Journal of Crohn's & colitis最新文献

Background and aims: Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi), but data in ulcerative colitis (UC) remain limited. We aimed to assess the effectiveness and safety of initiating a second JAKi in patients with UC previously treated with another JAKi.

Methods: We conducted a multicenter retrospective study, including patients with UC starting a second JAKi after prior JAKi exposure. The primary endpoint was Week 12 steroid-free clinical remission (SFCR-rectal bleeding subscore = 0, stool frequency subscore ≤ 1, and no steroids).

Results: We included 243 patients (median follow-up: 38 [21-57] weeks). At Weeks 12, 26, and 52, SFCR was achieved in 116/243 (48%), 120/243 (49%), and 69/243 (28%), respectively. Secondary loss of response to the first JAKi was associated with higher SFCR at Week 12 compared to primary failure (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.11-3.30, P = 0.02). Higher baseline disease activity (OR = 0.68, 95% CI = 0.68-0.55, P < 0.01) and steroid use (OR = 0.23, 95% CI = 0.13-0.42, P < 0.01) had lower odds of Week 12 SFCR. Endoscopic remission occurred in 22/243 (9%) (

Conclusion: Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might reduce the likelihood of success with the second JAKi.

Background and aims: Immunogenicity and the development of an undetectable drug level is a modifiable cause of anti-tumor necrosis factor (anti-TNF) treatment failure. We modeled the clinical utility of pre-treatment HLA-DQA1*05:01 and HLA-DQA1*05:05 allele subtype testing to guide immunomodulator use in patients with Crohn's disease treated with an anti-TNF.

Methods: The Personalised Anti-TNF Therapy in Crohn's Disease study is a UK-wide, prospective observational study of infliximab and adalimumab in anti-TNF-naïve patients with active Crohn's disease. Rates of drug-clearing antibody development, defined by the presence of anti-TNF antibodies and undetectable drug levels, were estimated using the Kaplan-Meier method. Genetic association tests were performed using Cox proportional hazards regression.

Results: About 40% of participants carried an actionable HLA-DQA1*05 allele subtype. HLA-DQA1*05:01 (hazard ratio [HR] 1.87 [95% CI: 1.37-2.53], P < .0001) and HLA-DQA1*05:05 (HR 2.45 [95% CI: 1.32-4.54], P = .004) were the most significant allele subtypes associated with the development of drug-clearing antibodies in infliximab- and adalimumab-treated patients, respectively. Immunomodulator use increased the time to drug-clearing antibodies in all patients treated with infliximab. In adalimumab-treated patients, only individuals who carried the HLA-DQA1*05:05 allele subtype benefited from combination immunomodulator use with a number needed to treat of 4.6 (95% CI: 2.4-20.5) to prevent one episode of a drug-clearing antibody.

Discussion: Pre-treatment four-digit HLA testing informs on anti-TNF treatment choice and immunomodulator use. In HLA-DQA1*05:01 carriers, adalimumab monotherapy should be used and infliximab avoided. In HLA-DQA1*05:05 carriers, infliximab or adalimumab can be used with a concomitant immunomodulator. In patients who do not carry either HLA-DQA1*05:01 or HLA-DQA1*05:05, adalimumab monotherapy or infliximab with a concomitant immunomodulator are recommended.

Autoimmune blistering diseases (AIBDs) may occur as adverse effects of various therapies, including biologics. Data on their association with IL-23 inhibitors in ulcerative colitis (UC) remain limited. We report the case of a 59-year-old man with UC who developed pruritic cutaneous bullae emerging within days following mirikizumab infusion. Histopathological examination and direct immunofluorescence demonstrated findings consistent with an AIBD. Following the withdrawal of mirikizumab, the residual cutaneous lesions progressively improved under corticosteroid therapy, suggesting a temporal association with the biologic exposure. This case highlights that mirikizumab may represent a potential trigger of an AIBD in susceptible individuals with UC. Clinicians should be aware of this rare but relevant complication to ensure timely recognition and management.

Background & aims: In ulcerative colitis (UC), therapeutic goals are evolving beyond symptom control toward endoscopic and histologic healing. However, optimal strategies to achieve these targets are undefined, and the implementation of treat-to-target (T2T) in patients with minimal symptoms despite ongoing intestinal inflammation remains unexplored. This study evaluated the real-world effectiveness of endoscopy-guided optimization in this population.

Methods: TACTIC-UC is a retrospective, single-centre study including UC patients undergoing endoscopy-guided optimization of anti-TNF agents, vedolizumab, or ustekinumab. Eligible cases had quiescent or mild symptoms (partial Mayo score 0-4) but moderate-to-severe endoscopic activity (endoscopic Mayo Score, eMS ≥ 2) and underwent treatment optimization within 1 month after index endoscopy. The primary outcome was mucosal healing (MH, eMS ≤ 1) within 1 year. Secondary endpoints included endoscopic remission (ER, eMS = 0), histo-endoscopic mucosal remission (HEMR, eMS = 0 + Nancy Index = 0-1), biomarker trends, steroid use, adverse events, and treatment persistence.

