Somatic inflammatory gene mutations in human ulcerative colitis epithelium.

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1-7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8-11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

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.

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials.

INTRODUCTION: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. METHODS: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. RESULTS: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. CONCLUSION: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn's Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study.

BACKGROUND: Crohn's disease (CD) significantly affects patients' health-related quality of life and well-being. AIMS: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients' lives and identifies communication gaps between patients and health care professionals (HCPs). METHODS: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. CONCLUSION: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Bowel Urgency in Ulcerative Colitis: Current Perspectives and Future Directions.

Bowel urgency (BU), the sudden or immediate need for a bowel movement, is one of the most common and disruptive symptoms experienced by patients with ulcerative colitis (UC). Distinct from the separate symptom of increased stool frequency, BU has a substantial negative impact on quality of life and psychosocial functioning. Among patients with UC, BU is one of the top reasons for treatment dissatisfaction and one of the symptoms patients most want improved. Patients may not discuss BU often due to embarrassment, and healthcare providers may not address the symptom adequately due to the lack of awareness of validated tools and/or knowledge of the importance of assessing BU. The mechanism of BU in UC is multifactorial and includes inflammatory changes in the rectum that may be linked to hypersensitivity and reduced compliance of the rectum. Responsive and reliable patient-reported outcome measures of BU are needed to provide evidence of treatment benefits in clinical trials and facilitate communication in clinical practice. This review discusses the pathophysiology and clinical importance of BU in UC and its impact on the quality of life and psychosocial functioning. Patient-reported outcome measures developed to assess the severity of BU in UC are discussed alongside overviews of treatment options and clinical guidelines. Implications for the future management of UC from the perspective of BU are also explored.

Rapid and Sustained Symptom Relief in Patients With Ulcerative Colitis Treated With Filgotinib: Data From the Phase 2b/3 SELECTION Trial.

INTRODUCTION: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1-15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL.

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

BACKGROUND: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis. METHODS: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522. FINDINGS: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment. INTERPRETATION: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. FUNDING: Gilead Sciences.

Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665.

Multicenter epidemiological survey of pneumatosis intestinalis in Japan.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. METHODS: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. RESULTS: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425). DISCUSSION: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

Potential benefits of immunomodulator use with vedolizumab for maintenance of remission in ulcerative colitis.

BACKGROUND AND AIM: This study aimed to determine the efficacy and safety of vedolizumab treatment with or without concomitant immunomodulator use in Japanese patients with moderate-to-severe ulcerative colitis. METHODS: Among enrolled patients in a phase 3 study conducted in Japan (clinicaltrials.gov, NCT02039505), data from patients allocated to 300-mg intravenous vedolizumab for induction and maintenance phases were used for this exploratory analysis. Efficacy endpoints were clinical response, clinical remission, and mucosal healing at week 10 and clinical remission and mucosal healing at week 60, and disease worsening and treatment failure during the maintenance phase. RESULTS: At week 10, the differences in clinical response, clinical remission, and mucosal healing rates between the subgroups (those with concomitant immunomodulator use minus those without) were 0.7 (95% confidence interval: -14.3, 15.7), 3.3 (95% confidence interval: -8.5, 15.2), and 1.8 (95% confidence interval: -13.0, 16.5), respectively. At week 60, the differences in clinical remission and mucosal healing between the subgroups with and without concomitant immunomodulator use were 26.1 (95% confidence interval: -3.5, 55.6) and 29.9 (95% confidence interval: 1.4, 58.4), respectively. The proportions of patients without treatment failure at day 330 of the maintenance phase were 90.7% with concomitant immunomodulator use and 73.7% without. No marked differences in incidence of infections were observed between subgroups. CONCLUSIONS: This study suggested the possibility that concomitant immunomodulator use may be beneficial to maintain the clinical efficacy of vedolizumab.

Safety and efficacy of long-term tofacitinib treatment in East Asian patients with ulcerative colitis in OCTAVE Open.

