Sleep Characteristics and Rest-Activity Rhythms Are Associated with Gastrointestinal Symptoms Among Adults with Inflammatory Bowel Disease.

BACKGROUND: Sleep disturbance is common in inflammatory bowel disease (IBD) and is associated with poorer quality of life and increased disease activity; however, sleep is a multidimensional process, and little is known about specific sleep characteristics and rest-activity rhythms (RARs) in this population. AIMS: The purposes were to (1) describe sleep characteristics and RARs; (2) compare sleep characteristics and RARs and GI symptoms by disease activity; and (3) describe associations between sleep characteristics, RARs, and GI symptoms among adults with IBD. METHODS: We conducted a cross-sectional study of adults with IBD. We measured sleep characteristics and RARs (continuous wrist actigraphy); GI symptoms (PROMIS-GI); and disease activity (physicians' global assessment). We conducted cosinor and nonparametric analyses to compute RAR variables and bivariate analyses to address the aims. RESULTS: The sample included 37 participants [age M = 38 years (SD = 13.8) and 21 (56.8%) female], of whom 23 (60.6%) were in remission. Sleep efficiency [M = 82.91% (SD 5.35)] and wake after sleep onset (WASO) [M = 42.26 min (SD 18.57)] were not associated with disease activity. Inter-daily stability of the RAR was associated with heartburn/reflux (r = - .491, p = .005) and gas/bloating (r = - .469, p = .008). Intra-daily variability of the RAR was associated with heartburn/reflux (r = .421, p = .018). CONCLUSIONS: People with IBD may have disrupted RARs, which are associated with GI symptoms. Research is needed to improve understanding of these associations and to develop interventions to improve these characteristics in adults with IBD.

JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages.

JAK2 genetic variants are associated with inflammatory bowel disease (IBD) and JAK inhibitors are being evaluated for therapy targeting immune-mediated diseases, including IBD. As JAK pathway-mediated cytokine regulation varies across cell types and stimulation conditions, we examined how JAK signaling and IBD-associated JAK2 variants regulate distinct acute and chronic microbial product exposure outcomes in human myeloid cells, consistent with the conditions of initial entry and ongoing intestinal tissue residence, respectively. Macrophages from controls and ulcerative colitis patients carrying the IBD-risk rs10758669 CC genotype showed increased JAK2 expression and nucleotide-binding oligomerization domain 2-induced JAK2 phosphorylation relative to AA carriers. Interestingly, the threshold of JAK2 expression and signaling determined pattern-recognition receptor (PRR)-induced outcomes; whereas anti-inflammatory cytokines progressively decreased with lower JAK2 expression, proinflammatory cytokines switched from decreased to increased secretion below a certain JAK2 expression threshold. Low JAK2-expressing rs10758669 AA macrophages were above this threshold; consequently, both PRR-induced pro- and anti-inflammatory cytokines were decreased. However, relative to rs10758669 CC risk carriers, AA carrier macrophages switched to increased nucleotide-binding oligomerization domain 2-induced proinflammatory cytokines at lower therapeutically used JAK inhibitor doses. Importantly, JAK inhibitors increased proinflammatory cytokines secreted by peripheral macrophages following chronic PRR stimulation and by human intestinal myeloid cells following exposure to intestinal pathogens. Mechanistically, the decreased response to and secretion of autocrine/paracrine IL-10, IL-4, IL-22 and thymic stromal lymphopoietin regulated these JAK-dependent outcomes in myeloid cells. Taken together, the JAK signaling threshold determines whether PRR-induced pro- and anti-inflammatory cytokines are reciprocally regulated in myeloid cells; consideration of JAK2 genotype and targeting of specific cell types might improve JAK-targeted therapy in immune-mediated diseases.

Knowledge Gaps in the Management of Postoperative Crohn's Disease: A US National Survey.

BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated. CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.

Longitudinal Changes in Symptom Cluster Membership in Inflammatory Bowel Disease.

PURPOSE: To describe changes in symptom cluster membership over 1 year and to examine which demographic and clinical factors predict changes in symptom cluster membership among adults with inflammatory bowel disease. DESIGN: A retrospective longitudinal study of the Crohn's & Colitis Foundation of America Partners Cohort from 2012 to 2015. METHODS: We measured symptoms of pain interference, fatigue, sleep disturbance, depression, and anxiety. We used latent transition analysis to describe changes in symptom cluster membership (baseline, 6 months, and 12 months) and multinomial regressions to examine factors associated with symptom cluster membership transition. FINDINGS: Four groups were identified (N = 5,296): high symptom burden (32.3%-35.3%), low symptom burden (24.2%-27.1%), physical symptoms (19.0%-20.9%; pain, fatigue, sleep disturbance), and psychological symptoms (20.0%-21.5%; depression, anxiety). The probability of staying in the same group was .814 to .905. Moving from active disease into remission was associated with moving from the high burden to low burden and psychological symptom groups. CONCLUSIONS: Symptom cluster membership was quite stable over 1 year. Research is needed to understand the underlying etiology of symptom clusters better and to develop interventions to reduce symptom burden in this vulnerable population. CLINICAL RELEVANCE: Careful consideration of symptom management options should be done with patients to select options that are effective and potentially target multiple symptoms.

Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis.

OBJECTIVES: Early appendectomy is inversely associated with the development of UC. However, the impact of appendectomy on the clinical course of UC is controversial, generally favouring a milder disease course. We aim to describe the effect appendectomy has on the disease course of UC with focus on the timing of appendectomy in relation to UC diagnosis. DESIGN: Using the National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium database of patients with UC, the risk of colectomy was compared between patients who did and did not undergo appendectomy. In addition, we performed a meta-analysis of studies that examined the association between appendectomy and colectomy. RESULTS: 2980 patients with UC were initially included. 111 (4.4%) patients with UC had an appendectomy; of which 63 were performed prior to UC diagnosis and 48 after diagnosis. In multivariable analysis, appendectomy performed at any time was an independent risk factor for colectomy (OR 1.9, 95% CI 1.1 to 3.1), with appendectomy performed after UC diagnosis most strongly associated with colectomy (OR 2.2, 95% CI 1.1 to 4.5). An updated meta-analysis showed appendectomy performed either prior to or after UC diagnosis had no effect on colectomy rates. CONCLUSIONS: Appendectomy performed at any time in relation to UC diagnosis was not associated with a decrease in severity of disease. In fact, appendectomy after UC diagnosis may be associated with a higher risk of colectomy. These findings question the proposed use of appendectomy as treatment for UC.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Symptom clusters in adults with inflammatory bowel disease.

Symptoms (pain, fatigue, sleep disturbance, depression, and anxiety) in inflammatory bowel disease (IBD) are associated with reduced quality of life. Understanding how IBD symptoms cluster and the clinical and demographic factors associated with symptom clusters will enable focused development of symptom management interventions. The study purposes were to (i) identify symptom cluster membership among adults with IBD and (ii) examine associations between demographic (age, gender, race/ethnicity, and education) and clinical factors (smoking status, time since diagnosis, medication type, IBD type, disease activity), and membership in specific symptom cluster groups. We conducted a retrospective study of data from the Crohn's and Colitis Foundation of America's (CCFA) Partners Cohort and used Patient Reported Outcome Measurement Information System (PROMIS) measures to measure pain interference, fatigue, sleep disturbance, anxiety, and depression. The sample included 5,296 participants with IBD (mean age 44, 72% female). In latent class analysis (LCA), four groups of participants were identified based on symptoms: "low symptom burden" (26% of sample), "high symptom burden" (38%), "physical symptoms" (22%), and "psychological symptoms" (14%). In multinomial regression, female gender, smoking, corticosteroids, Crohn's disease, and active disease state were associated with membership in the high symptom burden group. Additional research is needed to test interventions that may be effective at reducing symptom burden for individuals with IBD.

Global Health Education in Gastroenterology Fellowship: A National Survey.

BACKGROUND: Interest in global health (GH) education is increasing across disciplines. AIMS: To assess exposure to and perception of GH training among gastroenterology fellows and program directors across the USA. METHODS: Design: Electronic survey study. SETTING: The questionnaire was circulated to accredited US gastroenterology fellowship programs, with the assistance of the American Gastroenterological Association. PARTICIPANTS: Gastroenterology program directors and fellows. RESULTS: The questionnaire was returned by 127 respondents (47 program directors, 78 fellows) from 55 training programs (36 % of all training programs). 61 % of respondents had prior experience in GH. 17 % of programs offered GH curriculum with international elective (13 %), didactic (9 %), and research activity (7 %) being the most common. Fellows had adequate experience managing hepatitis B (93 %), cholangiocarcinoma (84 %), and intrahepatic duct stones (84 %). 74, 69 and 68 % reported having little to no experience managing hepatitis E, tuberculosis mesenteritis, or epidemic infectious enteritis, respectively. Most fellows would participate in an elective in an underserved area locally (81 %) or a 4-week elective abroad (71 %), if available. 44 % of fellows planned on working or volunteering abroad after fellowship. Barriers to establishing GH curriculum included funding (94 %), scheduling (88 %), and a lack of standardized objectives (78 %). Lack of interest, however, was not a concern. Fellows (49 %), more than faculty (29 %) (χ 2 = 21.9; p = 0.03), believed that GH education should be included in fellowship curriculum. CONCLUSIONS: Program directors and trainees recognize the importance of GH education. However, only 17 % of ACGME-approved fellowship programs offer the opportunity. Global health curriculum may enhance gastroenterology training.

