Summary Background Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to ...identify the optimal strategy to prevent postoperative disease recurrence. Methods In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00989560. Findings Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio OR 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 82% of 122 vs 45 87% of 52; p=0·51) and (33 27% of 122 vs 18 35% of 52; p=0·36), respectively. Interpretation Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. Funding AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.
Background & Aims Little is known about in utero exposure to and postnatal clearance of anti–tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and ...infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. Methods We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. Results The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval CI, 0.94–1.49) and 1.97 for infliximab (95% CI, 1.50–2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9–5.0) and 7.3 months for infliximab (95% CI, 6.2–8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09–6.78; P = .02). Conclusions In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.
IMPORTANCE: High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool ...processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity. OBJECTIVE: To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool. DESIGN, SETTING, AND PARTICIPANTS: A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017. INTERVENTIONS: Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months. MAIN OUTCOMES AND MEASURES: The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. RESULTS: Among 73 patients who were randomized (mean age, 39 years; women, 33 45%), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% 95% CI, 4%-42%; odds ratio, 5.0 95% CI, 1.2-20.1; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group. CONCLUSIONS AND RELEVANCE: In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12613000236796
INTRODUCTIONPoor sleep quality has been associated with inflammatory bowel disease (IBD) activity, although studies incorporating actigraphy suggest that the perception of sleep differs rather than ...objective difference in sleep quality. Short sleep duration has been associated with increased pro-inflammatory cytokines that have been implicated in the pathogenesis of IBD.METHODSAn observational study incorporated home-based polysomnography that was conducted within twelve weeks of an objective assessment of IBD activity such as calprotectin, colonoscopy, or MRI. Participants completed a survey on subjective measures of sleep quality, clinical IBD activity, depression, and anxiety. Polysomnography results were normalized by standardized results for a healthy population matched by gender and age.RESULTSTwenty participants were included in the final analysis. Those with objective evidence of active IBD had shorter stage 2 sleep duration, leading to shorter NREM sleep and total sleep time. Sleep latency was also longer in those with active IBD, leading to worse sleep efficiency-despite no difference in time available for sleep between the two groups. These changes persisted after normalization of polysomnography results by health population age and gender matched norms. Depression scores correlated with sleep latency and stage 2 sleep duration and were associated with objectively active IBD.CONCLUSIONSObjectively confirmed active IBD was associated with shorter sleep duration. Observed sleep changes may, in part, relate to coexistent depression. Further research should consider the utility of changes in sleep duration and quality as a means of longitudinally assessing objective IBD activity.
Abstract
The gut microbiome has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Studies suggest that the IBD gut microbiome is less diverse than that of the unaffected ...population, a phenomenon often referred to as dysbiosis. However, these studies have heavily focused on bacteria, while other intestinal microorganisms—fungi, protozoa, and bacteriophages—have been neglected. Of the nonbacterial microbes that have been studied in relation to IBD, most are thought to be pathogens, although there is evidence that some of these species may instead be harmless commensals. In this review, we discuss the nonbacterial gut microbiome of IBD, highlighting the current biases, limitations, and outstanding questions that can be addressed with high-throughput DNA sequencing methods. Further, we highlight the importance of studying nonbacterial microorganisms alongside bacteria for a comprehensive view of the whole IBD biome and to provide a more precise definition of dysbiosis in patients. With the rise in popularity of microbiome-altering therapies for the treatment of IBD, such as fecal microbiota transplantation, it is important that we address these knowledge gaps to ensure safe and effective treatment of patients.
Lay Summary
Fungi, protozoa, and bacteriophages are often neglected in gut microbiome research of inflammatory bowel disease. Here, we review what is currently known of these microbes in inflammatory bowel disease and how they can be studied using high-throughput DNA sequencing methods.
Background & Aims Crohn’s disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated ...whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa. Methods We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn’s disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn’s disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients. Results Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 μg/g before surgery to 166 μg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 μg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 μg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 μg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 μg/g at 6 months to 180 μg/g at 12 months and 109 μg/g at 18 months. Conclusions In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.
Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in ...patients with moderately to severely active Crohn’s disease with inadequate response or intolerance to conventional or biologic therapy.
GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn’s Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm.
Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn’s Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups.
At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. ClinicalTrials.gov, Number: NCT03466411.
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Guselkumab, an anti-interleukin-23, induced clinically meaningful improvements vs placebo at week 12 in patients with moderately to severely active Crohn’s disease with an inadequate response to, or intolerance to, conventional/biologic therapies.
Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. ...Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci ( NOD2, MHC , and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78 ), even after exclusion of NOD2, MHC , and 3p21 (p=9·23 × 10−18 ). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4 ). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
Summary
Access to bariatric surgery is limited, and the factors related to undergoing or not undergoing the procedure are poorly understood.
To this end, a systematic review of PubMed, Embase, ...PsycINFO, and CINAHL was conducted to deduce the factors associated with progression or non‐progression to bariatric surgery. Quantitative and qualitative English‐language articles ranging in date from database conception to September 2023 were included. Eligible studies employed adult participants (18 years of age or above) who had been referred for bariatric surgery.
A total of 57 studies were identified. Fifteen key factors were found, alongside six less frequently studied factors: age, sex, BMI, race and ethnicity, distance to clinic, socio‐economic status, insurance coverage, physical health, psychological health, eating history and habits, substance use and smoking, social influence and relationships, pre‐surgery process and requirements, surgery‐related concerns, choice of surgery, and others (emergency room visitation, COVID‐19 virus, health literacy, appearance perceptions, time‐off work, and stigma related to surgery).
No factors were found to be reliably associated with progression or non‐progression to bariatric surgery; however, the nature of these findings is tentative considering methodological flaws and limited research. Further studies are required to elucidate potential inequities in bariatric surgery access and educate policymakers and health professionals.
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