Journal of Crohn's & colitis最新文献

Introduction: Although randomized controlled trials (RCTs) are the gold standard for investigating the efficacy and safety of interventions, they present major operational challenges due to their complexity, time-consuming nature, and costs. To address some of these difficulties, RCTs nested in cohorts (RCTsNC) have been developed. The aim was to review the opportunities and challenges of RCTsNC in inflammatory bowel disease (IBD).

Methods: A literature search was conducted using MEDLINE, Embase, Cochrane and Clinicaltrials.gov from inception until March 2024 to identify studies focusing on this topic.

Results: RCTsNC is an emerging trial design, which has been successfully utilized across several medical disciplines but not IBD. It enables the use of longer-term longitudinal data for safety and efficacy assessment, and enhanced recruitment and follow up processes. Observational data for IBD, derived from research (cohort and case-control studies) and non-research sources (electronic health records and registries), provides access to comprehensive records for a large number of IBD patients, which could present an opportunity to enhance the performance of RCTsNC. Leveraging pre-existing cohorts and their organizational structures improves patient acceptance and is more economical compared to traditional randomized trials. It may permit researchers to address knowledge gaps in IBD (specific sub-populations, or the effect of environmental exposures on disease course). Limitations of RCTsNC include the risk of selection bias and constraints related to comparisons with placebo.

Conclusion: RCTsNC offers a promising opportunity for IBD research and provides an alternative study design given the challenges of conventional trial designs in the current IBD RCT landscape.

Background and aims: Patients with inflammatory bowel disease (IBD) may experience symptoms of sexual dysfunction (SD). However, the magnitude of this problem remains uncertain. Therefore, we performed a systematic review and meta-analysis to assess the prevalence of SD in adult patients with IBD.

Methods: MEDLINE, EMBASE, and EMBASE Classic (from inception to April 9, 2024) were searched to identify observational studies reporting the prevalence of SD in adult patients with IBD based on validated screening instruments. Data were extracted, and pooled prevalence (PP), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated.

Results: Of 1017 citations evaluated, 18 articles fulfilled the eligibility criteria, containing 2694 patients with IBD recruited from 13 different countries. The PP of SD in IBD patients was 50.6% (95% CI, 40.8%-60.5%; I2 = 96.3%) with an OR = 2.94 (95% CI, 1.99%-4.35%, I2 = 73.4) compared to healthy controls. When we considered ulcerative colitis (UC) or Crohn's disease (CD) separately, the PP of SD was 64.8% (95% CI, 45.1%-82.1%; I2 = 88.8%) in patients with UC and 58.3% (95% CI, 36.0%-79.0%; I2 = 95.3%) in patients with CD. In the subgroup analysis based on sex, the PP of SD was higher in females with IBD than in males (62.7% vs 34.0%; OR = 3.99, 95% CI, 2.80%-5.68%; I2 = 61.7%). Furthermore, the PP of SD was higher in patients with active disease than in patients with inactive disease (75.1% vs 34.2%; OR = 9.65, 95% CI, 1.02%-91.33%, I2 = 95.5%).

Conclusions: We demonstrated high prevalence of SD in IBD patients, especially in women. Encouraging gastroenterologists to screen for, and treat, these disorders with a holistic approach might improve quality of life of patients with IBD.

Background: Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC.

Methods: DSBs and RAD50 expression in inflammatory bowel disease (IBD) and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC.

Results: Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression was reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50IEC-KO activated the cytokine-cytokine receptor response, which was amplified through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficient cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice.

Conclusions: RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.

