Journal of Crohn's & colitis最新文献

Background and aims: Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients.

Methods: We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations.

Results: This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05).

Conclusions: We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity.

Clinical trial registration numbers: SERENE CD (NCT02065570), SERENE UC (NCT02065622).

Background and aims: During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a peptidyl arginine deiminase 4 (PAD4)-dependent manner, aggravating tissue injury and remodeling. In this study, we investigated the potential pro-fibrotic properties and signaling of NETs in Crohn's disease (CD).

Methods: NETs and activated fibroblasts were labeled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analyzed by bulk RNA sequencing to uncover cell signaling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-κB pathway was evaluated by transfection of CCD-18Co fibroblasts with an NF-κB-luciferase reporter plasmid, incorporating C29 to block TLR2 signaling. A chronic dextran sulfate sodium (DSS) mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl).

Results: Immunofluorescence showed spatial colocalization of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of Toll-like receptor signaling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in an NF-κB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significant reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis.

Conclusions: NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-κB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD.

Background and aims: The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease [CD]. We aimed to determine whether disease location affects response to filgotinib, a Janus kinase [JAK] inhibitor, in patients with moderately-to-severely active Crohn's disease [CD] and applying appropriate methods to account for differences in measuring disease activity in the ileum compared with the colon.

Methods: This post-hoc analysis of data from the FITZROY phase 2 trial [NCT02048618] compared changes in the Crohn's Disease Activity Index [CDAI] and Simple Endoscopic Score for Crohn's Disease [SES-CD] among patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200 mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently when compared with colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location.

Results: Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission [CDAI < 150, 75.9% vs 41.6%] and endoscopic response [SES-CD reduction by 50%, 52.5% vs 15.5%] at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location [mean difference in ΔCDAI between ileal-dominant vs isolated colonic disease + 9.24 [95% CI: -87.19, +105.67], p = 0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p = 0.48.

Conclusions: Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

Background and aims: Postoperative recurrence requiring medical treatment intensification or redo surgery is common after ileocolic resection (ICR) for Crohn's disease (CD). This study aimed to identify a subgroup of CD patients for whom ICR could achieve durable remission.

Methods: This retrospective follow-up study analyzed 592 CD patients who underwent ICR (2013-2015) in a nationwide prospective cohort. Patients with >36 months follow-up were included. Primary outcome was durable remission, defined as the absence of endoscopic recurrence and/or medical treatment intensification. Uni- and multivariate analyses identified predictive factors for durable remission.

Results: Among 268 included patients, 59% had B2 phenotype, 70% had a first ICR, and 66% had postoperative medical treatment. After a median follow-up of 85 (36-104) months, 52 patients (19%) experienced durable remission, of whom 24 (46%) didn't require medical treatment and 28 (54%) maintained the same postoperative treatment, including anti-tumor necrosis factor in 15/28 patients (54%). Surgery could stabilize the disease course in 112 patients (41.7%), including 22.4% endoscopic recurrence that didn't require CD treatment initiation or intensification. Durable remission rate was significantly increased in B1 phenotype vs B2/B3 (n = 7/18;39% vs n = 45/250;18%, P = .030) and in first ICR vs redo ICR (n = 43/184;23% vs n = 9/80;11%, P = .023). In multivariate analysis, B1 phenotype was the only independent predictive factor for durable remission (odds ratio = 3.59, IC 95%, 1.13-11.37, P = .030).

Conclusions: Surgery for CD achieved durable remission in 20%, rising to 40% in those with a B1 phenotype. These results support surgery as a viable alternative to medical treatment, offering treatment-free durable remission and preserving medical treatment options.

Background and aims: Crohn's perianal fistula healing rates remain low. We evaluated the efficacy of a protocolized multidisciplinary treatment strategy optimizing care in adults with Crohn's perianal fistulas.

Methods: A new treatment strategy was established at a single tertiary center. The strategy comprised 3 dynamic stages of care directed toward achieving and maintaining fistula healing. Stage A, active disease, focused on early commencement and proactive escalation of biologic therapies and structured surgical reviews ensuring adequate fistula drainage and conditioning. Stage B, optimized disease with a seton in situ, focused on consideration for seton removal and appropriateness of definitive surgical closure and/or ablative techniques. Stage C, healed disease, focused on proactive care maintenance. Sixty patients were sequentially enrolled and prospectively followed for ≥12 months. Endpoints included clinical healing and radiologic remission in those with clinically active fistulas, and relapse in those with healed fistulas.

Results: At baseline, 52% (n = 31) and 48% (n = 29) had clinically active and healed fistulas, respectively. For patients with clinically active fistulas, 71% achieved clinical healing after 22 months, with estimated healing rates of 39% and 84% at 1 and 2 years, respectively. Radiologic remission was achieved in 25%, significantly higher than baseline inclusion rates of 6%. For patients with healed fistulas, 7% experienced clinical relapse after 23 months, with no significant change in radiologic remission, 80% versus 86% at baseline.

Conclusions: A protocolized treatment strategy proactively optimizing care resulted in high rates of clinical healing and improved radiologic remission of Crohn's perianal fistulas. Controlled-matched studies are needed.

Introduction: It remains unclear why up to 30% of ulcerative colitis (UC) patients do not respond to tumor necrosis factor inhibitors (TNFi). Validated biomarkers for nonresponse (N)R) are lacking. Most studies investigating underlying mechanisms do not differentiate between pharmacokinetic and inflammatory mechanisms. We therefore aimed to develop a framework to correct for mucosal drug exposure (MDE) and applied this to mucosal cytokine profiles previously linked to (N)R.

