Hiroshi Nakase

Background and Aims: Multiple advanced therapies are available for the treatment of Crohn’s disease (CD). Treatment patterns in newly diagnosed patients and the factors associated with persistence remain unclear. We present interim results of the iCREST-CD registry describing treatment patterns and persistence with advanced therapies. Methods: Patients aged ≥16 years with newly diagnosed CD and who had no prior exposure to advanced therapies were enrolled. Persistence of advanced therapies was estimated using Kaplan–Meier analyses, and associated factors were identified using multivariable Cox proportional hazards models. Persistence was also compared between patients who initiated therapy early or later after diagnosis. Results: Of 672 patients (68.2% male; mean age 29.4 ± 13.1 years), 498 (74.1%) initiated advanced therapy: infliximab (IFX; 121), adalimumab (ADA; 244), ustekinumab (UST; 107), or vedolizumab (VDZ; 26). Advanced therapy was initiated within 1 year of diagnosis in 404 (60.1%). The 36-month treatment persistence rates for IFX, ADA, UST, and VDZ were 77.5%, 75.7%, 79.8%, and 49.0%, respectively. After propensity score adjustment using inverse probability of treatment weighting, the early initiation was associated with greater persistence than delayed initiation, although the difference did not reach statistical significance (hazard ratio, 0.61; 95% confidence interval, 0.35-1.09; P = .067). Conclusions: A high prevalence of early advanced therapy use and a high level of persistence with first-line advanced therapy were identified in this national cohort. Early initiation was associated with greater treatment persistence than delayed initiation, suggesting the potential clinical relevance of earlier advanced therapy use in routine practice. These findings require confirmation in other prospective studies aiming to evaluate early intervention strategies. Registration: The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (umin.ac.jp/ctr Identifier: UMIN000032237) prior to initiation.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is managed according to clinical practice guidelines that integrate evidence appraisal with regional healthcare contexts. This narrative, comparative review examined selected guideline documents from the Japanese Society of Gastroenterology (JSGE), European Crohn’s and Colitis Organisation (ECCO), American Gastroenterological Association (AGA), and American College of Gastroenterology (ACG) using the JSGE guidelines as the organizing framework to highlight similarities and differences in recommendation direction and contextual nuance. The analysis focused on the guideline architecture and selected domains of monitoring and medical therapy, with particular attention to how document structure, scope, publication timing, and update strategies shape the interpretation of similarities and differences in recommendation direction. Across the guideline systems, general agreement in overall direction was observed regarding the shift from symptom-based assessment alone towards objective monitoring, the sustained role of 5-aminosalicylic acid (5-ASA) in the treatment of UC, the expanding integration of advanced therapies, and the adoption of risk-based surveillance principles for IBD-associated colorectal neoplasia. The most notable divergence concerned the use of 5-ASA in CD treatment: the JSGE guidelines retained a more pragmatic role for this therapy, whereas the recent ECCO, AGA, and ACG guidelines generally limited routine use. Treatment withdrawal and de-escalation emerged as particularly heterogeneous domains, reflecting the uneven treatment of drug-specific recommendations. The JSGE guidelines were notable for their distinctive single-volume integration of diagnostic criteria, treatment strategy, and follow-up, as well as their explicit inclusion of Japan-specific considerations, such as nucleoside diphosphate-linked moiety X-type motif 15 genotyping, cytapheresis, and oral tacrolimus. These findings suggest that apparent differences among IBD guidelines should be understood not only as differences in clinical judgment, but also as products of guideline architecture, update timing, and intended scope.

Background: Carotegrast methyl is an oral α4-integrin antagonist used to induce remission in patients with ulcerative colitis with an inadequate response to 5-aminosalicylate (5-ASA). This multicenter, retrospective observational study evaluated the clinical usefulness of carotegrast methyl in real-world practice. Methods: Patients with an inadequate response to 5-ASA who received carotegrast methyl were included. Clinical data were collected during and after treatment for up to 52 weeks. The primary endpoint was the response rate at week 8. The remission rate at week 8, response/remission rate at end of treatment, cumulative response/remission rate, and adverse drug reactions were also assessed. Effectiveness was evaluated using the patient reported outcomes-2 measure (sum of Mayo subscores for stool frequency and rectal bleeding). Results: Data were collected from 196 patients, of whom 180 were evaluable for effectiveness. The PRO-2-defined response and remission rates at week 8 were 57.8% and 43.3%, respectively, and the rates at the end of treatment (median treatment duration: 83.5 days) were 58.9% and 50.0%, respectively. The cumulative PRO-2-defined response/remission rates increased until week 16, followed by a slight further increase. Adverse drug reactions occurred in 31 of 196 patients (15.8%, 43 events), with no serious events. Conclusions: In terms of patient-reported symptom improvement, carotegrast methyl is an effective and well-tolerated treatment for patients with ulcerative colitis who have an inadequate response to 5-ASA. A substantial proportion of patients responded to 8 weeks of treatment. Continued treatment for up to 16 weeks may improve symptoms, even in patients with insufficient response at week 8.

