Citations

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. Methods Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. Results Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. Conclusions Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

Abstract Background There is a scarcity of data regarding the role of histopathology evaluation in Crohn’s disease (CD) and how it relates to endoscopy. Mirikizumab (miri) has shown efficacy in Ph2 studies in CD and ulcerative colitis (UC). Here we explore the agreement of histologic response and remission with endoscopic outcomes after 12 and 52 weeks of treatment with miri in a phase 2 randomized clinical trial (SERENTIY; NCT02891226) in patients with moderate-to-severe CD. Methods Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Those who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); due to small numbers, maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies were obtained during endoscopy at W0, 12 and 52 from the edge of the ulcers and the most inflamed mucosa in terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum; N=10/patient, 2 per location with the more severe score used), and scored by central readers blind to study treatment, timepoint, and response status. Histologic endpoints were defined post-hoc but prior to performing the analyses (see Table footnotes for definitions). Cohen’s Kappa Coefficient was used to evaluate the degree of agreement of two measures. Results At Week 12, there was an overall 69.6% agreement in histologic and endoscopic response, and 84.2% agreement between histologic remission and endoscopic remission (Table 1). After 52 weeks of miri treatment, the agreement between histologic and endoscopic response was 61.9%, while the agreement between histologic and endoscopic remission was 70.6% (Table 2). Interestingly, in every comparison, the percentage of patients achieving the histologic outcome but not the endoscopic outcome was greater than that of patients achieving the endoscopic outcome but not the histologic outcome. Conclusion Histologic and endoscopic outcomes demonstrated fair association after both 12 and 52 weeks of miri treatment. Histologic endpoints, despite the stringent criteria, appear to be more sensitive to change than endoscopic endpoints. However, variability of biopsy sampling may be an additional factor contributing to these differences.

Abstract Background The role of histopathology evaluation in Crohn’s disease (CD) is not precisely defined. Due to the heterogeneity of phenotypes, the discontinuity of distribution, and the transmural nature of inflammation, the interpretation of histologic outcomes is complex. To analyze how histology relates to established outcomes in CD, we examined association between histologic and endoscopic disease activity measured by frequently used scores (simple endoscopic score for Crohn’s disease [SES-CD], Robarts histopathology index [RHI], global histological activity score [GHAS]) and the association between histologic or endoscopic severity with inflammatory biomarkers in a cohort of patients with moderate-to-severe CD. Methods Patients (N=191) who were enrolled in a phase 2 randomized clinical trial (NCT02891226) in patients with moderate-to-severe CD were assessed at baseline (BL) for endoscopic disease location and severity as measured by SES-CD. Biopsies were obtained during BL endoscopy from the edge of the ulcers and the most inflamed mucosa in terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum; N=10/patient, 2 per location with the more severe score used), and scored by central readers blind to study treatment, timepoint, and response status using RHI and both modified and active GHAS (mGHAS: Q1, 3, 4, 5, 6; aGHAS: Q1, 4, 5, 6; see Fig. 1). Inflammatory biomarkers included fCLP and CRP; log-transformed values are used. Linear correlations between measures were determined using Pearson correlation coefficients (PCC) as exploratory analyses. Nominal p values are presented. Results SES-CD correlated well with all 3 histologic measures examined (Fig. 1). While both fCLP and CRP correlated more closely with endoscopy than with histologic measures, fCLP had higher correlation with each histologic measure than CRP (Fig. 2). 64% of patients had the same disease location at BL when measured by endoscopy or histology. Patients with endoscopic colonic disease displayed histologic ileal involvement in up to 20% of cases, while 13% of patients with endoscopic ileal disease demonstrated histologic colonic involvement (Table 1). Conclusion Although histologic disease activity in CD, as determined by 3 different measures, correlates well with endoscopic assessment of disease, histologic involvement provides complementary information on disease distribution and extension. Further analyses are required to understand the additive role of mucosal histology in CD.

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02891226) in patients with Crohn’s disease (CD). The histologic results at Week (W)12 induction and W52 maintenance are presented here. Methods Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Patients who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies from terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum) were obtained during endoscopy at W0, 12 and 52 and scored blind to treatment and response status. Ileum and colon scores were reported separately. Colon scores were derived from the sum of the 4 colonic segments, and total intestine scores from the 4 colonic segments plus ileum. Endpoints were defined post-hoc but prior to performing the analyses and only included patients with active histologic disease at BL (see Table). Histologic response was defined as: a) absence of neutrophils in lamina epithelialis, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or GHAS ≥50% from BL. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Deep histologic remission was defined as histologic remission combined with absence of chronic inflammatory cell infiltration of the lamina propria. For assessment of total intestine inflammation, the criteria for response, remission or deep remission must have been met in all 5 bowel segments. Results At W12, histologic response and remission were significantly higher in all segments of the 1000mg group versus PBO (response: ileum p<0.01, total intestine p<0.01, colon p<0.05; remission: ileum p<0.05, colon p<0.05, total intestine p<0.01). Among the W12 improvers, both histologic response and histologic remission at W52 were similar in ileum and colon in the IV/IV group, but lower in ileum than colon in the IV/SC group. All but 2 patients with remission at W52 were in deep histologic remission. Conclusion Patients treated with miri achieved and sustained histologic response and remission over 52 weeks of treatment. Among patients with W52 histologic remission, all but 2 patients achieved deep remission.

AbstractIntroductionMicroscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence‐based guidelines to improve the medical care of patients suffering from this disorder.MethodsGuidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method.ResultsThese guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence‐based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice.ConclusionThese guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.