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Longer Colonoscopy Withdrawal Time Is Associated With the Detection of Visible Dysplasia in Patients With Inflammatory Bowel Disease.

Background: Colonoscopy withdrawal time (CWT) of at least 6-9 minutes is the minimum time needed for adequate adenoma detection in the general population. The ideal CWT in patients with inflammatory bowel disease (IBD) has not been determined. We aimed to identify the optimal CWT associated with the detection of visible dysplasia in patients with IBD. Methods: This is a retrospective study from 1/1/2017 to 9/1/2022 of adult patients with IBD in endoscopic healing undergoing surveillance via high-definition white light colonoscopy. The primary outcome was the association of CWT with visible dysplasia detection. Results: A total of 259 patients (mean age 56 ±â€…14.8 years; 51.3% female, 68% with ulcerative colitis; 8.9% with primary sclerosing cholangitis) underwent 330 colonoscopies. Patients with visible dysplasia were more likely to be older (P < .001) and have a personal history of visible dysplasia (P < .001) and invisible dysplasia (P = .023). The mean CWT was significantly longer in the visible dysplasia group at 26 minutes (interquartile range [IQR] 20-38.5) vs. 21 minutes (IQR 15-28) in procedures without visible dysplasia (P < .001). On multivariable analysis, increased age (P < .001), increased CWT (P = .001), and personal history of visible dysplasia (P = .013) were independently associated with the detection of visible dysplasia. A CWT of ≥15 minutes (odds ratio [OR] 2.71; 95% confidence interval [CI], 1.11-6.6; P = .02] and not ≥9 minutes (OR 2.57; 95% CI, 0.33-20.2; P = .35) is significantly associated with detection of visible dysplasia. Conclusions: For patients with IBD undergoing surveillance via high-definition white light colonoscopy, the mean CWT was independently associated with the detection of visible dysplasia.

Relationship between proximal Crohn's disease location and disease behavior and surgery: a cross-sectional study of the IBD Genetics Consortium.

OBJECTIVES: In classifying Crohn's disease (CD) location, proximal (L4) disease includes esophagogastroduodenal (EGD) and jejunal disease. Our aim was to determine the influence of proximal disease on outcomes of behavior and need for surgery and to determine if there was significant clinical heterogeneity between EGD and jejunal disease. METHODS: We performed a cross-sectional query of the NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) Inflammatory Bowel Disease Genetics Consortium (IBDGC) database of patients with a confirmed diagnosis of CD and phenotyped per the IBDGC manual. Presence of any L4, L4-EGD, L4-jejunal, and non-L4 disease (L1-ileal, L2-colonic, and L3-ileocolonic) was compared with demographic features including age, race, ethnicity, smoking and inflammatory bowel disease (IBD) family history, diagnosis age, disease duration, clinical outcomes of inflammatory, stricturing or penetrating behavior, and CD abdominal surgeries. Univariate and multivariable analyses were performed with R. RESULTS: Among 2,105 patients with complete disease location data, 346 had L4 disease (175 L4-EGD, 115 L4-jejunal, and 56 EGD and jejunal) with 321 having concurrent L1-L3 disease. In all, 1,759 had only L1-L3 disease. L4 vs. non-L4 patients were more likely (P<0.001) to be younger at diagnosis, non-smokers, have coexisting ileal involvement, and have stricturing disease. L4-jejunal vs. L4-EGD patients were at least twice as likely (P<0.001) to have had ileal disease, stricturing behavior, and any or multiple abdominal surgeries. Remarkably, L4-jejunal patients had more (P<0.001) stricturing behavior and multiple abdominal surgeries than non-L4 ileal disease patients. Logistic regression showed stricturing risks were ileal (without proximal) site (odds ratio (OR) 3.18; 95% confidence interval 2.23-4.64), longer disease duration (OR 1.33/decade; 1.19-1.49), jejunal site (OR 2.90; 1.89-4.45), and older age at diagnosis (OR 1.21/decade; 1.10-1.34). Multiple surgery risks were disease duration (OR 3.74/decade; 3.05-4.64), penetrating disease (OR 2.60; 1.64-4.21), and jejunal site (OR 2.39; 1.36-4.20), with short duration from diagnosis to first surgery protective (OR 0.87/decade to first surgery; 0.84-0.90). CONCLUSIONS: Jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either EGD or ileal (without proximal) disease. The Montreal site classification should be revised to include separate designations for jejunal and EGD disease.

EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn's disease activity: role of cross-sectional imaging.

