-term multiorgan sequalae after recovery, which is termed 'long COVID-19' or 'post-acute COVID-19 syndrome'. Little is known about long-term gastrointestinal (GI) consequences, occurrence of post-infection functional gastrointestinal disorders and impact the virus may have on overall intestinal health. In this review, we put forth the various mechanisms which may lead to this entity and possible ways to diagnose and manage this disorder. Hence, making physicians aware of this spectrum of disease is of utmost importance in the present pandemic and this review will help clinicians understand and suspect the occurrence of functional GI disease post recovery from COVID-19 and manage it accordingly, avoiding unnecessary misconceptions and delay in treatment.

Low prevalence of Clostridioides difficile infection in acute severe ulcerative colitis: A retrospective cohort study from northern India.

BACKGROUND: The incidence of Clostridioides difficile infection (CDI) is high in ulcerative colitis and is associated with disease flares and adverse outcomes. However, the data on the dynamics of CDI in patients with acute severe ulcerative colitis (ASUC) is rather scarce. We evaluated the prevalence of CDI in patients with ASUC. METHODS: This retrospective analysis of a prospectively maintained cohort admitted to the All India Institute of Medical Sciences, India, from May 2016 to December 2021, included patients with ASUC (as per Truelove and Witts criteria) who were tested for CDI. CDI testing was performed using enzyme-linked immunoassay for toxins A and B. Risk factors for developing CDI were analyzed along with short-term outcomes of ASUC. Steroid failure was defined as the need for medical rescue therapy or colectomy. RESULTS: Total 153 patients with ASUC were included (mean age 34.92 ± 12.24 years; males 56.2%; disease duration 36 (IQR: 16-55.5) months, pancolitis 67.3%). Ninety-eight (63.4%), 72 (47%) and 10 (6.5%) patients, respectively, had received steroids, azathioprine and biologics in the past. Forty patients (26.14%) had a prior history of ASUC. Among risk factors for CDI, 14% of the patients had prior admission within 30 days, 22.2% had a recent history of antibiotics and 3.9% had long-term non-steroidal anti-inflammatory drug intake. Only one sample was positive for Clostridioides difficile toxin assay. Tissue Cytomegalovirus DNA-PCR positivity was noted in 57 patients (37.3%). Fifty-seven patients (37.3%) had steroid failure, 35 required medical rescue therapy and 30 (19.6%) required colectomy (eight after medical rescue therapy failure). CONCLUSION: Despite antecedent risk factors for CDI, the overall prevalence of CDI in ASUC was low and the outcomes were determined by underlying disease severity.