The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.

Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1ß maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

Clinical Update on the Prevention and Management of Postoperative Crohn's Disease Recurrence.

PURPOSE OF REVIEW: Despite advances in therapeutics, a significant portion of patients with Crohn's disease still require surgical management. In this article, we present updates to the natural history, prognostication and postoperative monitoring, and novel therapeutics in the prevention and treatment of postoperative Crohn's disease recurrence. RECENT FINDINGS: Clinical risk factors have been associated with higher rates of postoperative recurrence (POR), and in recent studies demonstrate an increased cumulative risk with presence of additional risk factors. Additional novel clinical, histologic, and "-omic" risk factors for recurrence have recently been elucidated, including the role of the mesentery on recurrence and perioperative intraabdominal septic complications. High-risk patients benefit most from medical prophylaxis, including anti-TNF with or without immunomodulator therapy to prevent recurrence. New biologics such as vedolizumab and ustekinumab have emerging evidence in the use of prophylaxis, especially with recent REPREVIO trial data. Non-invasive disease monitoring, such as cross-sectional enterography, intestinal ultrasound, and fecal calprotectin, have been validated against ileocolonoscopy. Recent advances in the prediction, prevention, and monitoring algorithms of postoperative Crohn's disease may be leading to a reduction in postoperative recurrence. Ongoing trials will help determine optimal monitoring and management strategies for this at-risk population.

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Risk Prediction and Comparative Efficacy of Anti-TNF vs Thiopurines, for Preventing Postoperative Recurrence in Crohn's Disease: A Pooled Analysis of 6 Trials.

BACKGROUND & AIMS: The superiority of anti-TNF-α agents to thiopurines for the prevention of postoperative recurrence of Crohn's disease (CD) after ileocolonic resection remains controversial. In this meta-analysis of individual participant data (IPD), the effect of both strategies was compared and assessed after risk stratification. METHODS: After a systematic literature search, IPD were requested from randomized controlled trials investigating thiopurines and/or anti-TNF-α agents after ileocolonic resection. Primary outcome was endoscopic recurrence (ER) (Rutgeerts score ≥i2) and secondary outcomes were clinical recurrence (Harvey-Bradshaw Index/Crohn's Disease Activity Index score) and severe ER (Rutgeerts score ≥i3). A fixed effect network meta-analysis was performed. Subgroup effects were assessed and a prediction model was established using Poisson regression models, including sex, smoking, Montreal classification, CD duration, history of prior resection and previous exposure to anti-TNF-α or thiopurines. RESULTS: In the meta-analysis of IPD, 645 participants from 6 studies were included. In the total population, a superior effect was demonstrated for anti-TNF-α compared with thiopurine prophylaxis for ER (relative risk [RR], 0.52; 95% confidence interval [CI], 0.33-0.80), clinical recurrence (RR, 0.50; 95% CI, 0.26-0.96), and severe ER (RR, 0.41; 95% CI, 0.21-0.79). No differential subgroup effects were found for ER. In Poisson regression analysis, previous exposure to anti-TNF-α and penetrating disease behavior were associated with ER risk. The advantage of anti-TNF-α agents as compared with thiopurines was observed in low- and high-risk groups. CONCLUSIONS: Anti-TNF-α is superior to thiopurine prophylaxis for the prevention of endoscopic and clinical postoperative CD recurrence after ileocolonic resection. The advantage of anti-TNF-α agents was confirmed in subgroup analysis and after risk stratification.

