Differences of clinical phenotype between familial and sporadic Crohn's disease in East China.

PURPOSE: Family history is one of the strongest risk factors for inflammatory bowel diseases (IBD) while studies about the clinical phenotype of familial IBD are limited. This study aimed to compare the phenotypic features of familial Crohn's disease (CD) with sporadic CD. METHODS: Familial CD was defined as CD patients having one or more first, second, third, fourth degree, or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distribution, extraintestinal manifestations, and complications at diagnosis, as well as treatment regimen and surgery, were compared between familial and sporadic CD. RESULTS: The familial CD was associated with a higher rate of past appendectomy history (P = 0.009), more intestinal perforation at onset (P = 0.012), more MRI results of anal lesion (P = 0.023), and gastrointestinal perforation (P = 0.040) at diagnosis, higher rate of past intestinal surgery history (P = 0.007), more number of intestinal surgeries (P = 0.037), longer duration of follow-up (P = 0.017), lower rate of taking biologicals for current maintenance (P = 0.043), lower tendency to upgrade to biologicals during follow-up (P = 0.013), higher possibility to experience gastrointestinal obstruction (P = 0.047), and abdominal abscess during follow-up (P = 0.045). CONCLUSION: Familial CD is associated with a more aggressive clinical phenotype.

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

Risk of Tuberculosis and Hepatitis B Reactivation in Patients With Crohn's Disease on Ustekinumab: A Nationwide Real-World Study.

BACKGROUND: Ustekinumab (UST) was approved in China for moderate-to-severe Crohn's disease (CD) in 2020. The prevalence rates of tuberculosis and hepatitis B virus (HBV) infection are high in China, and no guideline clearly states that tuberculosis chemoprophylaxis or prophylactic anti-HBV therapy should be prescribed before UST administration. This study aimed to assess the risk of tuberculosis and HBV reactivation in CD patients with latent tuberculosis infection (LTBI) and previous HBV infection receiving UST. METHODS: A multicenter retrospective cohort study was carried out at 68 hospitals in China to assess 721 adult CD cases administered UST between May 1, 2020, and December 31, 2021. CD and concurrent LTBI or HBV carrier were included. Hepatitis B serology, T-SPOT.TB, and tuberculin skin tests were performed at baseline. The primary outcome was tuberculosis or HBV reactivation. RESULTS: Patients with CD-concomitant LTBI or who were HBV carriers receiving UST therapy were retrospectively enrolled from 15 hospitals in China. A total of 53 CD with LTBI patients and 17 CD with HBV carrier patients receiving UST were included. Treatment and follow-up durations were 50 ± 20 weeks and 50 ± 15 weeks in the LTBI and HBV carrier groups, respectively. A total of 25 CD patients with LTBI underwent chemoprophylaxis and 28 did not. A total of 11 HBV carriers had antiviral prophylaxis and 6 did not. No patient experienced tuberculosis or HBV reactivation or liver dysfunction during follow-up. CONCLUSIONS: UST was safe for treatment of CD because no patient developed tuberculosis, persistent hepatitis, or acute liver failure during therapy, whether with a prophylactic regimen or not, based on our sample size and limited follow-up time.

Epithelial CRL4DCAF2 Is Critical for Maintaining Intestinal Homeostasis Against DSS-Induced Colitis by Regulating the Proliferation and Repair of Intestinal Epithelial Cells.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is currently gaining an increasing global interest. Intestinal epithelial barrier dysfunction is crucial toward developing IBD; however, the underlying mechanisms are not yet elucidated. This study is aimed at elucidating the function of CRL4DCAF2, an E3 ligase, toward mediating intestinal homeostasis. METHODS: Colon samples were collected from patients with IBD and healthy individuals to examine the expression of CRL4DCAF2. CRL4DCAF2 conditional knockdown in mouse intestinal epithelial cells (IECs) (DCAF2EKD) were constructed. DCAF2EKD and their littermate control (DCAF2EWT) were treated with dextran sodium sulfate (DSS) to induce acute colitis. Transcriptome analysis was performed on inflamed colon samples obtained from the mice. Cell cycle regulators were evaluated using real-time polymerase chain reaction (PCR), while tight junction and apoptosis proteins were examined via immunofluorescence and western blot. RESULTS: CRL4DCAF2 expression was significantly decreased in the inflamed IBD epithelium, and low expression of CRL4DCAF2 associated with high recurrence risk. Mice with DCAF2 specific knockout in IECs suffer from embryonic death. Multiple genes involved in cell proliferation, immune response, and gap junction were differentially expressed in inflamed colon from DCAF2EKD compared with DCAF2EWT. Furthermore, conditional downregulation of CRL4DCAF2 in the intestinal epithelium induced primarily epithelial damage, increased intestinal permeability, and diminished tight junction protein expression. In vivo and in vitro cell transfection experiments revealed that CRL4DCAF2 enhanced cell proliferation by promoting p21 ubiquitination and degradation, thereby inhibiting G2/M cell cycle. In addition, CRL4DCAF2 can also inhibit IEC apoptosis and promote cell autophagy. CONCLUSIONS: CRL4DCAF2 downregulation in IECs promotes intestinal barrier dysfunction and inhibits IEC proliferation, thus making it more susceptible to inflammation.

