Faculty Bibliography

BACKGROUND:Individuals with inflammatory bowel disease (IBD) are at increased risk of fracture. It is unclear if this risk varies by recent histological activity. AIMS/OBJECTIVE:To determine the fracture risk in IBD during periods with and without histological inflammation. METHODS:We studied a nationwide cohort of 54,591 individuals diagnosed with IBD in 1990-2016 with longitudinal data on ileo-colorectal biopsies. Fractures were identified by inpatient and hospital-based outpatient diagnoses. We derived Cox regression estimated hazard ratios (HRs) for fracture during 12 months following a histological inflammation (vs. histological remission) record after adjusting for socio-demographics, comorbidities, IBD duration, IBD-related surgery and hospitalization. We adjusted sensitivity analyses for medical IBD treatment including corticosteroids. RESULTS:Mean age of patients was 44.0 (SD = 18.3) and 45.5 (SD = 17.1) years at biopsy with histological inflammation and remission, respectively. For histological inflammation, there were 1.37 (95% CI 1.29-1.46) fractures per 100 years' follow-up versus 1.31 (95% CI 1.19-1.44) for remission (adjusted [a]HR 1.12; 95% CI 1.00-1.26; p = 0.04). HRs were similar with histological inflammation of Crohn's disease (1.11; 95% CI 0.91-1.36) and ulcerative colitis (1.18; 95% CI 1.02-1.36). Estimates were consistent across age groups. An overall small excess risk of any fracture remained after accounting for corticosteroids. A more prominently raised fracture risk was observed in corticosteroid-naïve IBD patients with histological inflammation versus histological remission (aHR 1.41; 95% CI 1.07-1.85). The aHR of hip fracture following histological inflammation was 1.29 (95% CI 0.87-1.92). CONCLUSIONS:Histological inflammation in IBD predicted a small increase in short-term fracture risk. Measures to reduce disease activity may reduce fracture risk in IBD.

BACKGROUND:Outcomes of inflammatory bowel disease (IBD) following flare complicated by enteric infection (EI) are limited by follow-up duration and insufficient assessment of the role of non-Clostridioides difficile pathogens. We compared 2-year IBD outcomes following flare with and without EI. METHODS:We performed a retrospective cohort study of adults evaluated with stool PCR testing for IBD flare. Subjects were stratified by presence of EI at flare and were matched for age, sex, and date to those without EI. The primary outcome was a composite of steroid-dependent IBD, colectomy, and/or IBD therapy class change/dose escalation at 2 years. Additional analyses were performed by dividing the EI group into C. difficile infection (CDI) and non-CDI EI, and further subdividing non-CDI EI into E. coli subtypes and other non-CDI EI. RESULTS:We identified 137 matched subjects, of whom 62 (45%) had EI (40 [29%] CDI; 17 [12%] E. coli). Enteric infection at flare was independently associated with the primary outcome (adjusted odds ratio, 4.14; 95% confidence interval [CI], 1.62-11.5). After dividing EI into CDI and non-CDI EI, only CDI at flare was independently associated with the primary outcome (adjusted odds ratio, 4.04; 95% CI, 1.46-12.6). After separating E. coli subtypes from non-CDI EI, E. coli infection and CDI at flare were both independently associated with the primary outcome; other EI was not. CONCLUSIONS:Enteric infection at flare-specifically with CDI-is associated with worse IBD outcomes at 2 years. The relationship between E. coli subtypes at flare and subsequent IBD outcomes requires further investigation.

Fecal microbiota transplantation (FMT) prevents recurrent C. difficile infections (rCDI) in IBD. Patients. Bezlotoxumab is also indicated to prevent rCDI. We assess the impact of FMT in combination with bezlotoxumab in patients with IBD and rCDI. We conducted a multicenter randomized placebo-controlled trial. All received a single colonoscopic FMT. Patients were randomized 1:1 to receive bezlotoxumab or placebo. Sixty-one patients were enrolled (30 received treatment and 31 placebo. Overall, 5 participants (8%) experienced a CDI recurrence; 4 in the treatment arm, 1 in placebo (13% vs 3%, p=0.15). There was no clear benefit to the combination approach compared to FMT alone.

