Faculty Bibliography

BACKGROUND:Chronic intestinal inflammation is a well-established driver of colorectal dysplasia in inflammatory bowel disease (IBD). However, the role of metabolic factors such as obesity remains poorly understood. We evaluated whether chronic obesity, measured using five-year longitudinal body mass index (BMI), is independently associated with colorectal dysplasia in patients with IBD. METHODS:using all outpatient measurements over a five-year period prior to the index colonoscopy. Multivariable conditional logistic regression was used to evaluate the association between obesity and dysplasia, adjusting for established dysplasia risk factors and surveillance-related variables. RESULTS:A total of 312 patients were included (156 dysplasia cases and 156 matched controls). Dysplasia cases had significantly longer IBD duration compared with controls (median 12.1 vs. 8.0 years, p < 0.01) and were more likely to have a history of prior colorectal dysplasia (16.0% vs. 3.8%, p < 0.01). In multivariable analysis, obesity was independently associated with colorectal dysplasia (adjusted odds ratio [aOR] 2.23, 95% CI 1.08-4.57). Longer disease duration (aOR 1.05 per year, 95% CI 1.02-1.08) and prior dysplasia (aOR 4.88, 95% CI 1.69-14.06) were also independently associated with dysplasia. In a secondary model adjusting for additional surveillance-related and structural colonic factors, obesity remained significantly associated with dysplasia (aOR 2.11, 95% CI 1.05-4.24). CONCLUSIONS:Obesity is independently associated with colorectal dysplasia in patients with IBD, suggesting that metabolic factors contribute to neoplastic risk beyond traditional inflammation-driven pathways. Incorporation of metabolic risk into dysplasia risk stratification may improve CRC prevention strategies in IBD.

GOAL/OBJECTIVE:To investigate the safety of corticosteroid escalation before antimicrobial treatment among inflammatory bowel disease (IBD) flares associated with an enteric infection. BACKGROUND:Corticosteroids are often necessary to treat individuals with IBD; however, there is concern that immunosuppression in the setting of a gastrointestinal infection may worsen outcomes. METHODS:We conducted a retrospective study of adults (18 y or older) hospitalized for an IBD flare (2015 to 2023) who received both systemic corticosteroids and antimicrobials for a gastrointestinal infection. The primary outcome was a composite of in-hospital death, IBD-related surgery, need for intensive care unit, toxic megacolon, or acute kidney injury, stratified by timing of corticosteroid escalation (before vs. after antimicrobial initiation). Outcomes at 90 days were also collected in a secondary analysis. RESULTS:Overall, 76 individuals were included; 48 (63.2%) had ulcerative colitis. The most common infection was Clostridioides difficile (n=50; 65.8%), and the majority of patients (n=51, 67.1%) received corticosteroid initiation (or escalation) before antimicrobials. There was no significant difference in the development of the primary (9.8% vs. 8.0%, P=1.00) or secondary (29.4% vs. 32.0%, P=0.82) outcome based on corticosteroid initiation before versus after antimicrobial initiation. Among patients with C. difficile, similar results were seen. CONCLUSIONS:Among patients hospitalized with an IBD flare complicated by enteric infection, initiation or escalation of corticosteroids before antimicrobial therapy did not increase the risk of in-hospital or 90-day adverse events. This study supports the notion that corticosteroids can be safely utilized while awaiting the results of the gastrointestinal infectious testing.

