Faculty Bibliography

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.

INTRODUCTION/BACKGROUND:Following ileocolic resection (ICR), the clinical importance and prognostic implications of histologic activity on biopsies in Crohn's disease (CD) patients with endoscopic remission are not well defined. The aim of this study was to determine if histologic activity in patients with endoscopic remission is associated with future risk of endoscopic and/or radiologic postoperative recurrence (POR). METHODS:In this multicenter retrospective cohort study, adult patients with CD who underwent ICR between 2009 and 2020 with endoscopic biopsies of ileal mucosa from Rutgeerts i0 on index colonoscopy were included. The composite rate of endoscopic (Rutgeerts score ≥i2b) and radiologic (active inflammation on imaging) recurrence was compared in patients with and without histologic activity using a Kaplan-Meier survival analysis. A multivariable Cox proportional hazard regression model including clinically relevant risk factors of POR, postoperative biologic prophylaxis, and histology activity was designed. RESULTS:A total of 113 patients with i0 disease on index colonoscopy after ICR were included. Of these, 42% had histologic activity. Time to POR was significantly earlier in the histologically active versus normal group ( P = 0.04). After adjusting for clinical risk factors of POR, histologic activity (HR 2.37, 95% CI 1.17-4.79; P = 0.02) and active smoking (HR 2.54, 95% CI 1.02-6.33; P = 0.05) were independently associated with subsequent composite POR risk. DISCUSSION/CONCLUSIONS:In patients with postoperative CD, histologic activity despite complete endoscopic remission is associated with composite, endoscopic, and radiographic recurrence. Further understanding of the role of histologic activity in patients with Rutgeerts i0 disease may provide a novel target to reduce disease recurrence in this population.

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.

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.

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: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/UNASSIGNED:Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn's disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of <50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR). METHODS/UNASSIGNED:-test and Fisher's exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS/UNASSIGNED: = .005). Median time to first endoscopic recurrence in FC ≥ 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively. CONCLUSIONS/UNASSIGNED:In this real-world cohort, FC < 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence.

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.

Effective immunity requires a large, diverse naive T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization were required to prevent this proapoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naive T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.

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.