BACKGROUND AND AIM: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present safety and efficacy data from patients from East Asia (Japan, Korea, and Taiwan) in OCTAVE Open, an open-label, long-term extension study. METHODS: Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg twice daily (BID); all others received tofacitinib 10 mg BID. Proportions and IRs (unique patients with events/100 patient-years) were calculated for adverse events (AEs) of special interest. Efficacy endpoints were evaluated up to 36 months. RESULTS: In OCTAVE Open, 105/944 patients were from East Asia (tofacitinib 5 mg BID, n = 22; tofacitinib 10 mg BID, n = 83). Overall, 87.6% and 24.8% of patients had AEs and serious AEs, respectively; IRs (95% CI) for AEs of special interest were herpes zoster (HZ; non-serious and serious), 6.07 (3.40-10.02); serious infections, 1.47 (0.40-3.76); opportunistic infections, 1.91 (0.62-4.45); major cardiovascular adverse events, 0.37 (0.01-2.04); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.37 (0.01-2.04); and NMSC, 0.00 (0.00-1.35). No deaths, venous thromboembolic events, or gastrointestinal perforations occurred. At month 36, 68.2% and 54.2% of patients had a clinical response, 68.2% and 53.0% had endoscopic improvement, and 63.6% and 49.4% were in remission with tofacitinib 5 and 10 mg BID, respectively. CONCLUSIONS: The HZ IR in East Asian patients was numerically higher versus the global study population; excluding HZ, tofacitinib safety and efficacy were consistent with the global study population.

Lack of Increased Risk of Lymphoma with Thiopurine Therapy Regardless of Dose and Duration of Treatment in Japanese Patients with Inflammatory Bowel Diseases.

BACKGROUND: Immunomodulator therapy (e.g., thiopurines) has been linked to an increased malignancy risk, in patients with inflammatory bowel diseases (IBDs), which increases with treatment duration, based on studies mainly in Caucasian patients. However, our previous real-world study, of Japanese patients with IBDs, indicated no overall increased risk of non-Hodgkin lymphoma (NHL) with thiopurine treatment. OBJECTIVES: This subanalysis investigated the influence of thiopurine IBD treatment dose and duration, on incidence of NHL in Japanese patients. METHOD: The Medical Data Vision (MDV) claims database (17.8 million patients; April 2008-January 2018) was used to analyze incidence rate ratios (IRRs) of NHL, in eligible patients (≥1 diagnosis of ulcerative colitis or Crohn's disease) and no malignancy at diagnosis or first prescription of a thiopurine. Age- and sex-adjusted IRRs and 95% confidence interval for NHL were calculated as the incident cases compared in the subgroups versus the overall IBD population. RESULTS: Among 75,673 patients with IBDs, 103 cases of NHL were recorded. There was no overall increase in the risk of developing NHL among Japanese patients treated with thiopurines. The IRRs relative to the overall IBD population were 1.88, 1.42, and 0.38 for <1 year, 1-3 years, and ≥3 years of thiopurine treatment. There were no differences in NHL incidence when grouping patients by mean daily thiopurine dose prescribed, age, or disease subgroups. CONCLUSION: Dose or duration of thiopurine treatment did not explain a lack of increased risk of NHL with thiopurine use in Japanese patients with IBDs.

Accuracy of Ultrasound for Evaluation of Colorectal Segments in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The accuracy of ultrasound for evaluation of individual colorectal segments in patients with inflammatory bowel diseases (IBD) has not been evaluated in a systematic review. We evaluated the diagnostic accuracy of ultrasound in different colorectal segments of patients with IBD. METHODS: We searched publication databases from inception through March 2019 for studies that assessed the accuracy of ultrasound in detection of inflammation in right, transverse, and left colon and in rectum in patients with IBD, using findings from colonoscopy as the reference standard. Subgroup analyses were performed including IBD type, patient age, body mass index, and study design. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Nineteen studies (1101 patients) were included in the qualitative synthesis. After we assessed the risk of bias, 7 studies (comprising 84 patients with Crohn's disease and 420 patients with ulcerative colitis) were included in the meta-analysis. Bowel wall thickness ≥ 3 mm identified colorectal segments with inflammation with 86.4% pooled sensitivity (95% CI, 76.1%-92.7%) and 88.3% pooled specificity (95% CI, 58.1%-97.6%). In rectum only, bowel wall thickness ≥ 3 mm identified inflammation with 74.5% sensitivity (95% CI, 53.0%-88.3%) and 69.5% specificity (95% CI, 33.6%-91.1%). Diagnostic accuracy was comparable among subgroups. Increased bowel wall flow and loss of stratification had higher true-positive odds ratios. CONCLUSIONS: Based on meta-analysis of patient-level data, ultrasound has higher diagnostic accuracy for detecting inflammation in colon than rectum in patients with IBD. Studies are needed to increase the accuracy of ultrasound detection of inflammation in rectum.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665.

P028 Communicating Needs and Features of IBD Experiences (CONFIDE) Survey: Patient and Healthcare Professional Perspectives on Experience of Ulcerative Colitis Symptoms.