Methods: In a prospective international cohort, we studied patients with active moderate-severe UC starting TNFi treatment. Patients underwent endoscopy before (baseline) and after induction treatment (follow-up). NR was defined as the absence of Mayo endoscopic subscore improvement by central read or need for colectomy. The ratio of mucosal concentrations of TNFi/TNF was used to define high or low MDE. Mucosal concentrations of interleukin-6 (IL-6), Oncostatin M (OSM), interleukin-10 (IL-10), and interleukin-12/23p40 (IL-12/IL-23p40) were measured.

Results: Fifty-four UC patients were included (43 infliximab, 11 adalimumab) of whom 39 (72%) were endoscopic responders (after a median treatment of 62 days [48-96]). NR with high MDE had high IL-6 at both time points. R with low MDE exhibited low mucosal IL-10 at baseline. At follow-up, high OSM was associated with NR (irrespective of MDE) and high IL-12/IL-23p40 with R.

Conclusions: We incorporated MDE in mucosal cytokine research to avoid bias due to the insufficient presence of anti-TNF. When applied to mucosal cytokines previously linked to (N)R, IL-6 appears to drive inflammation in TNFi-resistant UC patients, while OSM seems to parallel inflammation and does not cause refractoriness.

Background and aims: Achieving histological remission is a desirable emerging treatment target in ulcerative colitis (UC), yet its assessment is challenging due to high inter- and intraobserver variability, reliance on experts, and lack of standardization. Artificial intelligence (AI) holds promise in addressing these issues. This systematic review, meta-analysis, and meta-regression evaluated the AI's performance in assessing histological remission and compared it with that of pathologists.

Methods: We searched Medline/PubMed and Scopus databases from inception to September 2024. We included studies on AI models assessing histological activity in UC, with or without comparison to pathologists. Pooled performance metrics were calculated: sensitivity, specificity, positive and negative predictive value (PPV and NPV), observed agreement, and F1 score. A pairwise meta-analysis compared AI and pathologists, while sub-meta-analysis and meta-regression evaluated heterogeneity and factors influencing AI performance.

Results: Twelve studies met the inclusion criteria. AI models exhibited strong performance with a pooled sensitivity of 0.84 (95% CI, 0.80-0.88), specificity 0.87 (0.84-0.91), PPV 0.90 (0.87-0.92), NPV 0.80 (0.71-0.88), observed agreement 0.85 (0.82-0.89), and F1 score 0.85 (0.82-0.89). AI models demonstrated no significant differences with pathologists for specificity, observed agreement, and F1 score, while they were outperformed by pathologists for sensitivity and NPV. AI models for the adult population were linked to reduced heterogeneity and enhanced AI performance at meta-regression.

Conclusions: AI shows significant potential for assessing histological remission in UC and performs comparably to pathologists. Future research should focus on standardized, large-scale studies to minimize heterogeneity and support widespread AI implementation in clinical practice.

Background: Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are frequently experienced by patients and may lead to severe symptoms and fatigue. However, the reporting patterns of these outcomes in IBD randomized controlled trials (RCTs) are not clear.

Methods: We searched placebo-controlled phase 3 RCTs of advanced therapies in IBD and assessed the frequency and means of reporting EIM and fatigue data in these studies.

Results: Thirty-three phase 3 RCTs for Crohn's disease (CD) (n = 16) or ulcerative colitis (UC) (n = 16) were identified between 2002 and 2023. While all trials (16/16) in CD collected some EIM data, we could only ascertain 6/16 (38%) collected EIM data in UC trials. Fewer than one-third (9/32, 28%) reported EIM prevalence at baseline; fewer reported the improvement with active treatment (9%). Fatigue was measured in 20/32 trials (63%).

Conclusions: EIM and fatigue data are inconsistently collected in RCTs of IBD. Standardizing collection methods across RCTs would provide greater insight on these agents and their efficacy in treating these manifestations of disease.

Background and aims: The natural history of Crohn's disease leading to intestinal failure is not well characterised. This study aims to describe the clinical course of Crohn's disease preceding intestinal failure and to compare disease course and burden between Crohn's disease patients with and without intestinal failure.

Methods: Patients with Crohn's disease complicated by intestinal failure from Rigshospitalet, Copenhagen [n = 182] and a nationwide Danish Crohn's disease cohort without intestinal failure [n = 22,845] were included. Using nationwide registries in Denmark, disease course was determined from hospitalisations, surgeries, and outpatient medications, and disease burden was determined from employment and mortality data.

Results: The 10-year cumulative incidence of intestinal failure following Crohn's disease diagnosis declined from 2.7% prior to 1980 to 0.2% after 2000. Compared with Crohn's disease patients without intestinal failure, those with intestinal failure experienced significantly longer duration of severe disease [50 vs 19 years per 100 patient-years, p < 0.01], secondary to greater corticosteroid use [71% vs 60%, p = 0.02], inpatient contacts [98% vs 55%, p < 0.01], and abdominal surgeries [99% vs 48%, p < 0.01]. However, exposure to biologics was not different between the two groups [20.4% vs 21%, p = 0.95], and duration on biologics was shorter in Crohn's disease patients with intestinal failure [2068 vs 4126 days per 100 patient-years, p = 0.02]. Standard mortality ratio in Crohn's disease patients with intestinal failure was 3.66 (97.5% confidence interval [CI] 2.79, 4.72].

Conclusion: Patients with Crohn's disease complicated by intestinal failure experienced a more persistently severe preceding course of Crohn's disease but were not more likely to be treated with biological therapy.