The Groupe d'Etude sur les Affections Inflammatoires Digestives (GETAID) was founded in Paris in 1983 by Professor Robert Modigliani and colleagues. From the beginning, the aim of this international (France, Belgium, and Switzerland), multicenter, French-speaking group was to address clinical questions raised by patients or physicians in their daily practice or the inflammatory bowel disease community, by focusing on clinical research on treatments through randomized controlled trials, prospective cohorts, and cross-sectional studies, quantifying the severity of various facets of the disease when necessary for these studies. This very innovative approach has contributed to the advancement of knowledge in inflammatory bowel diseases by publishing more than 120 original articles in peer-reviewed journals throughout the GETAID's 40-year history, most of them in top publications in gastroenterology and hepatology journals. In this paper, we will see what GETAID's contribution has been over the last 4 decades and review the reasons for its success and forthcoming challenges.

Background: We aimed to evaluate the impact of advanced medical therapies (biologicals and small molecules) on time to colectomy and oncological outcomes in ulcerative colitis (UC).

Methods: This cohort study included UC patients who underwent colectomy between 2003 and 2022 at 2 referral centers in Belgium and the Netherlands. Exposure was the use of advanced medical therapies. Primary outcomes were time to colectomy and colorectal cancer (CRC) rate, compared between 4 periods: P1 (2003-2007), P2 (2008-2012), P3 (2013-2017), and P4 (2018-2022). Secondary outcomes were oncological outcomes, including incidental cancers found unexpectedly in resection specimens or during endoscopic follow-up for medication switch.

Results: Among 716 patients, the usage of advanced therapies increased from 36.8% in P1 to 89.7% in P4 (P < .0001). Median time to colectomy remained comparable (P1: 7.1 years [interquartile ranges (IQR), 2.8-12.9] vs P4: 7.2 years [IQR, 2.7-14.6]; P = not significant). Colectomy and colorectal cancer was diagnosed in 72 (10.1%) patients, with no significant change over time (P = .44). Proportion of CRC was lower in patients treated with advanced therapies (4.7% vs 23.6%, P < .0001) and related to a shorter follow-up (median 6.1 vs 10.3 years, P < .0001). Advanced therapy patients had higher incidental cancer rates (37.5% vs 8.3%, P = .002), which was associated with reduced CRC-related survival (HR for CRC-related death: 3.3, 95% CI 1.17-9.4; P = .02).

Conclusion: Despite increased usage of advanced medical therapies, time to resection and CRC rates have remained unchanged in UC patients undergoing colectomy over the past 2 decades. Advanced therapy patients had higher incidental cancers rates, associated with decreased CRC survival. Awareness of timely colectomy is crucial for this group.

Background and aims: Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) regulates the internalization of growth factor receptors such as the epithelial growth factor receptor (EGFR). Given the crucial function of such receptors in intestinal epithelial cells (IECs), we assessed the involvement of PTPN23 in intestinal homeostasis and epithelial proliferation.

Methods: We generated mouse models with constitutive (PTPN23fl/flVilCre+/-) or inducible (PTPN23fl/flVilCreERT+/-) deletion of PTPN23 in IEC. To elucidate the functional consequences of PTPN23 deletion in IEC, we performed barrier function studies, flow cytometry, RNAseq, and in vivo experiments applying EGFR inhibition, antibiotic treatment, or co-housing approaches to further delineate the observed phenotype.

Results: Deletion of PTPN23 in IECs resulted in a severe early-onset phenotype in both models. Mice were characterized by elongated colon, epithelial hyperproliferation, splenomegaly, and diarrhea leading to the death of the mice within 3 weeks of PTNP23 deletion. Compromised gut barrier integrity resulted in enhanced bacterial translocation accompanied by reduced IgA transcytosis in PTPN23fl/flVilCreERT+/- compared to wild-type mice. Although EGFR surface expression was increased upon PTPN23-deletion, inhibition of EGFR signaling did not prevent disease. In contrast, and in accordance with defective bacterial handling, antibiotic treatment, but not co-housing, fully rescued the phenotype.

Conclusions: The absence of PTPN23 in IECs leads to lethal dysregulation of intestinal homeostasis, triggered by bacterial infiltration due to defects in the intestinal epithelial barrier and impaired IgA transcytosis. Thus, we identify PTPN23 as a novel key player in preserving intestinal epithelial homeostasis, ultimately preventing bacterial overgrowth and excessive immune activation in the intestine.