BACKGROUND: Moderate-to-severe ulcerative colitis (UC) and Crohn's disease (CD) are associated with substantial quality of life and economic burdens (Kawalec, 2016). The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to further the understanding of the experience and impact of symptoms on patients' lives and elucidate any gaps in communication between healthcare professionals (HCPs) and patients with moderate-to-severe UC and CD in the United States (US), Europe, and Japan. These data focus on US patients with UC and US HCPs. METHODS: An online, quantitative, cross-sectional survey was conducted with HCPs (n=200) and patients with moderate-to-severe UC (n=200) in the US between May (HCPs) and July (patients) 2021. Moderate-to-severe UC was defined using criteria based on previous treatment experience, steroid use and/or hospitalization. The HCP survey included physicians (89%) and non-physician HCPs (11%) who are responsible for making prescribing decisions. Data collected included perspectives on the experience and impact of symptoms in patients with moderate-to-severe UC. RESULTS: The top three symptoms currently (past month) and ever suffered by patients (mean age: 40.4, 61.5% male) were diarrhea (62.5% and 74.0%, respectively), bowel urgency (47.0% and 61.5%) and increased stool frequency (38.5% and 57.5%). Blood in stool was reported by 27.0% of patients as currently suffering, and 51.0% ever. According to HCPs (78.0% male), the top three symptoms reported by patients were diarrhea (73.5% ranked in top 3), blood in stool (69.0%), and increased stool frequency (37.5%). Bowel urgency was recorded in the top 3 patient-reported symptoms by 24.0% of HCPs. Patients self-rated their disease-severity as 10.5% (n = 21) mild UC, 71.0% (n = 142) moderate UC, 17.5% (n = 35) severe UC, and 1.0% (n = 2) patients did not know. Bowel urgency was more frequently reported in patients with severe disease (62.9%, n = 22) when compared with those with mild-to-moderate disease (42.9%, n = 70). Among the overall patient population, 76.5% (n = 153) were receiving advanced therapies (biologic or novel oral therapy). Bowel urgency was currently experienced by 46.4% of these patients. Only 38.2% of patients felt completely comfortable reporting bowel urgency to their HCP. Of patients not comfortable reporting bowel urgency, 62.2% (n = 23) reported they felt embarrassed talking about it. Among HCPs, 75.5% (n = 151) reported they proactively discussed bowel urgency at routine appointments. Those HCPs who reported that they do not proactively discuss bowel urgency (24.5%, n = 49) cited the main reason as they expect the patient to bring it up (46.9%, n = 23). CONCLUSION: Bowel urgency is the second-most commonly reported symptom by patients with moderate-to-severe UC but is not among the HCP-perceived top three most reported symptoms. A substantial proportion of patients with moderate-to-severe UC receiving advanced therapies continue to report bowel urgency. A communication gap between patients and HCPs was identified and highlights the under appreciation of bowel urgency as an important symptom impacting patients' daily life.

Post-marketing analysis for biosimilar CT-P13 in inflammatory bowel disease compared with external data of originator infliximab in Japan.

BACKGROUND AND AIM: CT-P13, an infliximab (IFX) biosimilar, was approved for treatment of inflammatory bowel disease. However, no comparison with the originator IFX in this indication has been conducted in Japan where endemic levels of tuberculosis and hepatitis virus infection are not low. We evaluated the safety and efficacy in real-world data of CT-P13 and compared with originator IFX data in Japan. METHODS: In a prospective post-marketing surveillance (PMS) study, patients who received CT-P13 in a 28-month period from January 2015 were followed up for 2 years. By conducting Japanese administrative database search (DBS) for the same period of PMS, data of the originator IFX including treatment persistence, tuberculosis incidence, and liver injury were analyzed retrospectively and compared with the corresponding PMS data of CT-P13. RESULTS: CT-P13 persistence in PMS (n = 640) and IFX persistence in DBS (n = 4113) were almost similar between patients who switched from the originator and patients who continued on the originator, and also between the biologics-naïve patient groups. There were no differences in the incidences of tuberculosis and hepatic injury (Tuberculosis: 2 patients [0.31%] with CT-P13, 10 patients [0.24%] with the originator, P = 0.75; Hepatic injury: 18.5% with CT-P13, 15.4% with the originator, P = 0.22). Most of the patients with hepatic injury continued treatment in PMS and DBS at similar rates (80.8% vs 83.6%, P = 0.65). CONCLUSION: The results of long-term PMS of CT-P13 compared with external reference data from an administrative database suggested that the biosimilar and its originator were comparably useful in real-world clinical practice.

Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.

BACKGROUND AND AIM: Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly-onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world-leading aging society. METHODS: The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC-related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging. RESULTS: The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = -0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5-6.5) and surgery (OR: 2.7, 95% CI, 0.98-7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99-2.0] and 2.3 [95% CI, 0.8-6.3], respectively). CONCLUSION: Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses.

Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease.

BACKGROUND AND AIM: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. METHODS: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. RESULTS: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. CONCLUSION: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.