OBJECTIVES: In Crohn's disease (CD), clinical symptoms correspond poorly to inflammatory disease activity. Biomarkers reflective of mucosal and bowel wall inflammation would be useful to monitor disease activity. The EMBARK study evaluated disease activity in patients with ulcerative colitis (UC) and CD, and used endoscopy with or without cross-sectional imaging for biomarker discovery. METHODS: UC (n=107) and CD (n=157) patients were characterized and underwent ileocolonoscopy (ICO). A subset of CD patients (n=66) also underwent computed tomography enterography (CTE). ICO and CTE were scored by a gastroenterologist and radiologist who incorporated findings of inflammation into a single score (ICO-CTE) for patients that underwent both procedures. Serum and fecal biomarkers were evaluated for association with the Mayo Clinic endoscopy score in UC patients and with ICO alone or ICO-CTE in CD patients. Individual biomarkers with a moderate degree of correlation (P≤0.3) were evaluated using multivariate analysis with model selection using a stepwise procedure. RESULTS: In UC, ordinal logistic regression using Mayo Clinic endoscopy subscore selected the combination of fecal calprotectin and serum matrix metalloproteinase 9 (MMP9; pseudo R(2)=0.353). In CD, we found that use of the ICO-CTE increased specificity of known biomarkers. Using ICO-CTE as the dependent variable for biomarker discovery, the selected biomarkers were the combination of fecal calprotectin, serum MMP9, and serum IL-22 (r=0.699). CONCLUSIONS: Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.

Impact of thiopurine dose in anti-tumor necrosis factor combination therapy on outcomes in inflammatory bowel disease.

Background: Combination therapy with thiopurines and anti-tumor necrosis factor (TNF) is superior to monotherapy in Crohn's disease (CD) and ulcerative colitis (UC). The optimal dose of thiopurines in combination therapy remains unclear. We investigated the impact of thiopurine dose in combination therapy on outcomes in inflammatory bowel disease (IBD). Methods: This was a single-center, retrospective study of patients with IBD treated with thiopurine and anti-TNF combination therapy between 1/2012 and 11/2020. A therapeutic dose of thiopurines was defined as ≥1 mg/kg for 6-mercaptopurine and ≥2 mg/kg for azathioprine. The primary outcome was anti-drug antibody (ADA) formation in patients on a therapeutic thiopurine dose vs. a lower thiopurine dose group. Secondary outcomes included steroid-free clinical remission, endoscopic healing (absence of ulcers/erosions in CD and Mayo endoscopic score ≤1 for UC), and normal serum C-reactive protein (CRP) in patients who were on combination therapy. Results: A total of 108 patients were included (median age 31.5 years; 58.3% male). A therapeutic dose of thiopurine was used in 19%. In the therapeutic thiopurine dose group, 23.8% developed ADA vs. 29.9% (P=0.58) in the lower dose group. No significant differences were noted between the therapeutic and lower dose thiopurine groups in terms of steroid-free clinical remission (57.1% vs. 60.9%, P=0.75), endoscopic healing (55% vs. 60%, P=0.69), and normal CRP (52.4% vs. 52.9%, P=0.27). Conclusion: In our cohort of patients with IBD on anti-TNF combination therapy, thiopurine dose was not associated with significant differences in anti-TNF immunogenicity and clinical outcomes.

Early Flexible Sigmoidoscopy Improves Clinical Outcomes in Acute Severe Ulcerative Colitis.

Objectives: Guidelines recommend performing a flexible sigmoidoscopy in patients hospitalized with acute severe ulcerative colitis (ASUC). However, it is unclear if time to sigmoidoscopy affects relevant clinical outcomes. We aimed to assess the impact of early sigmoidoscopy on clinical outcomes using a well-characterized cohort of patients with ASUC. Methods: This is a single-center, retrospective study of all patients hospitalized with ASUC from January 1, 2012 to November 1, 2021. Early sigmoidoscopy was defined as occurring within 72 hours of admission while delayed sigmoidoscopy was defined as occurring >72 hours after admission. Primary outcomes were cumulative days of intravenous (IV) corticosteroid (CS) use, length of hospital stay, and colectomy rates. Secondary outcomes were time to infliximab (IFX) rescue and inpatient opioid medication use. Results: A total of 112 patients hospitalized with ASUC who underwent sigmoidoscopy were included in the analysis. Eighty-seven patients (78%) had early sigmoidoscopy and 25 (22%) had delayed sigmoidoscopy. Patients in the early sigmoidoscopy group were exposed to significantly fewer days of IV CS (4.5 vs 9.2 days; P < .001), had shorter hospital stays (6.4 vs 19.3 days; P < .001), and shorter time to IFX rescue (3.5 vs 6.4 days; P = .004). Rates of colectomy in the early and delayed sigmoidoscopy groups were 17% versus 28%, respectively (P = .23). Longer time to sigmoidoscopy was associated with a 16% increased risk of colectomy (HR = 1.16, P = .002). Conclusions: In this well-characterized cohort, early sigmoidoscopy in ASUC was associated with favorable clinical outcomes. These findings highlight the benefits of early sigmoidoscopy in patients with ASUC. Larger prospective studies are needed to corroborate these findings.