BACKGROUND/UNASSIGNED:Proposed treatment algorithms favor the use of upadacitinib in medically refractory Crohn's disease (CD) and ulcerative colitis (UC). There has not yet been data published regarding efficacy of prolonged induction in CD or the efficacy of re-escalation to induction dosing in patients with either CD or UC. The aim of this study was to evaluate the real-world efficacy and safety of prolonged and/or re-escalation upadacitinib therapy in patients with inflammatory bowel disease (IBD) and prior inadequate response to standard upadacitinib treatment. METHODS/UNASSIGNED:This was a retrospective, dual-center study of the efficacy of prolonged induction or re-escalation of upadacitinib in patients with IBD with prior inadequate response to standard upadacitinib treatment. RESULTS/UNASSIGNED:Fifty-five patients met eligibility criteria. Thirty-nine (70.9%) persisted on upadacitinib therapy while 16 (29.1%) met the primary endpoint for upadacitinib failure. Of those that had comparative objective data, 62.5% had improvement in endoscopic activity, 100% had normalization of an elevated CRP, and 83.3% experienced a decrease in FCP by >50%. There were no new safety signals. CONCLUSION/UNASSIGNED:Over two-thirds of patients met the primary endpoint of persistence on therapy without requiring surgery, steroids, or additional biologic/small molecule inhibitor during follow-up. In a subset of patients who had adequate baseline and follow up objective data, the majority of patients had improvement in mucosal healing, decrease by 50% in FCP, and normalization of CRP. This study shows promising results that prolonged upadacitinib induction or dose re-escalation may improve clinical outcomes in a medically refractory patient population.

INTRODUCTION/BACKGROUND:Fecal microbiota, live-jslm (RBL) is the first single-dose, microbiota-based product approved by the US Food and Drug Administration and Health Canada to prevent recurrent Clostridioides difficile infection (rCDI) following standard-of-care antibiotics. The phase 3 PUNCH CD3-OLS study enrolled participants with numerous comorbidities and permitted inclusion of participants hospitalized due to rCDI. The safety and efficacy of RBL were evaluated in this subgroup analysis of hospitalized participants from PUNCH CD3-OLS. METHODS:The hospitalization subgroup included participants hospitalized for rCDI within 90 days prior to RBL administration. Participants received a single dose of RBL 24-72 h after completion of standard-of-care antibiotic treatment for rCDI. These exploratory analyses evaluated the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs), treatment success at 8 weeks, sustained clinical response at 6 months, and incidence of rehospitalization for rCDI during study participation. RESULTS:The hospitalization subgroup included 74 of 697 (10.6%) participants. Within 6 months following RBL administration, 47 (63.5%) and 350 (56.7%) participants in the hospitalization and nonhospitalization subgroups experienced TEAEs, respectively; most TEAEs were of mild to moderate severity. Serious TEAEs in the hospitalization subgroup were frequently related to preexisting conditions; none were related to RBL or its administration. Most participants (87.8% [65/74]) in the hospitalization subgroup were not rehospitalized within 6 months. Treatment success at 8 weeks was 62.5% (45/72) and 75.1% (449/598) among participants in the hospitalization and nonhospitalization subgroups, respectively. Of those achieving treatment success, 86.7% (39/45) and 91.3% (410/449) had sustained clinical response through 6 months in the hospitalization and nonhospitalization subgroups, respectively. CONCLUSION/CONCLUSIONS:RBL was safe and effective in a subgroup of hospitalized participants in the PUNCH CD3-OLS study. Efficacy in this subgroup was slightly lower than in nonhospitalized participants, but rCDI-related rehospitalization remained rare. TRIAL REGISTRATION/BACKGROUND:NCT03931941.