High-Dose Vitamin D Does Not Prevent Postoperative Recurrence of Crohn's Disease in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Vitamin D deficiency is common in Crohn's disease (CD). High-dose vitamin D had anti-inflammatory effects in preclinical studies and trials of patients with CD. We performed a randomized trial to determine whether high-dose vitamin D prevents postoperative recurrence of CD after ileocolonic resection. METHODS: Patients with CD after ileocolonic resection with ileocolonic anastomosis were assigned randomly to groups given weekly 25,000 IU oral vitamin D (n = 72) or placebo (n = 71) for 26 weeks, at 17 hospitals in The Netherlands and Belgium, from February 2014 through June 2017. Patients were assessed at baseline and at weeks 2, 6, 12, and 26 for laboratory and clinical parameters, and underwent ileocolonoscopy at 26 weeks. The primary end point was endoscopic recurrence (modified Rutgeerts score, ≥i2b, as assessed by blinded readers) at 26 weeks. Secondary end points included clinical recurrence (Crohn's disease activity index, ≥220), quality of life (measured by the 36-Item Short Form Health Survey, Inflammatory Bowel Disease Questionnaire, and EuroQol, a 5-dimension questionnaire), and outcomes associated with the baseline serum concentration of vitamin D. RESULTS: In the vitamin D group, serum levels of 25-hydroxy vitamin D increased from a median of 42 nmol/L at baseline to 81 nmol/L at week 26 (P < .00001), whereas levels did not change significantly in the placebo group and remained unchanged at 43 nmol/L. In the intention-to-treat analysis, the proportion of patients with endoscopic recurrence at 26 weeks did not differ significantly between the vitamin D vs the placebo group (58% vs 66%; P = .37). The cumulative rate of clinical recurrence did not differ significantly between the groups (18.1% in the vitamin D group vs 18.3% in the placebo group; P = .91). Quality of life improved slightly over time in both groups, but did not differ significantly between groups (P = .07). There were few adverse events in either group. CONCLUSIONS: High-dose vitamin D, compared with placebo, did not reduce the incidence of postoperative endoscopic or clinical recurrence of CD in patients who underwent ileocolonic resection with ileocolonic anastomosis. ClinicalTrials.gov no: NCT02010762.

Dietary Inflammatory Potential and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND & AIMS: Inflammation is a potential mechanism through which diet modulates the onset of inflammatory bowel disease. We analyzed data from 3 large prospective cohorts to determine the effects of dietary inflammatory potential on the risk of developing Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data from 166,903 women and 41,931 men in the Nurses' Health Study (1984-2014), Nurses' Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). Empirical dietary inflammatory pattern (EDIP) scores were calculated based on the weighted sums of 18 food groups obtained via food frequency questionnaires. Self-reported CD and UC were confirmed by medical record review. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 328 cases of CD and 428 cases of UC over 4,949,938 person-years of follow-up. The median age at IBD diagnosis was 55 years (range 29-85 years). Compared with participants in the lowest quartile of cumulative average EDIP score, those in the highest quartile (highest dietary inflammatory potential) had a 51% higher risk of CD (HR 1.51; 95% CI 1.10-2.07; Ptrend = .01). Compared with participants with persistently low EDIP scores (at 2 time points, separated by 8 years), those with a shift from a low to high inflammatory potential of diet or persistently consumed a proinflammatory diet had greater risk of CD (HR 2.05; 95% CI 1.10-3.79 and HR 1.77; 95% CI 1.10-2.84). In contrast, dietary inflammatory potential was not associated with the risk of developing UC (Ptrend = .62). CONCLUSIONS: In an analysis of 3 large prospective cohorts, we found dietary patterns with high inflammatory potential to be associated with increased risk of CD but not UC.

Environmental factors associated with biological use and surgery in inflammatory bowel disease.

BACKGROUND AND AIM: While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best-known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification. METHODS: Seven hundred twenty-eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate-adjusted logistic regression modeling. RESULTS: No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated. CONCLUSIONS: We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor-made interventions, and preventive strategies in IBD.

Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease: results from two large prospective cohort studies.

OBJECTIVE: To examine the relationship between Mediterranean diet and risk of later-onset Crohn's disease (CD) or ulcerative colitis (UC). DESIGN: We conducted a prospective cohort study of 83 147 participants (age range: 45-79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI. RESULTS: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0-2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0-2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD. CONCLUSION: In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD.

A Diet Low in Red and Processed Meat Does Not Reduce Rate of Crohn's Disease Flares.

