Endoscopic scoring indices for assessing disease severity in familial adenomatous polyposis: Systematic review.

Background and study aims There is limited consensus on the optimal method for measuring disease severity in familial adenomatous polyposis (FAP). We aimed to systematically review the operating properties of existing endoscopic severity indices for FAP. Methods We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2023 to identify randomized controlled trials (RCTs) that utilized endoscopic outcomes or studies that evaluated the operating properties of endoscopic disease severity indices in FAP. Results A total of 134 studies were included. We evaluated scoring indices and component items of scoring indices, such as polyp count, polyp size, and histology. Partial validation was observed for polyp count and size. The most commonly reported scoring index was the Spigelman classification system, which was used for assessing the severity of duodenal involvement. A single study reported almost perfect interobserver and intra-observer agreement for this system. The InSIGHT polyposis staging system, which was used for assessing colorectal polyp burden, has been partially validated. It showed substantial interobserver reliability; however, the intra-observer reliability was not assessed. Novel criteria for high-risk gastric polyps have been developed and assessed for interobserver reliability. However, these criteria showed a poor level of agreement. Other scoring indices assessing the anal transition zone, duodenal, and colorectal polyps have not undergone validation. Conclusions There are no fully validated endoscopic disease severity indices for FAP. Development and validation of a reliable and responsive endoscopic disease severity instrument will be informative for clinical care and RCTs of pharmacological therapies for FAP.

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.

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.