Background: Impaired intestinal epithelial barrier has been considered to be associated with an increasing variety of gastrointestinal diseases, especially inflammatory bowel disease (IBD) encompassing Crohn's disease (CD) and ulcerative colitis (UC). We aimed to investigate the role of Gasdermin B (GSDMB) in modulating intestinal epithelial barrier integrity and proposed a promising therapeutic strategy.

Methods: Gasdermin B expression was evaluated in adult CD samples by molecular biology means and single-cell transcriptomes. We generated GSDMB (Rosa26-lsl/lsl-GSDMB;Villin-Cre) and one of its functional missense variant rs2305480 (Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre) intestinal epithelial-specific knock in mice to observe the functions of GSDMB in intestinal epithelial barrier. RNA-seq analysis as well as human and murine intestine-derived organoids were used to determine the pathogenic mechanism of GSDMB.

Results: The expression of GSDMB was increased during active intestinal inflammation and principally localized in intestinal epithelial cells (IECs). Rosa26-lsl/lsl-GSDMB;Villin-Cre mice developed enterocolitis and exhibited aberrant intestinal barrier integrity. Mechanistically, epithelial GSDMB modulated hyperactive unfolded protein response of IECs by up-regulating BHLHA15 to mediate intestinal barrier injury. Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre mice with the mutant rs2305480 of GSDMB aggravated such inflammatory effects.

Conclusion: We have uncovered an important and previously unrecognized role of GSDMB in intestinal homeostasis, which represents a potential therapeutic target for intestinal inflammation.

Background: Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified that are strongly associated with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti-αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease, or other cholestatic liver diseases and their persistence after proctocolectomy.

Methods: We detected anti-αVβ6 by an enzyme-linked immunosorbent assay in sera collected at 2 German tertiary centers, including healthy controls (N = 62), UC (N = 36), Crohn's disease (CD, N = 65), PSC-inflammatory bowel diseases (IBD) (78 samples from N = 41 patients), PSC without IBD (PSC, 41 samples from N = 18 patients), primary biliary cholangitis (PBC, N = 24), autoimmune hepatitis (AIH, N = 32), secondary sclerosing cholangitis (SSC, N = 12), and metabolic dysfunction-associated steatotic liver disease (MASLD, N = 24). In addition, sera after proctocolectomy were studied (44 samples/N = 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections, and colon of PSC patients.

Results: Anti-αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC, or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti-αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease.

Conclusions: Anti-αVβ6 frequently occurs in patients suffering from PSC, especially in PSC-IBD. Anti-αVβ6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.

Background: Endoscopy and biopsy are the standard tools for the diagnosis of inflammatory bowel disease (IBD) and the assessment of treatment response. Severe endoscopic lesions (SEL) are commonly observed in IBD, but have been poorly described in the literature. The aim of this review is to provide an overview of the current understanding and gaps in knowledge about these lesions.

Methods: We performed a systematic review of studies of SEL in patients with IBD. A search was performed in MEDLINE, Embase, and Cochrane CENTRAL databases in July 2024. Studies were eligible if they investigated SEL, its involvement in the disease, its evolution with treatment, and its prognostic implications.

Results: We found 1172 articles in the Pubmed database and 46 were included. Of the various definitions of SEL used in the literature, most of them are based on the most severe endoscopic items from existing endoscopic scores, but none have been validated. Despite the paucity of literature, the prevalence of SEL is estimated to be 33%-75% in acute severe ulcerative colitis (ASUC) and 22.5%-87% in Crohn's disease (CD). In terms of prognosis, SEL are associated with steroid refractoriness in ASUC and do not affect response to infliximab or ciclosporin. In CD, the response to biologics, especially anti-TNF, is not affected by the presence of SEL.

Conclusions: There is currently no validated definition of SEL in IBD. When present, they are associated with steroid failure in the setting of ASUC, but do not affect response to anti-TNF in either CD or ASUC.