An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials

Background & Aims: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. Methods: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. Results: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. Conclusions: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty

Histologic scoring indices for evaluation of disease activity in Crohn's disease

Histologic assessment of mucosal disease activity has been increasingly used in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently existing histologic scoring indices remain unclear. A systematic review was undertaken to evaluate the development and operating characteristics of available histologic disease activity indices in Crohn's disease. Electronic searches of MEDLINE, EMBASE, PubMed, and the Cochrane Library (CENTRAL) databases from inception to 20 July 2016 were supplemented by manual reviews of bibliographies and abstracts submitted to major gastroenterology meetings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organisation). Any study design (e.g. randomised controlled trial, cohort study, case series) that evaluated a histologic disease activity index in patients with Crohn's disease was considered for inclusion. Study participants included adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic or endoscopic criteria. Two authors independently reviewed the titles and abstracts of the studies identified from the literature search. The full text of potentially relevant citations were reviewed for inclusion and the study investigators were contacted as needed for clarification. Any disagreements regarding study eligibility were resolved by discussion and consensus with a third author.Two authors independently extracted and recorded data using a standard form. The following data were recorded from each eligible study: number of patients enrolled; number of patients per treatment arm; patient characteristics: age and gender distribution; description of histologic disease activity index utilized; and outcomes such as content validity, construct validity, criterion validity, responsiveness, intra-rater reliability, inter-rater reliability, and feasibility. Sixteen reports of 14 studies describing 14 different numerical histological indices fulfilled the inclusion criteria.Inter-rater reliability was assessed in one study. For the Naini and Cortina Score, estimates of correlation were 'almost perfect', ranging from r = 0.94 to 0.96. The methodological quality of this study with respect to reliability was 'good'.With respect to validity, correlation estimates between various histological scoring systems and Crohn's disease activity as measured by objective markers of inflammation (including C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and fecal lactoferrin); endoscopic disease activity scores; clinical disease activity scores; and quality of life questionnaires were reported. Comparisons between histologic scoring indices and endoscopic scoring indices ranged from no correlation to 'substantial' (r = 0.779). The methodological quality of the studies that explored validity ranged form 'poor' to 'good'.Responsiveness data were available in seven studies. After subjects were administered a treatment of known efficacy, statistically significant change in the index score was demonstrated in five studies with respect to six indices. Two studies failed to indicate whether there was statistically significant change in the index score post-treatment. With regard to methodological quality, six of the studies were rated as 'poor' and one of the studies was rated as 'fair'.Feasibility was assessed by one study. The Naini and Cortina Score was shown to be simple to use and feasible for every given case. Currently there is no fully validated histological scoring index for evaluation of Crohn's disease activity. Development of a validated histological scoring index for Crohn's disease is a clinical and research priorit

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

PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis

Background & Aims: Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). Methods: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. Results: PTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. Conclusions: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75