A practical guide to combination advanced therapy in inflammatory bowel disease.

PURPOSE OF THE REVIEW: To provide an overview of the current literature regarding the use of advanced combination therapy (ACT) in patients with inflammatory bowel disease (IBD). Although the treatment of IBD has come a long way, many patients do not respond or will lose response to currently available treatments over time. ACT has been proposed as a model to create sustained remission in difficult-to-treat IBD patient populations. This review discusses the available literature supporting the use of ACT, followed by practical tips for applying this model of treatment to clinical practice. RECENT FINDINGS: Both observational and controlled evidence have demonstrated that there may be an increased benefit of ACT in specific IBD patient populations compared to advanced targeted immunomodulator (TIM) monotherapy. Additional data is required to understand how to best use combination TIMs and the long-term risks associated with this strategy. SUMMARY: While the literature has demonstrated the potential for benefit in both Crohn's disease and ulcerative colitis, the use of ACT is currently off-label and long-term controlled data is needed. The successful application of ACT requires careful consideration of both patient and disease profiles as well as close monitoring of treatment response and adverse events.

Operating Properties of Disease Activity Indices in Pediatric Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn's disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized. RESULTS: Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn's Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn's Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn's Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation. CONCLUSIONS: The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

The operating properties of pediatric inflammatory bowel disease clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices in this population.

Upadacitinib for the treatment of moderate-to-severe Crohn's disease.

Despite an increasing number of therapies for Crohn's disease (CD), half of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. Inhibition of Janus kinases (JAKs) has emerged as an important therapeutic target for CD. Upadacitinib is an orally administered selective JAK1 inhibitor, which is effective for the induction and maintenance of remission in moderately-to-severely active CD, including in patients with prior failure of biological therapy. Nonselective JAK inhibition has been associated with thromboembolic disease, cardiovascular events and malignancy in patients older than 50 years with rheumatoid arthritis and pre-existing cardiovascular risk factors, which should be considered upon prescription. Upadacitinib is the first and currently only oral advanced therapy for CD.

Not all patients with Crohn's disease (CD) get better with treatment. Blocking Janus kinases (JAKs), enzymes that promote inflammation in the gut, could help these patients. The treatment upadacitinib blocks JAK1 (an enzyme transmitting inflammatory signals) and decreases inflammation in the gut. It eases symptoms. It also resolves gut inflammation in patients with CD. Regarding side effects, JAK inhibitors can cause blood clots in veins, and in the lungs, heart attacks, cancer and infections. Further studies are needed, but caution is advised. Upadacitinib is the first advanced therapy for CD given by mouth.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

Impact of Treatment Response on Risk of Serious Infections in Patients With Crohn's Disease: Secondary Analysis of the PYRAMID Registry.

BACKGROUND & AIMS: Traditional risk factors for serious infections with advanced therapies in patients with Crohn's disease (CD) have been assessed at baseline before starting therapy. We evaluated the impact of treatment response on the risk of serious infections in adalimumab-treated patients with CD through secondary analysis of the PYRAMID registry (NCT00524537). METHODS: We included patients with CD who initiated adalimumab and classified them as treatment responders (achieved steroid-free clinical remission based on patient-reported outcomes) vs nonresponders (not in steroid-free clinical remission) at 6 months after treatment initiation (landmark). We compared the risk of serious infections between responders vs nonresponders between 6 and 36 months after treatment initiation through stabilized inverse probability of treatment weighting Cox proportional hazards model. RESULTS: Of 1515 adalimumab-treated patients, 763 (50.4%) were classified as responders at 6 months (37 ± 13 y; 56% female; disease duration, 9.5 ± 8.5 y). Compared with nonresponders, responders were less likely to have moderate to severe symptoms (55.6% vs 33%), or require steroids (45.5% vs 17.3%) or opiates (6.6% vs 1.3%) at baseline, without any differences in disease location, perianal disease, and prior CD complications. During follow-up evaluation, using stabilized inverse probability of treatment weighting, responders were 34% less likely to experience serious infections compared with nonresponders (hazard ratio, 0.66; 95% CI, 0.46-0.96). Risk of gastrointestinal and extraintestinal infections was lower in responders vs nonresponders. CONCLUSIONS: Patients with CD who respond to adalimumab have a lower risk of developing serious infections compared with nonresponders. These findings underscore that initiation of advanced therapy for CD may lower the risk of serious infections through effective disease control and avoidance of corticosteroids.

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.

Composite Assessment Using Intestinal Ultrasound and Calprotectin Is Accurate in Predicting Histological Activity in Ulcerative Colitis: A Cohort Study.