Background and Aims: Risankizumab, an interleukin‐23p19 antibody, is effective for Crohn's disease in trials; however, Japanese real‐world data remain limited. We assessed its clinical effectiveness, endoscopic outcomes, treatment persistence, and safety in a multicenter cohort. Methods: We retrospectively included patients with Crohn's disease treated with risankizumab (September 2022–February 2025) across eight centers. The CDAI‐based effectiveness analysis was restricted to patients with moderate‐to‐severely active disease at baseline (CDAI ≥ 220). Primary endpoints were corticosteroid‐free clinical remission at Weeks 12 and 52. Secondary endpoints included clinical remission and response, endoscopic response and remission, Kaplan–Meier analysis of treatment persistence, adverse events, and subgroup outcomes by prior advanced therapy and ustekinumab exposure. Segment‐based scores compared ileal and colonic outcomes at the first on‐treatment endoscopy in paired cases. Results: Among 180 patients, 51 had moderate‐to‐severely active disease at baseline and comprised the primary effectiveness population. Among evaluable patients in this population, corticosteroid‐free clinical remission rates were 31% (15/48), 52% (22/42), and 57% (16/28) at Weeks 12, 28, and 52, respectively; clinical remission rates were 40%, 55%, and 61%, respectively. Overall endoscopic response and remission rates were 58% (26/45) and 29% (13/45), respectively. Colonic endoscopic improvement outcomes favored the naïve subgroups (advanced therapy–naïve vs. advanced therapy–exposed: response 100% vs. 60%, p = 0.017; remission 80% vs. 26.7%, p = 0.009; ustekinumab‐naïve vs. ustekinumab‐exposed: response 95.2% vs. 44.4%, p = 0.005; remission 71.4% vs. 11.1%, p = 0.004). Ileal endoscopic improvement showed a similar trend but was not statistically significant. The Week 52 persistence rate was 87%; adverse events occurred in 12% of patients, with no discontinuations related to adverse events. Conclusions: Risankizumab was associated with corticosteroid‐free clinical remission among patients with moderate‐to‐severely active Crohn's disease included in the primary effectiveness analysis, together with endoscopic improvement in the paired‐endoscopy cohort. Clinical and endoscopic outcomes, as well as treatment persistence, were generally more favorable in advanced therapy‐ and ustekinumab‐naïve patients.

Background: Soluble Fas (sFas) plays multiple roles in tumorigenesis and cancer dissemination by avoiding apoptosis via connection to Fas ligand. We assessed associations of serum sFas levels with the incidence of extrahepatic biliary tract cancer (eBTC) in a prospective case–control study nested in the Japan Collaborative Cohort Study. Methods: A baseline survey was conducted from 1988 using blood samples from 39,242 individuals (35% of 110,585). Patients diagnosed with eBTC before the end of 1997 were regarded as cases. Odds ratios (OR) for cancer incidence associated with sFas were estimated by conditional logistic regression. Results: This study included 73 cases and 215 controls. Participants with high sFas showed an elevated risk of cancer (P trend = 0.01), and the third tertile of sFas showed a higher risk compared with the first tertile [OR, 3.27; 95% confidence interval (CI), 1.37–7.80]. In both gallbladder and extrahepatic bile duct cancers (n = 33 and 40, respectively), high sFas was associated with elevated risk (P trend = 0.04 and 0.02, respectively). In women and the nonelderly, subjects in the highest tertiles showed a higher cancer risk. Limiting subjects to those followed for over 2 years, high sFas was related to cancer risk (P trend = 0.02), and the third tertile showed a higher risk compared with the first (OR, 3.03; 95% CI, 1.14–8.07). Conclusions: High serum sFas may be related to future risk of eBTC. Impact: These findings highlight the need for additional studies of this biomarker in large prospective cohorts and through integrated analysis involving other cohorts.

Background: Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of moderate-to-severe Crohn’s disease (CD). This post hoc analysis reports the efficacy and safety of upadacitinib for CD in patients in East Asia enrolled in the phase 3 clinical trials. Methods: In two induction studies (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]), adults with moderately to severely active CD were randomized 2:1 to once-daily upadacitinib 45 mg or placebo for 12 weeks. In the 52-week U-ENDURE maintenance study (NCT03345823), patients with clinical response to upadacitinib induction therapy were rerandomized 1:1:1 to once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo. Data from patients in East Asia were evaluated. Results: In the induction studies, achievement of clinical and endoscopic outcomes occurred at higher rates with upadacitinib vs placebo at week 12 among the 204 patients in East Asia. Clinical remission per CD Activity Index (CDAI) and endoscopic response were achieved by 50.7% vs 20.6% and 61.8% vs 10.3% of patients in the upadacitinib 45-mg vs placebo groups, respectively. Similar trends for upadacitinib vs placebo were observed for the 117 patients in the maintenance study. Clinical remission per CDAI and endoscopic response were achieved by 41.5%, 54.8%, 8.8%, and 28.6%, 45.2%, 5.9% of patients receiving upadacitinib 15 mg, upadacitinib 30 mg, and placebo, respectively. The safety profile of upadacitinib was consistent with the global phase 3 population. Conclusions: Upadacitinib was efficacious in treating moderately to severely active CD among patients in East Asia and demonstrated a favorable benefit–risk profile.