An observational study of the effects of ω-3 polyunsaturated fatty acid-supplemented parenteral nutrition on postoperative complications in patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease. Most patients with CD require surgery but exhibit an elevated incidence of postoperative complications. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are considered beneficial for nutrition, anti-inflammation, immunity, and intestinal microflora balance in humans. This study assessed the effects of ω-3 PUFA-supplemented parenteral nutrition (PN) on postoperative complications in CD patients. METHODS: Overall, 186 CD patients undergoing bowel resection were recruited for this study. The patient data were collected from a prospectively maintained database. After surgery, 83 patients received ω-3 PUFA-supplemented PN, and 103 did not. The postoperative complications were compared between the groups. Complication risk factors were identified by univariate and multivariate analyses. RESULTS: Patients who received ω-3 PUFA-supplemented PN after surgery had lower C-reactive protein (CRP) levels on postoperative day 3 (57.2±5.3 vs. 43.5±3.9 mg/L, P=0.047) and shorter postoperative hospital stays (12.1±1.1 vs. 9.3±0.6 days, P=0.041) than those who did not. The ω-3 PUFA group exhibited significantly fewer overall complications (40.8% vs. 24.1%, P=0.016) and major complications (23.3% vs. 9.6%, P=0.014) than the control group. Postoperative complications were associated with infliximab, ω-3 PUFAs, CRP levels, operative time, and laparoscopic surgery. The multivariate regression revealed that preoperative infliximab use was a positive risk factor and postoperative ω-3 PUFA-supplemented PN was a negative risk factor for postoperative complications. CONCLUSIONS: ω-3 PUFA-supplemented PN reduced post-surgery inflammatory response of CD patients, which in turn decreased the postoperative complications and accelerated recovery.

Prophylactic Antitubercular Therapy Is Associated With Accelerated Disease Progression in Patients With Crohn's Disease Receiving Anti-TNF Therapy: A Retrospective Multicenter Study.

INTRODUCTION: Prophylactic antitubercular therapy (ATT) is widely prescribed in patients with Crohn's disease (CD) receiving antitumor necrosis factor (anti-TNF) treatment. However, antitubercular agents have been demonstrated to possess profibrotic effects. We aimed to evaluate whether ATT accelerated disease progression in patients with CD receiving anti-TNF treatment. METHODS: A retrospective, multicenter study was performed in CD patients presented with inflammatory behavior (B1) and treated with anti-TNF agents. Disease progression was defined as the development of a stricturing (B2) or penetrating (B3) phenotype. ATT users were propensity score-matched with non-ATT users. Survival and multivariable Cox analyses were used to identify factors associated with disease progression. RESULTS: We enrolled 441 patients, including 295 ATT users and 146 non-ATT users, with a median follow-up of 3.15 years (interquartile range: 1.6-4.7). The cumulative rates of disease progression in the ATT group were constantly higher than those in the non-ATT group after 1-, 3-, 5-, and 10-year follow-ups, respectively (P = 0.031). Multivariable Cox analysis identified ATT as an independent risk factor for disease progression using both the whole (hazard ratio = 2.22; 95% confidence interval: 1.11-4.48; P = 0.025) and propensity score-matched cohorts (hazard ratio = 2.35; 95% confidence interval: 1.07-5.14; P = 0.033). In subgroup analysis, patients receiving ATT ≥4.5 months had a significantly higher rate of disease progression compared with patients receiving ATT <4.5 months (P = 0.005) and non-ATT treatment (P = 0.036). DISCUSSION: Prophylactic ATT with duration over 4.5 months was associated with disease progression in patients with CD receiving anti-TNF treatment.

Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease.

INTRODUCTION: Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. AIMS: To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. METHODS: Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 109 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36. RESULTS: The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up. CONCLUSIONS: Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.

Postoperative Ratio of C-Reactive Protein to Albumin as a Predictive Marker in Patients with Crohn's Disease Undergoing Bowel Resection.