BACKGROUND & AIMS: Diet may be an important factor in the progression of Crohn's disease (CD). We performed a randomized controlled trial to determine whether reduced consumption of red and processed meats decreases the risk of symptomatic relapse of CD, analyzing results from the Food and Crohn's Disease Exacerbation Study (FACES) trial. METHODS: Adults with CD were recruited into the FACES trial from IBD Partners, an Internet-based cohort of patients with inflammatory bowel disease, from November 2013 through June 2015. Individuals who were in remission (CD activity index [sCDAI] scores of ≤150), had completed a biannual survey, and reported consumption of red meat at least once weekly were randomly assigned to groups that consumed a minimum of 2 servings/week of red or processed meat (high meat, n = 118) or not more than 1 serving per month (low meat, n = 96) for 49 weeks. The primary outcome was relapse of CD, defined as increase in sCDAI score by ≥70 points and to >150 or a need for CD surgery or new CD medication. A secondary outcome, moderate or severe relapse, was based on an increase in sCDAI to >219. RESULTS: During the trial, the high-meat groups reported consumption of 2 or more servings of red or processed meat during 98.5% of observed weeks compared with 18.8% of weeks for the low-meat group. Any and moderate to severe relapse occurred in 62% of participants in the high-meat group and 42% of participants in the low-meat group. There were no significant differences in time to any (P = .61) or moderate/severe (P = .50) relapse. CONCLUSIONS: In an analysis of data from the FACES trial, we found that among patients with CD in remission, level of red and processed meat consumption was not associated with time to symptomatic relapse. ClinicalTrials.gov, Number: NCT0192673.

Colonoscopy-guided therapy for the prevention of post-operative recurrence of Crohn's disease.

BACKGROUND: About half of patients with Crohn's disease (CD) require surgery within 10 years of diagnosis. Resection of the affected segment is highly effective, however the majority of patients experience clinical recurrence after surgery. Most of these patients have asymptomatic endoscopic recurrence weeks or months before starting with symptoms. This inflammation can be detected by colonoscopy and is a good predictor of poor prognosis.Therapy guided by colonoscopy could tailor the management and improve the prognosis of postoperative CD. OBJECTIVES: To assess the effects of prophylactic therapy guided by colonoscopy in reducing the postoperative recurrence of CD in adults. SEARCH METHODS: The following electronic databases were searched up to 17 December 2019: MEDLINE, Embase, CENTRAL, Clinical Trials.gov, WHO Trial Registry and Cochrane IBD specialized register. Reference lists of included articles, as well as conference proceedings were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and cohort studies comparing colonoscopy-guided management versus management non-guided by colonoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using both the Cochrane 'Risk of bias' tool for RCTs and Newcastle-Ottawa scale (NOS) for cohort studies. The primary outcome was clinical recurrence. Secondary outcomes included: endoscopic, surgical recurrence and adverse events. We calculated the risk ratio (RR) for each dichotomous outcome and extracted the hazard ratio (HR) for time-to-event outcomes. All estimates were reported with their corresponding 95% confidence interval (CI). Data were analysed on an intention-to-treat (ITT) basis. The overall quality of the evidence was evaluated using GRADE criteria. MAIN RESULTS: Two RCTs (237 participants) and five cohort studies (794 participants) met the inclusion criteria. Meta-analysis was not conducted as the studies were highly heterogeneous. We included two comparisons. Intensification of prophylactic-therapy guided by colonoscopy versus intensification guided by clinical recurrence One unblinded RCT and four retrospective cohort studies addressed this comparison. All participants received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group the therapy was intensified in case of endoscopic recurrence; in the control group the therapy was intensified only in case of symptoms. In the RCT, clinical recurrence (defined as Crohn's Disease Activity Index (CDAI) > 150 points) in the colonoscopy-based management group was 37.7% (46/122) compared to 46.1% (21/52) in the control group at 18 months' follow up (RR 0.82, 95% CI: 0.56 to 1.18, 174 participants, low-certainty evidence). There may be a reduction in endoscopic recurrence at 18 months with colonoscopy-based management (RR 0.73, 95% CI 0.56 to 0.95, 1 RCT, 174 participants, low-certainty evidence). The certainty of the evidence for surgical recurrence was very low, due to only four cohort studies with inconsistent results reporting this outcome. Adverse events at 18 months were similar in both groups, with 82% in the intervention group (100/122) and 86.5% in the control group (45/52) (RR 0.95, 95% CI:0.83 to 1.08, 1 RCT, 174 participants, low-certainty of evidence).The most common adverse events reported were alopecia, wound infection, sensory symptoms, systemic lupus, vasculitis and severe injection site reaction. Perforations or haemorrhages secondary to colonoscopy were not reported. Initiation of prophylactic-therapy guided by colonoscopy versus initiation immediately after surgery An unblinded RCT and two retrospective cohort studies addressed this comparison. The control group received prophylactic therapy immediately after surgery, and in the colonoscopy-based management group the therapy was delayed up to detection of endoscopic recurrence. The effects on clinical and endoscopic recurrence are uncertain (clinical recurrence until week 102: RR 1.16, 95% CI 0.73 to 1.84; endoscopic recurrence at week 102: RR 1.16, 95% CI 0.73 to 1.84; 1 RCT, 63 participants, very low-certainty evidence). Results from one cohort study were similarly uncertain (median follow-up 32 months, 199 participants). The effects on surgical recurrence at a median follow-up of 50 to 55 months were also uncertain in one cohort study (RR 0.79, 95% CI 0.38 to 1.62, 133 participants, very low-certainty evidence). There were fewer adverse events with colonoscopy-based management (54.8% (17/31)) compared with the control group (93.8% (30/32)) but the evidence is very uncertain (RR 0.58, 95% CI 0.42 to 0.82; 1 RCT, 63 participants). Common adverse events were infections, gastrointestinal intolerance, leukopenia, pancreatitis and skin lesions. Perforations or haemorrhages secondary to colonoscopy were not reported. AUTHORS' CONCLUSIONS: Intensification of prophylactic-therapy guided by colonoscopy may reduce clinical and endoscopic postoperative recurrence of CD compared to intensification guided by symptoms, and there may be little or no difference in adverse effects. We are uncertain whether initiation of therapy guided by colonoscopy impacts postoperative recurrence and adverse events when compared to initiation immediately after surgery, as the certainty of the evidence is very low. Further studies are necessary to improve the certainty of the evidence of this review.

Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression.

OBJECTIVE: Depression is associated with IBD, but the effect of antidepressants on IBD has been sparsely studied. We assessed the impact of depression and antidepressant therapies on the development of IBD. DESIGN: The Health Improvement Network (THIN) was used to identify a cohort of patients with new-onset depression from 1986 to 2012. THIN patients who did not meet the defining criteria for depression were part of the referent group. The outcome was incident Crohn's disease (CD) or ulcerative colitis (UC). Cox proportional hazards modelling was performed to evaluate the rate of Crohn's disease or UC development among patients with an exposure of depression after controlling for age, sex, socioeconomic status, comorbid conditions, smoking, anxiety and antidepressant use including atypical antidepressants, mirtazapine, monoamine oxidase inhibitors (MAOI), serotonin norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), serotonin modulators; and tricyclic antidepressants (TCA). RESULTS: We identified 403 665 (7.05%) patients with incident depression. Individuals with depression had a significantly greater risk of developing CD (adjusted HR=2.11, 95% CI 1.65 to 2.70) and UC (adjusted HR=2.23, 95% CI 1.92 to 2.60) after controlling for demographic and clinical covariates. SSRI and TCA were protective against CD, whereas mirtazapine, SNRI, SSRI, serotonin modulators and TCA were protective for UC. CONCLUSION: Patients with a history of depression were more likely to be diagnosed with IBD. In contrast, antidepressant treatments were selectively protective for Crohn's disease and UC. These results may impact counselling and management of depression and IBD.

Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials.

INTRODUCTION: There is a lack of studies on the optimal anti-tumor necrosis factor (anti-TNF) agent for postoperative prophylaxis of Crohn's disease (CD) recurrence. Therefore, we conducted a network meta-analysis (NMA) of prospective trials to compare the efficacy of anti-TNF agents in the prevention of postoperative endoscopic and clinical recurrence of CD following ileocolonic resection. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and recent American gastroenterology association (AGA) meeting abstracts through August 2017. We selected prospective studies comparing anti-TNF agents among each other or to other agents in the setting of postoperative prevention of CD recurrence. We performed a NMA using a frequentist approach with generalized pairwise modeling and inverse variance heterogeneity method. RESULTS: We identified 9 studies, including 571 patients and 5 treatment agents, among which 2 anti-TNF drugs (adalimumab and infliximab). Compared with infliximab, our NMA yielded the following results for endoscopic recurrence: adalimumab [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.18-4.75], thiopurines (OR, 4.11; 95% CI, 0.68-24.78), placebo (OR, 4.39; 95% CI, 0.70-27.68), and Mesalamine (OR, 37.84; 95% CI, 3.77-379.42). For clinical recurrence: adalimumab (OR, 1.03; 95% CI, 0.17-6.03), thiopurines (OR, 1.40; 95% CI, 0.20-10.02), placebo (OR, 1.77; 95% CI, 1.01-3.10), and mesalamine (OR, 16.54; 95% CI, 1.55-176.24). CONCLUSIONS: On the basis of a NMA combining direct and indirect evidence either adalimumab or infliximab may be used in the postoperative prophylaxis of CD recurrence. There is currently a lack of evidence on the use of other anti-TNF agents in this setting.