BACKGROUND: Beyond endoscopic remission, histological remission in ulcerative colitis (UC) is predictive of clinical outcomes. Intestinal ultrasound (IUS) may offer a noninvasive surrogate marker for histological activity; however, there are limited data correlating validated ultrasound and histological indices. AIM: Our aim was to determine the correlation of IUS activity in UC with a validated histological activity index. METHODS: Twenty-nine prospective, paired, same-day IUS/endoscopy/histology/fecal calprotectin (FC) cases were included. Intestinal ultrasound activity was determined using the Milan Ultrasound Criteria, histological activity using the Nancy Histological Index, endoscopic activity using Mayo endoscopic subscore and Ulcerative Colitis Endoscopic Index of Severity, and clinical activity using the Simple Clinical Colitis Activity Score. RESULTS: Histological activity demonstrated a significant linear association with overall IUS activity (coefficient 0.14; 95% CI, 0.03-0.25; P = .011). Intestinal ultrasound activity was also significantly associated with endoscopic activity (0.32; 95% CI, 0.14-0.49; P < 0.001), total Mayo score (0.31; 95% CI, 0.02-0.60; P = .036) but not FC (0.10; 95% CI, -0.01 to 0.21; P = .064) or clinical disease activity (0.04; 95% CI, -0.21 to 0.28; P = .768). A composite of IUS and FC showed the greatest association (1.31; 95% CI, 0.43-2.18; P = .003) and accurately predicted histological activity in 88% of cases (P = .007), with sensitivity of 88%, specificity 80%, positive predictive value 95%, and negative predictive value 57%. CONCLUSIONS: Intestinal ultrasound is an accurate noninvasive marker of histological disease activity in UC, the accuracy of which is further enhanced when used in composite with FC. This can reduce the need for colonoscopy in routine care by supporting accurate point-of-care decision-making in patients with UC.

Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Withdrawal of immunomodulators (IMMs) or tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases (IBDs) in remission on combination therapy is attractive. We evaluated the efficacy and safety of (1) IMM, or (2) TNF antagonist withdrawal in patients with IBD in sustained remission on combination therapy. METHODS: Through a systematic review till March 31, 2023, we identified randomized controlled trials (RCTs) that compared the efficacy and safety of IMM or TNF antagonist withdrawal vs continued combination therapy, in patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy. Primary outcome was risk of relapse and serious adverse events at 12 months. We conducted meta-analysis to calculate relative risk (RR) and 95% confidence interval (CI) and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: We identified 8 RCTs with 733 patients (77% with Crohn's disease, 91% on infliximab-based combination therapy). On meta-analysis of 5 RCTs, there was no difference in the risk of relapse between patients with IMM withdrawal (continued TNF antagonist monotherapy) vs continued combination therapy (16.8% vs 14.9%; RR, 1.15; 95% CI, 0.75-1.76) without heterogeneity (low certainty of evidence). TNF antagonist withdrawal (continued IMM monotherapy) was associated with 2.4-times higher risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38-4.01), with minimal heterogeneity (low certainty of evidence). There was no difference in the risk of serious adverse events with IMM or TNF antagonist withdrawal vs continued combination therapy. CONCLUSIONS: In patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy, de-escalation with TNF antagonist withdrawal, but not IMM withdrawal, was associated with an increased risk of relapse.

Real-world effectiveness and safety of ustekinumab in bio-naive patients with moderate-to-severe Crohn's disease: A Canadian multi-center study.

BACKGROUND: Clinical practice guidelines recommend ustekinumab as a first-line biological treatment option for moderately-to-severely active Crohn's disease (CD). However, there is limited real-world effectiveness and safety data in bio-naïve patients. AIMS: To assess ustekinumab effectiveness and safety in bio-naïve CD patients. METHODS: Medical charts were reviewed retrospectively at seven Canadian centers. The primary outcome was the proportion of patients achieving clinical remission at Month 6 following ustekinumab initiation. Secondary outcomes included clinical, biochemical, and endoscopic response, and remission at Months 4, 6 and 12. Ustekinumab safety was assessed over the one-year follow-up period. RESULTS: 158 charts were reviewed. Clinical remission was achieved by 50.0% (36/72), 67.7% (105/155), and 73.7% (84/114) of patients at Months 4, 6, and 12, respectively. At these study timepoints, biochemical remission was observed in 65.2% (43/66), 71.6% (63/88), and 73.9% (68/92) of patients. At Months 6 and 12, endoscopic remission was observed in 40.5% (15/37) and 56.3% (27/48) of patients, respectively. Most participants (93.5%; 145/155) persisted on ustekinumab through Month 12. No serious adverse drug reactions were reported. CONCLUSION: In this real-world study, ustekinumab presents as an effective first-line biologic for induction and maintenance of remission among bio-naïve Canadian patients with moderately-to-severely active CD.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