BACKGROUND: The ratio of C-reactive protein (CRP) to albumin (CAR) has a significant correlation with postoperative complications and acts as a predictor in patients with pancreatic cancer and colorectal cancer. However, whether the CAR can be used to predict complications in Crohn's disease (CD) patients after surgery has not yet been reported. METHODS: A total of 534 CD patients undergoing surgery between 2016 and 2020 were enrolled. The risk factors of postoperative complications were assessed by univariate and multivariate analyses. The cutoff values and the accuracy of diagnosis for the CAR and postoperative CRP levels were examined with receiver operating characteristic (ROC) curves. RESULTS: The rate of postoperative complications was 32.2%. The postoperative CAR (OR 13.200; 95% CI 6.501-26.803; P < 0.001) was a significant independent risk factor for complications. Compared with the CRP level on postoperative day 3, the CAR more accurately indicated postoperative complications in CD patients (AUC: 0.699 vs. 0.771; Youden index: 0.361 vs. 0.599). ROC curves showed that the cutoff value for the CAR was 3.25. Patients with a CAR ≥ 3.25 had more complications (P < 0.001), a longer postoperative stay (15.5 ± 0.6 d vs. 9.0 ± 0.2 d, P < 0.001), and more surgical site infections (48.2% vs. 5.7%, P < 0.001) than those with a CAR < 3.25. CONCLUSIONS: Compared to the CRP level, the CAR can more accurately predict postoperative complications and can act as a predictive marker in CD patients after surgery.

Targeted versus universal tuberculosis chemoprophylaxis in 1968 patients with inflammatory bowel disease receiving anti-TNF therapy in a tuberculosis endemic region.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis. AIMS: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients. RESULTS: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05). CONCLUSIONS: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions.

Preoperative hypoalbuminemia is an independent risk factor for postoperative complications in Crohn's disease patients with normal BMI: A cohort study.

BACKGROUND: Malnutrition is universal in Crohn's disease (CD). The body mass index (BMI) is used to assess nutritional status to predict postoperative complications in CD patients. However, some CD patients have a normal BMI. The aim of this study was to evaluate risk factors for postoperative complications in CD patients with normal preoperative BMI values. METHODS: This retrospective observational study included 315 CD patients who underwent surgical treatment between December 2012 and January 2020. Patient data were collected from a prospectively maintained database. The risk factors for postoperative complications in CD patients with normal BMI values were identified by univariate and multivariate analyses. RESULTS: In total, 315 eligible patients were included. The incidence of postoperative complications was 30.8%, consisting of 22.5% mild complications and 18.4% major complications. The albumin level, the C-reactive protein level, laparoscopic surgery, and operative time were significantly associated with postoperative outcomes. Multivariate analysis showed that a low preoperative albumin level (P = 0.013, OR = 2.991, 95% CI: 1.255-7.131) was an independent risk factor for postoperative complications in CD patients with normal BMI values. CONCLUSIONS: A low preoperative albumin level was a risk factor for postoperative complications in CD patients with normal BMI values. Although some patients have a normal BMI, clinicians should still consider the preoperative albumin level in CD patients to evaluate their nutritional status and provide timely intervention to reduce the risk of postoperative complications.

Compare risk factors associated with postoperative infectious complication in Crohn's disease with and without preoperative infliximab therapy: a cohort study.

PURPOSES: The incidence of postoperative complication is higher in Crohn's disease (CD) compared with other intestinal disease. There is less published data yet on the comparison of risk factors to predict postoperative complications in CD exposed and unexposed to previous infliximab therapy. Also the relationship between infliximab and postoperative infectious complications is still controversial. Our aim is to compare the risk factors to predict infectious complications in CD with and without preoperative infliximab and to clarify relationship between infliximab and infectious complications. METHODS: This retrospective study included 390 patients from June 2014 to June 2018. Postoperative complications were compared in patients with and without preoperative infliximab. Univariate and multivariable analyses were performed to identify risk factors. RESULTS: Eighty-five patients received infliximab within 8 weeks of surgery. A total of 129 patients had postoperative complications, with 35 receiving infliximab. No significant differences of whole postoperative complications were found in CD with and without infliximab (p = 0.073). However, patients receiving infliximab suffered more infectious complications (p = 0.010). Preoperative infliximab was confirmed to be an independent risk factor in infectious complications (p = 0.042). Multivariate analysis suggested that increased erythrocyte sedimentation rate (ESR) was an independent risk factor for infectious complications in patients receiving preoperative infliximab (p = 0.022), and increased C-reactive protein was an independent risk factor in patients not receiving preoperative infliximab (p = 0.019). CONCLUSIONS: Preoperative use of infliximab ≤ 8 weeks was independently associated with infectious complications in CD. Risk factors were different in predicting postoperative complications in CD with and without infliximab, and preoperative ESR and C-reactive protein were risk factors, respectively.

Platelet-to-lymphocyte percentage ratio index: a simple non-invasive index to monitor the endoscopic activity in Crohn's disease.

