Histologic Healing Rates of Medical Therapies for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials and examined the relationship between histologic and endoscopic outcomes. METHODS: MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for randomized controlled trials of aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random-effect or fixed-effect models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. RESULTS: Seventy-four studies (68 induction and 7 maintenance) were identified. Topical aminosalicylate enemas [37.2%, 95% confidence interval (CI), 29.0-46.3] and suppositories (44.9%, 95% CI, 28.9-62.3) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR = 4.14, 95% CI, 2.35-7.31), aminosalicylate suppositories (RR = 3.94, 95% CI, 1.26-12.32), and budesonide multimatrix (RR = 1.47, 95% CI 1.08-1.99) had higher histologic remission rates than placebo. Data were lacking for biologics and immunosuppressives. The pooled histologic remission rate for placebo in induction studies was 10.4% (95% CI, 7.1-15.2). Histologic and endoscopic remission correlated strongly (r = 0.66; 95% CI, 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity and corticosteroid use were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates when active-arm data were analyzed. CONCLUSIONS: Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow CIs. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.

Methods to Summarize Discrete-Choice Experiments in a Systematic Review: A Scoping Review.

BACKGROUND AND OBJECTIVE: Systematic reviews of discrete-choice experiments (DCEs) are being increasingly conducted. The objective of this scoping review was to identify and describe the methodologies that have been used to summarize results across DCEs. METHODS: We searched the electronic databases MEDLINE and EMBASE from inception to March 18, 2021, to identify English-language systematic reviews of patient preferences that included at least two DCEs and extracted data on attribute importance. The methods used to summarize results across DCEs were classified into narrative, semi-quantitative, and quantitative (meta-analytic) approaches and compared. Approaches to characterize the extent of preference heterogeneity were also described. RESULTS: From 7362 unique records, we identified 54 eligible reviews from 2010 to Mar 2021, across a broad range of health conditions. Most (83%) used a narrative approach to summarize findings of DCEs, often citing differences in studies as the reason for not formally pooling findings. Semi-quantitative approaches included summarizing the frequency of the most important attributes, the frequency of attribute statistical significance, or tabulated comparisons of attribute importance for each pair of attributes. One review conducted a meta-analysis using the maximum acceptable risk. While reviews often commented on the heterogeneity of patient preferences, few (6%) addressed this systematically across studies. CONCLUSION: While not commonly used, several semi-quantitative and one quantitative approach for synthesizing results of DCEs were identified, which may be useful for generating summary estimates across DCEs when appropriate. Further work is needed to assess the validity and usefulness of these approaches.

The Application of Preference Elicitation Methods in Clinical Trial Design to Quantify Trade-Offs: A Scoping Review.

BACKGROUND AND OBJECTIVE: Patients can express preferences for different treatment options in a healthcare context, and these can be measured with quantitative preference elicitation methods. OBJECTIVE: Our objective was to conduct a scoping review to determine how preference elicitation methods have been used in the design of clinical trials. METHODS: We conducted a scoping review to identify primary research studies, involving any health condition, that used quantitative preference elicitation methods, including direct utility-based approaches, and stated preference studies, to value health trade-offs in the context of clinical trial design. Studies were identified by screening existing systematic and scoping reviews and with a primary literature search in MEDLINE from 2010 to the present. We extracted study characteristics and the application of preference elicitation methods to clinical trial design according to the SPIRIT checklist from primary studies and summarized the findings descriptively. RESULTS: We identified 18 eligible studies. The included studies applied patient preferences to five areas of clinical trial design: intervention selection (n = 1), designing N-of-1 trials (n = 1), outcome selection and weighting composite and ordinal outcomes (n = 12), sample size calculations (n = 2), and recruitment (n = 2). Using preference elicitation methods led to different decisions being made, such as using preference-weighted composite outcomes instead of equally weighted composite outcomes. CONCLUSION: Preference elicitation methods are infrequently used to design clinical trials but may lead to changes throughout the trial that could affect the evidence generated. Future work should consider measurement challenges and explore stakeholder perceptions.

Systematic review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease.

BACKGROUND: Janus kinase (JAK) inhibitors represent a novel therapeutic class for treatment of inflammatory bowel disease. AIMS: To determine the efficacy and safety of JAK inhibitors compared to placebo for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: PubMed, Embase and CENTRAL were systematically searched to November 1, 2018. Randomised placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC were eligible. Open-label extension studies without a placebo comparator arm were excluded. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. RESULTS: A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomised to placebo (n = 844), tofacitinib (n = 1882), filgotinib (n = 130), peficitinib (n = 176), upadacitinib (n = 387) or TD-1473 (n = 31). JAK inhibitor treatment was associated with induction of clinical remission in CD (RR, relative risk 1.38 [95% confidence interval CI 1.04-1.83], P = 0.025, I2  = 14%) and UC (RR 3.07 [95% CI 2.03-4.63], P < 0.001, I2  = 0%). In UC, JAK inhibitor treatment was associated with induction of endoscopic remission (endoscopic Mayo subscore MCSe = 0/1) (RR 2.43 [95% CI 1.64-3.59], P < 0.001, I2  = 27%) and mucosal healing (MCSe = 0) (RR 5.50 [95% CI 2.46-12.32], P < 0.001, I2  = 0%). JAK inhibitor treatment increased the risk of infection compared to placebo (RR 1.40 [95% CI 1.18-1.67], P < 0.001, I2  = 0%), particularly for herpes zoster. CONCLUSIONS: JAK inhibitors are effective for inducing clinical remission in CD and induction of clinical and endoscopic remission in UC, although are associated with an increased risk of infectious complications.