Considerations for Colorectal Neoplasia Detection in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up. SUMMARY: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team. Each team member has unique responsibilities for maximizing dysplasia detection in IBD trials. KEY MESSAGES: Sponsors should work in accordance with scientific guidelines to standardize imaging procedures, design the protocol to ensure the trial population is safeguarded, and oversee trial conduct. The site endoscopist should remain updated on best practices to tailor sponsor protocol-required procedures to patient needs, examine the mucosa for disease activity and potential dysplasia during all procedures, and provide optimal procedure videos for central read analysis. Central readers may detect dysplasia or colorectal cancer and a framework to report these findings to trial sponsors is essential. Synergistic relationships between all team members in IBD clinical trials provide an important opportunity for extended endoscopic evaluation and colorectal neoplasia identification.

Incidence and Prevalence of Primary Sclerosing Cholangitis: A Meta-analysis of Population-based Studies.

BACKGROUND: Primary sclerosing cholangitis is a chronic liver disease associated with significant morbidity, mortality, and healthcare utilization. We conducted a systematic review and meta-analysis of population-based studies of the incidence and prevalence of primary sclerosing cholangitis. METHODS: Medline and Embase were systematically searched to identify population-based studies of a defined geographic area and reported the incidence or prevalence of primary sclerosing cholangitis in the general population. Meta-analyses, using random-effects, were performed to calculate overall and country-specific incidence (per 100 000 persons/year) and prevalence rates (per 100 000 persons) with 95% confidence intervals. RESULTS: The 14 studies on incidence and the 12 for prevalence originated from North America, Asia, Europe, and Oceania. Incidence and prevalence rates of primary sclerosing cholangitis were 0.87 (95% confidence interval, 0.59-1.29) and 13.53 (95% confidence interval, 10.20-17.94) per 100 000 persons, respectively. CONCLUSIONS: Both the prevalence and incidence of primary sclerosing cholangitis is low in the general population. Future studies on the incidence and prevalence of primary sclerosing cholangitis in the general population should be directed at Asia, Africa, and Latin America to allow for a more robust assessment of the global epidemiology of primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic liver disease with complications such as cirrhosis, cancer, and death. This study summarizes the incidence (0.87 per 100 000) and prevalence (13.53 per 100 000) of PSC and highlight needs in research to study the epidemiology of PSC.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Use of external control arms in immune-mediated inflammatory diseases: a systematic review.

OBJECTIVES: External control arms (ECAs) provide useful comparisons in clinical trials when randomised control arms are limited or not feasible. We conducted a systematic review to summarise applications of ECAs in trials of immune-mediated inflammatory diseases (IMIDs). DESIGN: Systematic review with an appraisal of ECA source quality rated across five domains (data collection, study populations, outcome definitions, reliability and comprehensiveness of the dataset, and other potential limitations) as high, low or unclear quality. DATA SOURCES: Embase, Medline and Cochrane Central Register of Controlled Trial were searched through to 12 September 2023. ELIGIBILITY CRITERIA: Eligible studies were single-arm or randomised controlled trials (RCTs) of inflammatory bowel disease, pouchitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and atopic dermatitis in which an ECA was used as the comparator. DATA EXTRACTION AND SYNTHESIS: Two authors independently screened the search results in duplicate. The characteristics of included studies, external data source(s), outcomes and statistical methods were recorded, and the quality of the ECA data source was assessed by two independent authors. RESULTS: Forty-three studies met the inclusion criteria (inflammatory bowel disease: 16, pouchitis: 1, rheumatoid arthritis: 12, juvenile idiopathic arthritis: 1, ankylosing spondylitis: 5, psoriasis: 3, multiple indications: 4). The majority of these trials were single-arm (33/43) and enrolled adult patients (34/43). All included studies used a historical control rather than a contemporaneous ECA. In RCTs, ECAs were most often derived from the placebo arm of another RCT (6/10). In single-arm trials, historical case series were the most common ECA source (19/33). Most studies (31/43) did not employ a statistical approach to generate the ECA from historical data. CONCLUSIONS: Standardised ECA methodology and reporting conventions are lacking for IMIDs trials. The establishment of ECA reporting guidelines may enhance the rigour and transparency of future research.

Scoring indices for perianal fistulizing Crohn's disease: A systematic review.

BACKGROUND & AIMS: In this systematic review we summarize existing scoring indices for assessing disease activity and quality of life in perianal fistulizing Crohn's disease (PFCD) and highlight gaps in the literature. METHODS: MEDLINE, EMBASE, and CENTRAL were searched from 24 August 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: Fifty-three studies reported on the use of one clinical index (Perianal Disease Activity Index: PDAI), three PROMs and ten radiological indices. Twenty-five 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 standardized definitions and thresholds for outcomes.

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.