Delays in Initiating Post-operative Prophylactic Biologic Therapy Are Common Among Crohn's Disease Patients.

BACKGROUND: Studies have shown that prophylactic biologic therapy can reduce post-surgical Crohn's disease recurrence. AIMS: We aimed to identify the frequency of delay and risk factors associated with a delay in the initiation of prophylactic post-surgical biologic therapy in high-risk patients. METHODS: We performed a cohort study of Crohn's disease patients who underwent a bowel resection. We identified those at risk of recurrence and explored multiple characteristics for those with and without a delay post-operatively. RESULTS: A total of 84 patients were included in our analysis of which 69.0% had a greater than 4-week delay and 56.0% a greater than 8-week delay in post-surgical biologic prophylaxis. Publicly insured patients had a 100% delay in post-surgical prophylaxis initiation (p = 0.039, p = 0.003 at 4 and 8 weeks, respectively). Patients on a biologic pre-surgery were less likely to have a delay (p < 0.001) in post-operative prophylaxis. Care at an inflammatory bowel disease (IBD) center was associated with timely therapy when considering a post-operative immunomodulator or biologic strategy. CONCLUSIONS: There are a substantial number of delays in initiating post-operative prophylactic biologic therapy in high-risk patients. Identifying susceptible patients by insurance type or absence of pre-operative therapy can focus future improvement efforts. Additionally, consultation with IBD-specialized providers should be considered in peri-surgical IBD care.

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial. OBJECTIVES: To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD. SEARCH METHODS: We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life. MAIN RESULTS: Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of anti-TNF-α participants (RR 1.13; 95% CI 0.83 to 1.53; 117 participants; 2 studies; I² = 0%; low certainty evidence). Purine analogue participants were more like than 5-ASA participants to have a SAE (RR 3.39, 95% CI 1.26 to 9.13, 311 participants; 3 studies; I² = 9%; very low certainty evidence), or to withdraw due to an AE (RR 2.21, 95% CI 1.28 to 3.81; 425 participants; 5 studies; I² = 0%; low certainty evidence). Commonly reported AEs across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, nasopharyngitis and flatulence. AUTHORS' CONCLUSIONS: Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.

Interventions for maintenance of surgically induced remission in Crohn's disease: a network meta-analysis.