Background and Aim: Upadacitinib, a selective Janus kinase 1 inhibitor, is approved to treat moderately to severely active ulcerative colitis (UC). This post hoc subanalysis evaluated the efficacy, safety, and pharmacokinetics of upadacitinib in patients in East Asia. Methods: U‐ACHIEVE (UC1; NCT02819635) and U‐ACCOMPLISH (UC2; NCT03653026) were Phase 3, multicenter, randomized, double‐blind, induction studies evaluating upadacitinib 45 mg or placebo daily in adults with moderately to severely active UC. Clinical responders to 8 weeks of upadacitinib induction were eligible to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo daily in the 52‐week U‐ACHIEVE maintenance study (UC3; NCT02819635). Efficacy outcomes, safety, and pharmacokinetics were evaluated among East Asian patients. Results: A higher proportion of East Asian patients achieved clinical remission with upadacitinib than placebo at induction Week 8 (UC1: n = 127, 31.4% vs. 7.3%; UC2: n = 114, 31.2% vs. 2.7%) and maintenance Week 52 (UC3: n = 184, upadacitinib 15 mg, 52.4%; upadacitinib 30 mg, 53.8%; placebo, 10.7%). Rates of endoscopic outcomes were higher with upadacitinib than with placebo across studies. No new safety signals were identified. Herpes zoster occurrences were low (UC1 and UC2: upadacitinib 45 mg, two events [in one patient]; placebo, zero events; UC3: upadacitinib 15 mg, five events; upadacitinib 30 mg, eight events; placebo, zero events). Pharmacokinetics and trends in the relationship between upadacitinib exposure and efficacy were consistent in the East Asian and global populations. Conclusion: Upadacitinib was generally well tolerated and effective for treating moderately to severely active UC in patients in East Asia, with a favorable benefit–risk profile consistent with the global population. Trial Registration: ClinicalTrials.gov identifier: NCT02819635, NCT03653026

Background/Aims: Fecal calprotectin (FC) reliably reflects both clinical and endoscopic disease activity in inflammatory bowel disease (IBD) and helps differentiate IBD from irritable bowel syndrome (IBS). The aim of this study was to determine the diagnostic utility of FC using the colloidal gold agglutination (CGA) method in distinguishing active-phase IBD from IBS in both children and adults. Methods: This prospective, multicenter, observational study was conducted across eight participating institutions. The primary goal was to validate the discriminatory ability and reference values of FC using the CGA method between patients with IBD in the active phase and those with IBS. Results: A total of 285 patients were analyzed, including 205 with ulcerative colitis (UC), 24 with Crohn’s disease, and 56 with IBS. In the receiver operating characteristic (ROC) curve analysis, FC demonstrated very high specificity (98%) for differentiating patients with active-phase IBD from those with IBS when a cutoff value of 500 µg/g was applied.With respect to endoscopic evaluation, the correlation between FC and cumulative endoscopic scores, which were calculated by summing segmental scores across the colon, was stronger in pediatric patients with UC (MES, rs = 0.48; cumulative MES, rs = 0.65) than in adult patients (MES, rₛ = 0.65; cumulative MES, rₛ = 0.69).Conclusion: FC measured using the CGA method proved to be a reliable and clinically meaningful biomarker for differentiating active IBD from IBS in adults and active UC from IBS in children. Comprehensive evaluation with cumulative endoscopic scores can be useful for understanding disease activity in pediatric patients with UC.

Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study

Background: Endoscopy is the standard for assessing mucosal activity in ulcerative colitis (UC), but reliable biomarkers are needed. This study evaluated serum amyloid A (SAA) as a potential biomarker by comparing it with established markers in UC. Methods: We retrospectively evaluated 182 patients with UC who underwent blood and stool testing within 14 days of colonoscopy at a tertiary care hospital between April 2017 and January 2025. Patients were classified into 4 groups according to the Mayo Endoscopic Subscore (MES). Baseline characteristics and laboratory and endoscopic variables were compared across groups. Results: Serum SAA levels demonstrated strong positive correlations with leucine-rich α-2-glycoprotein (LRG) (r = 0.752) and C-reactive protein (CRP) (r = 0.717). Significant associations were also observed between SAA and MES, Mayo score, partial Mayo score, and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) (all P < .01). SAA identified active endoscopic inflammation (MES ≥ 2) at a cutoff value of 4.1 mg/L, with an area under the curve (AUC) of 0.813 (95% CI, 0.731-0.894), sensitivity of 0.804, and specificity of 0.741. In addition, SAA differentiated MES 0 from MES 1 at a cutoff value of 2.6 mg/L, yielding an AUC of 0.683 (95% CI, 0.470-0.897), sensitivity of 0.706, and specificity of 0.714. Conclusions: SAA exhibits diagnostic performance comparable to, and in some respects exceeding, that of established inflammatory biomarkers in UC. Importantly, SAA effectively discriminates between MES 0 and MES 1, supporting its potential role as a sensitive marker of mucosal healing.