DESCRIPTION/METHODS:The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) Commentary is to discuss the risks of various malignancies in patients with inflammatory bowel diseases (IBD) and the impact of the available medical therapies on these risks. The CPU will also guide the approach to the patient with IBD who develops a malignancy or the patient with a history of cancer in terms of IBD medication management. METHODS:This CPU was commissioned and approved by the AGA Institute CPU committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This communication incorporates important and recently published studies in the field, and it reflects the experiences of the authors who are experts in the diagnosis and management of IBD.

The inflammatory bowel diseases (IBDs), comprising Crohn’s disease and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract. Individuals with IBD are at an increased risk of developing intestinal neoplasia, particularly colorectal neoplasia (CRN) (including colorectal dysplasia and colorectal cancer [CRC]), as a consequence of chronic colonic inflammation.^– Given that CRC in patients with IBD appears to be preceded by dysplastic changes in the colonic mucosa, prevention strategies to reduce CRC-associated morbidity and mortality have been recommended by multiple society guidelines and independent consensus groups, and include risk assessment, mitigation of inflammation with medical therapies, and screening and surveillance strategies with colonoscopy, with histopathologic assessments at appropriate intervals. Despite these efforts, prevention and management of neoplasia in IBD remains a complex and often confusing topic, requiring careful reappraisal of the evolving evidence base and practicable approaches to clinical practice.

BACKGROUND & AIMS/OBJECTIVE:Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histological disease activity. METHODS:Nationwide IBD cohort of Swedish women aged 15-44 years. We examined fertility rates during periods with vs. without histological inflammation (n=21,046; follow-up: 1990-2016) and during periods with vs. without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n=24,995; follow-up: 2006-2020). Accounting for socio-demographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live-births conceived during 12-month-periods of histological inflammation (vs. histological remission) and 3-month-periods of clinically active IBD (vs. quiescent IBD). RESULTS:During periods with vs. without histological inflammation, there were 6.35 (95%CI=5.98-6.73) and 7.09 (95%CI=6.48-7.70) live-births conceived per 100 person-years of follow-up, respectively, or one fewer child per fourteen women with 10 years of histological inflammation (aFRR=0.90; 95%CI=0.81-1.00). In women with histological inflammation fertility was similarly reduced in ulcerative colitis (UC, aFRR=0.89 [95%CI=0.78-1.02]) and Crohn's disease (CD, aFRR=0.86 [95%CI=0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95%CI=0.72-0.79) or one fewer child per six women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR=0.75 [95%CI=0.70-0.81]) and CD (aFRR=0.76 [95%CI=0.70-0.82]). Finally, also among women with clinically quiescent IBD, histological inflammation (vs. histological remission) was associated with reduced fertility (aFRR=0.85 [95%CI=0.73-0.98]). CONCLUSIONS:An association between histological and clinical activity and reduced female fertility in CD and UC was found. Notably, histological inflammation was linked to reduced fertility also in women with clinically quiescent IBD.

BACKGROUND & AIMS/OBJECTIVE: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.

BACKGROUND & AIMS/OBJECTIVE:Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear. METHODS:This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses. RESULTS:With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61). CONCLUSIONS:Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01).

BACKGROUND:Inflammatory bowel disease is a chronic, relapsing, and remitting inflammatory disorder that despite advances in medical therapy often requires hospitalization for treatment of acute flares with intravenous corticosteroids. Many patients will not respond to corticosteroids and require infliximab or cyclosporine as rescue therapy. If medical therapy fails, definitive surgical management is required. Recently, Janus Kinase inhibitors, including upadacitinib, have been proposed as an alternative rescue therapy. AIMS/OBJECTIVE:We hypothesized that upadacitinib may be effective in treating acute severe colitis. METHODS:A retrospective review of 12 inflammatory bowel disease patients admitted for acute severe colitis who received upadacitinib induction therapy was performed. The rates of surgery, repeat or prolonged steroid use, and re-admission within 90 days of index hospitalization were measured. The need for re-induction with upadacitinib, change in medical therapy, rates of clinical remission, change in 6-point partial Mayo score, and laboratory markers of inflammation were measured as secondary outcomes. RESULTS:Five patients met the primary composite endpoint including four patients requiring surgery and one additional patient being unable to withdraw steroids within 90 days of hospital discharge. One patient required re-induction with upadacitinib within 90 days and no patients required change in medical therapy within 90 days. Most patients who did not undergo surgery were in clinical remission within 90 days and showed clinical improvement with decreased 6-point partial Mayo scores. CONCLUSION/CONCLUSIONS:Upadacitinib may be effective salvage therapy for acute severe colitis, but larger controlled trials are required to validate these results.