BACKGROUND: Recent evidence has shown that the complete blood count (CBC) is abnormal in patients with Crohn's disease (CD). We aimed to investigate an effective CBC parameter and explore its impact on disease activity in a large CD cohort. METHODS: We performed a retrospective analysis of patients with established CD who underwent clinically indicated endoscopy at four tertiary centres in China between 2016 and 2020. Individual variables of the Simple Endoscopic Score for CD, CBC parameters, C-reactive protein (CRP) levels, erythrocyte sedimentation rate, and faecal calprotectin (FC) were independently reviewed by different investigators. The hold-out method was used to verify the predictive power of the established model. RESULTS: Data from a total of 1388 endoscopic procedures performed for 882 eligible CD patients were available with routine blood parameters and related indicators. The model using platelet-to-lymphocyte percentage ratio (PLpR) had high accuracy for identifying patients in endoscopic remission (ER), with an area under the curve (AUC) of 0.785 [95% confidence interval (CI): 0.784-0.787], which was comparable with that for CRP (AUC: 0.775, 95% CI: 0.774-0.777). Notably, the AUC of PLpR was significantly higher than that of CRP in patients with colonic disease and with a history of surgery. Moreover, after combining the FC with PLpR, the AUC value of FC + PLpR increased up to 0.892 (95% CI: 0.890-0.894) for identifying ER. CONCLUSIONS: We explored an index (PLpR) to identify CD patients in ER based on platelet and lymphocyte percentage from the CBC. PLpR helped evaluate the degree of disease activity and monitor the therapeutic response.

Glasgow prognostic score is a practical predictive index for postoperative intra-abdominal septic complications after bowel resection in Crohn's disease patients.

PURPOSE: Postoperative intra-abdominal septic complications (IASCs) are not uncommon in patients with Crohn's disease (CD). The appropriate index to predict postoperative IASCs in these individuals remains unknown. This study investigates whether the inflammation-based Glasgow prognostic score (GPS) is predictive in the setting of postoperative IASC CD patients who underwent elective bowel resection. METHODS: A consecutive cohort of 163 CD patients who underwent elective intestinal resection from July 2012 to March 2016 was retrospectively analyzed. Patients were divided into two GPS groups, one lower and one higher. The GPS was defined by serum levels of C-reactive protein and albumin. Univariate and multivariate analyses were conducted to identify risk factors for postoperative IASCs. RESULTS: Postoperative IASCs occurred in 25 (15.3%) patients. Compared with patients in the lower GPS group, patients with a higher GPS had a higher incidence of postoperative IASCs (9.85 vs. 38.71%, P < 0.001) and experienced longer postoperative hospital stay (10.53 ± 7.00 vs. 15.71 ± 9.17, P = 0.001). Univariate and multivariate analyses revealed preoperative GPS [odds ratio (OR) 5.016, 95% confidence interval (CI) 1.134-22.193, P = 0.034] and penetrating behavior (OR 4.495, 95% CI 1.377-14.670, P = 0.013) to be independent risk factors for postoperative IASCs. CONCLUSIONS: A preoperative GPS can serve as a useful index for predicting manifestation of postoperative IASCs after bowel resection in patients with CD. Perioperative optimization is required to improve postoperative outcomes for patients with higher GPS.

Vitamin D Deficiency Is Associated with Endoscopic Severity in Patients with Crohn's Disease.

BACKGROUND AND AIMS: Vitamin D deficiency is common in patients with Crohn's disease and is associated with disease activity. Relationship between vitamin D and endoscopic disease activity is unknown. The aim of the study is to determine the association between vitamin D status and endoscopic disease activity in CD patients. METHODS: Consecutive hospitalized CD patients from 2014 to 2016 who received vitamin D assessment and colonoscopy were retrospectively evaluated. Clinical disease activity was assessed by Crohn's disease activity index and C-reactive protein. Endoscopic activity was calculated using simple endoscopic score for Crohn's disease. RESULTS: Median serum 25OHD level of 131 patients was lower than healthy controls [21.1 nmol/L (11.8-32.3) versus 49.9 nmol/L (44.9-57.4), P = 0.007]. 125 (95%) patients had vitamin D deficiency and the rest (5%) had vitamin D insufficiency. Serum 25OHD was inversely correlated with CRP (r = -0.308, P < 0.001), CDAI (r = -0.582, P < 0.001), SES-CD (r = -0.294, P = 0.001), and endoscopic severity stratified by SES-CD (P = 0.001). CONCLUSION: Vitamin D deficiency was prevalent among hospitalized CD patients. Vitamin D levels were inversely correlated with endoscopic disease activity. Vitamin D status could be a biomarker in assessing disease activity among hospitalized CD patients in addition to CDAI and CRP.

Review of inflammatory bowel disease in China.

Inflammatory bowel disease mainly consisting of ulcerative colitis and Crohn's disease has been rising gradually during the last two decades in China. In this review article, we provide the latest epidemiological trends in incidence, prevalence, and mortality of IBD patients in China and summarize the risk factors and genetic susceptibility of Chinese IBD patients. We also compare these characteristics to those of IBD patients in Western countries.