BACKGROUND: Crohn's disease (CD) is a chronic disease of the gut. About 75% of people with CD undergo surgery at least once in their lifetime to induce remission. However, as there is no known cure for the disease, patients usually experience a recurrence even after surgery. Different interventions are routinely used in maintaining postsurgical remission. There is currently no consensus on which treatment is the most effective. OBJECTIVES: To assess the effects and harms of interventions for the maintenance of surgically induced remission in Crohn's disease and rank the treatments in order of effectiveness. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, and Embase from inception to 15 January 2019. We also searched reference lists of relevant articles, abstracts from major gastroenterology meetings, ClinicalTrials.gov, and the WHO ICTRP. There was no restriction on language, date, or publication status. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) that compared different interventions used for maintaining surgically induced remission in people with CD who were in postsurgical remission. Participants had to have received maintenance treatment for at least three months. We excluded studies assessing enteral diet, diet manipulation, herbal medicine, and nutritional supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant studies, extracted data, and assessed the risk of bias. Any disagreements were resolved by discussion or by arbitration of a third review author when necessary. We conducted a network meta-analysis (NMA) using a Bayesian approach through Markov Chain Monte Carlo (MCMC) simulation. For the pairwise comparisons carried out in Review Manager 5, we calculated risk ratios (RR) with their corresponding 95% confidence intervals (95% CI). For the NMA, we presented hazard ratios (HR) with corresponding 95% credible intervals (95% CrI) and reported ranking probabilities for each intervention. For the NMA, we focused on three main outcomes: clinical relapse, endoscopic relapse, and withdrawals due to adverse events. Data were insufficient to assess time to relapse and histologic relapse. Adverse events and serious adverse events were not sufficiently or objectively reported to permit an NMA. We used CINeMA (Confidence in Network Meta-Analysis) methods to evaluate our confidence in the findings within networks, and GRADE for entire networks. MAIN RESULTS: We included 35 RCTs (3249 participants) in the review. The average age of study participants ranged between 33.6 and 38.8 years. Risk of bias was high in 18 studies, low in four studies, and unclear in 13 studies. Of the 35 included RCTs, 26 studies (2581 participants; 9 interventions) were considered eligible for inclusion in the NMA. The interventions studied included 5-aminosalicylic acid (5-ASA), adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogues, sulfasalazine, and a combination of sulfasalazine and prednisolone. This resulted in 30 direct contrasts, which informed 102 mixed-treatment contrasts.The evidence for the clinical relapse network (21 studies; 2245 participants) and endoscopic relapse (12 studies; 1128 participants) were of low certainty while the evidence for withdrawal due to adverse events (15 studies; 1498 participants) was of very low certainty. This assessment was due to high risk of bias in most of the studies, inconsistency, and imprecision across networks. We mainly judged individual contrasts as of low or very low certainty, except 5-ASA versus placebo, the evidence for which was judged as of moderate certainty.We ranked the treatments based on effectiveness and the certainty of the evidence. For clinical relapse, the five most highly ranked treatments were adalimumab, infliximab, budesonide, 5-ASA, and purine analogues. We found some evidence that adalimumab (HR 0.11, 95% Crl 0.02 to 0.33; low-certainty evidence) and 5-ASA may reduce the probability of clinical relapse compared to placebo (HR 0.69, 95% Crl 0.53 to 0.87; moderate-certainty evidence). However, budesonide may not be effective in preventing clinical relapse (HR 0.66, 95% CrI 0.27 to 1.34; low-certainty evidence). We are less confident about the effectiveness of infliximab (HR 0.36, 95% CrI 0.02 to 1.74; very low-certainty evidence) and purine analogues (HR 0.75, 95% CrI 0.55 to 1.00; low-certainty evidence). It was unclear whether the other interventions reduced the probability of a clinical relapse, as the certainty of the evidence was very low.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing endoscopic relapse. Whilst there might be some evidence of prevention of endoscopic relapse with adalimumab (HR 0.10, 95% CrI 0.01 to 0.32; low-certainty evidence), no other intervention studied appeared to be effective.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing withdrawal due to adverse events. Withdrawal due to adverse events appeared to be least likely with sulfasalazine (HR 1.96, 95% Crl 0.00 to 8.90; very low-certainty evidence) and most likely with antibiotics (HR 53.92, 95% Crl 0.43 to 259.80; very low-certainty evidence). When considering the network as a whole, two adverse events leading to study withdrawal (i.e. pancreatitis and leukopenia) occurred in more than 1% of participants treated with an intervention. Pancreatitis occurred in 2.8% (11/399) of purine analogue participants compared to 0.17% (2/1210) of all other groups studied. Leukopenia occurred in 2.5% (10/399) of purine analogue participants compared to 0.08% (1/1210) of all other groups studied. AUTHORS' CONCLUSIONS: Due to low-certainty evidence in the networks, we are unable to draw conclusions on which treatment is most effective for preventing clinical relapse and endoscopic relapse. Evidence on the safety of the interventions was inconclusive, however cases of pancreatitis and leukopenia from purine analogues were evident in the studies. Larger trials are needed to further understand the effect of the interventions on endoscopic relapse.

Thiopurines prevented surgical recurrence in patients with Crohn's disease after intestinal resection: Strategy based on risk stratification.

BACKGROUND AND AIM: Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR. METHODS: This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors. RESULTS: A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001). CONCLUSIONS: Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

Enteral nutrition for maintenance of remission in Crohn's disease.