Results: A total of 164 optimization episodes were analysed in 142 patients. The 1-year cumulative probabilities of MH, ER, and HEMR were 54.2%, 28.8%, and 20.9%, respectively. In weighted analyses, anti-TNF-α therapies outperformed non-anti-TNF-α agents (vedolizumab and ustekinumab pooled together) across all outcomes: 66.3% versus 45.0% for MH, 39.3% versus 19.8% for ER, and 33.2% versus 8.1% for HEMR (all P-values < 0.05); consistent trends were confirmed in an exploratory 3-arm analysis incorporating synthetic data augmentation. Baseline steroid use and an eMS of 3 were independently associated with reduced probability of achieving endoscopic and histologic outcomes. No safety signals emerged. Endoscopic and histologic outcomes were associated with improved treatment persistence.

Conclusions: In UC patients with quiescent or mild symptoms but active endoscopic inflammation, endoscopy-guided optimization of biologics is effective in achieving deeper inflammatory control, supporting its integration into T2T strategies.

Background: Crohn's disease (CD) is characterized by epithelial barrier dysfunction and mucosal immune dysregulation. Dietary interventions have gained increasing attention as important therapeutic strategies. We evaluated whether an intermittent ketogenic diet (IKD), which elevates β-hydroxybutyrate (BHB), ameliorates CD via lysine β-hydroxybutyrylation (Kbhb) and elucidated the underlying mechanisms.

Methods: IL-10 knockout mice were allocated to three groups: continuous ketogenic diet (KD), IKD, or a normal diet. Disease activity index (DAI), histopathological changes, cytokine levels, and epithelial barrier integrity were evaluated. Regulatory T cells (Tregs) and Foxp3 expression were assessed by flow cytometry and quantitative real-time PCR (qRT-PCR). To elucidate the underlying mechanisms, we conducted metabolomic and transcriptomic analyses, pyrosequencing, and additional experiments.

Results: Both KD and IKD alleviated colonic inflammation, but IKD better prevented epithelial senescence. IKD increased colonic Treg infiltration and Foxp3 expression. Metabolomics revealed elevated BHB in IKD colons. BHB reduced inflammation and promoted Treg differentiation in a dose-dependent manner. Mechanistically, BHB induced Kbhb of S-adenosylhomocysteine hydrolase (AHCY), inhibiting its activity, leading to S-adenosylhomocysteine (SAH) accumulation, downregulating DNA methyltransferase 1 (DNMT1), and promoting Foxp3-TSDR demethylation to enhance Foxp3 transcription and Treg differentiation. IKD also enriched Akkermansia muciniphila, supporting gut and systemic BHB levels.

Conclusions: In an IL-10 knockout model, IKD improves intestinal barrier function and reshapes the gut microbiota. It is associated with BHB-induced Kbhb-mediated inhibition of AHCY, leading to SAH accumulation and DNMT1 downregulation, thereby promoting Treg differentiation. These findings suggest protective effects of IKD in the IL-10 knockout colitis model.

Background: We aimed to assess the risk of serious infections in patients with inflammatory bowel disease (IBD) exposed to different advanced therapies.

Methods: We linked nationwide registers and compared rates of incident serious infections in patients with Crohn's disease (CD) and ulcerative colitis (UC) exposed to medical therapies versus matched general population comparators during 2007-2023. We 1:1 propensity score-matched individuals with IBD to compare infection risk across therapies.

Results: We identified 55 866 patients with IBD naïve to immunomodulators (IMM) and advanced therapies, 20 392 exposed to IMM, 15 973 to anti-tumor necrosis factor (anti-TNF), 9035 to IMM with anti-TNF, 3948 to vedolizumab, 2926 to ustekinumab, 659 to tofacitinib, 987 to upadacitinib, 262 to filgotinib, and 163 to risankizumab with 987 366 matched comparators with up to 18 years of follow-up. Compared to the general population (incidence rate range 0.39-1.13 per 100 person-years [PY]), patients with IBD had a higher incidence of serious infections (naïve 2.31 per 100 PY; adjusted hazard ratio [aHR] 1.89, 95% confidence interval [CI] 1.84-1.94), IMM 3.27 per 100 PY (aHR 4.45, 95% CI 4.24-4.66), and advanced therapies 3.14-8.10 per 100 PY (aHR 3.45-10.55, 95% CI 3.04-26.65). Relative risks were elevated in the pediatric population, and for opportunistic and gastrointestinal infections. No differences in infection rates were observed in propensity score-matched comparisons of different advanced therapies.

Conclusion: Patients with IBD were at an increased risk of infections, even among those naïve to IMM and advanced therapies. There was no significant difference in the risk of infections across advanced therapy exposures.