BACKGROUND: Prevention of relapse is a major issue in the management of quiescent Crohn's disease (CD). Current therapies (e.g. methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant adverse events. Interventions that are effective and safe for maintenance of remission in CD are desirable. OBJECTIVES: The primary objectives were to evaluate the efficacy and safety of enteral nutrition for the maintenance of remission in CD and to assess the impact of formula composition on effectiveness. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to 27 July 2018. We also searched references of retrieved studies and reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) including participants of any age with quiescent CD were considered for inclusion. Studies that compared enteral nutrition with no intervention, placebo or any other intervention were selected for review. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included anthropometric measures (i.e. height and weight), quality of life (QoL), adverse events, serious adverse events and withdrawal due to adverse events. We calculated the risk ratio and 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference and 95% CI. A random-effects model was used for the statistical analysis. We used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes. MAIN RESULTS: Four RCTs (262 adult participants) met the inclusion criteria. One study (N = 33) compared an elemental diet to a non-elemental (polymeric) diet. One study (N = 51) compared a half elemental diet to a regular free diet. Another study (N = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group. One study (N= 83) compared a polymeric diet to mesalamine. Two studies were rated as high risk of bias due to lack of blinding or incomplete outcome data. The other two studies were judged to have an unclear risk of bias. The studies were not pooled due to differences in control interventions and the way outcomes were assessed.The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to adverse events is uncertain. Fifty-eight per cent (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57% (8/14) of participants in the polymeric diet group (RR 1.01, 95% CI 0.56 to 1.84; very low certainty evidence). Thirty-two per cent (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95% CI 0.59 to 159.93; low certainty evidence). Anthropometric measures, QoL, adverse events and serious adverse events were not reported as outcomes.The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates is uncertain. Thirty-five per cent (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64% (16/25) of participants in the free diet group (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). No adverse events were reported. This study reported no differences in weight change between the two diet groups. Height and QoL were not reported as outcomes.The effect of an elemental diet compared to 6-MP on relapse rates or adverse events is uncertain. Thirty-eight per cent (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23% (7/30) of participants in the 6-MP group (RR 1.61; 95% CI 0.73 to 3.53; very low certainty evidence). Three per cent (1/32) of participants in the elemental diet group had an adverse event compared to 13% (4/30) of participants in the 6-MP group (RR 0.23, 95% CI 0.03 to 1.98; low certainty evidence). Adverse events in the elemental diet group included surgery due to worsening CD. Adverse events in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1). No serious adverse events or withdrawals due to adverse events were reported. Weight, height and QoL were not reported as outcomesThe effect of a polymeric diet compared to mesalamine on relapse rates and weight is uncertain. Forty-two per cent (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55% (22/40) of participants in the mesalamine group (RR 0.76; 95% CI 0.49 to 1.19; low certainty evidence). The mean difference in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95% CI -4.62 to 8.42; low certainty evidence). Two participants in the polymeric diet group experienced nausea and four had diarrhoea. It is unclear if any participants in the mesalamine group had an adverse event. Height, QoL, serious adverse events and withdrawal due to adverse events were not reported as outcomes. AUTHORS' CONCLUSIONS: The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.

Impact of Environmental and Familial Factors in a Cohort of Pediatric Patients With Inflammatory Bowel Disease.

OBJECTIVES: The primary role of environment on inflammatory bowel disease (IBD) onset has been recently stressed. We aimed to investigate the effect of environmental factors in an IBD pediatric cohort. METHODS: A total of 467 subjects (264 IBD and 203 controls) were enrolled. All patients underwent a questionnaire including 5 different groups of environmental risk factors: family history of IBD and autoimmune diseases, perinatal period, home amenities and domestic hygiene, childhood diseases and vaccinations, and diet. RESULTS: In a multivariate model, mother's degree (odds ratio [OR]: 5.5; 2.5-11.6), duration of breast feeding >3rd month (OR: 4.3; 1.6-10.5), father's employment (OR: 3.7; 1.2-8.7), gluten introduction <6th month (OR: 2.8; 1.5-5), number of siblings <2 (OR: 2.8; 1.5-5.3), and family history of autoimmune diseases (OR: 2.7; 1.4-5.3) were significant risk factors for Crohn disease. Low adherence to Mediterranean diet (OR: 2.3; 1.2-4.5), gluten introduction <6th month (OR: 2.8; 1.6-4.9), and number of siblings <2 (OR: 2; 1.1-3.6) were significant risk factors for ulcerative colitis. Owning pets (OR: 0.3; 0.1-0.7) and bed sharing (OR: 0.2; 0.1-0.6) were protective factors for Crohn disease, whereas owning pets (OR: 0.4; 0.2-0.8) and family parasitosis (OR: 0.07; 0.01-0.4) were protective factors for ulcerative colitis. CONCLUSIONS: Our study confirms that environmental factors are closely linked to IBD onset and may partly explain IBD rise in developed countries.