BACKGROUND:The benefits of achieving endoscopic remission among older adults with inflammatory bowel disease (IBD) who have mild persistent disease activity are unknown. METHODS:This was a retrospective study of adults ≥ 60 with IBD who had mild or no disease activity on endoscopy from January 1, 2018-January 1, 2023. The primary outcome was a composite of major IBD-specific adverse events (hospitalizations, surgery, and prescription of corticosteroids for IBD-related symptoms) within 1 year of endoscopic assessment. Our secondary outcome was a composite of 1-year morbidity-related events (mortality, all-cause hospitalization, infection requiring antibiotics, venous thromboembolism, cardiovascular events, and osteoporotic fractures). We also assessed outcomes at 5 years. RESULTS:Among 504 patients, 192 (38.1%) had mild endoscopic disease and 312 (61.9%) were in endoscopic remission, with a median disease duration of 11 years. On multivariable analysis, mild endoscopic disease activity increased the odds of a 1-year adverse IBD-specific outcome (aOR 4.16, 95% CI 2.10-8.24), with similar results at 5 years. Furthermore, mild endoscopic disease was associated with increased odds of experiencing an adverse morbidity-related outcome within 1 year as compared to endoscopic remission (aOR 1.56, 95% CI 1.01-2.43). CONCLUSIONS:Among older adults with prevalent IBD, mild endoscopic disease activity, as compared to endoscopic remission, was associated with increased odds of adverse IBD-specific and morbidity-related outcomes at 1 year, with this risk persisting for IBD-specific outcomes at 5 years. These findings highlight the importance of achieving endoscopic remission, which may confer both short- and longer-term benefits in this population.

BACKGROUND:Surgery in select individuals with inflammatory bowel disease (IBD) may obviate the need for future IBD-related treatment. AIMS/OBJECTIVE:To characterise individuals who remain treatment-free during the first 5 years after initial IBD-related surgery. METHODS:We performed a nationwide cohort study using the Swedish National Patient Register and the ESPRESSO histopathology to identify individuals undergoing first IBD-related intestinal resection for Crohn's disease (CD) or total colectomy for ulcerative colitis (UC) between 2007 and 2018. We calculated adjusted odds ratios (aORs) for the need for any IBD-related therapy within the first 5 years post surgery. RESULTS:We included 1709 individuals with CD and 1010 with UC. At 5 years, 21.5% with CD and 42.4% with UC remained 'treatment free'. Being 'treatment free' 5 years after surgery was more common among patients with CD who had longer preoperative disease duration and older adults with UC. It was less common among individuals with extraintestinal manifestations of disease (CD aOR 0.64, 95% CI 0.43-0.97; UC aOR 0.48, 95% CI 0.31-0.73) and patients with CD who had chronic obstructive pulmonary disease. CONCLUSIONS:Surgery obviated the need for future therapy in 22% of patients with CD and 42% with UC. Absence of extraintestinal manifestations, older age in UC, and longer disease duration and absence of chronic obstructive pulmonary disease in CD may highlight an opportunity for precision surgery to identify those most likely to achieve long-term benefit from surgical intervention.

BACKGROUND:Individuals with inflammatory bowel disease (IBD) have an elevated risk of colorectal neoplasia (CRN), including colorectal dysplasia and cancer (CRC). Despite surveillance strategies to prevent CRC, the clinical course of dysplasia types remains poorly understood. METHODS:We conducted a nationwide cohort study using the Swedish Patient Register and the ESPRESSO histopathology cohort to identify patients diagnosed with IBD between 1969 and 2023. Patients were classified according to their first (baseline) incident episode of dysplasia (no dysplasia, ND; indefinite, IND; low-grade, LGD; high-grade, HGD). Our primary outcome was future advanced CRN (HGD or CRC) during follow-up. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were estimated using Cox regression. RESULTS:We identified 54,534 patients with IBD, including 1,320 with a first (baseline) episode of dysplasia (264 IND, 1031 LGD, 25 HGD), and 53,214 with ND. Over a median follow-up of 13.3 years, 2.3% of ND patients had future advanced CRN compared to 5.3% of IND patients (aHR 1.85, 95% CI 1.09-3.15) and 8.3% of LGD patients (aHR 3.51, 95% CI 2.77-4.45). Of those with HGD, 40% developed CRC (aHR 47.88, 95% CI 25.53-89.80). Risk factors for future dysplasia included male sex, younger age at diagnosis, extensive colitis, primary sclerosing cholangitis, and histologic inflammation. CONCLUSION/CONCLUSIONS:Patients with IBD and dysplasia have a significantly increased risk of future dysplasia, particularly among patients with HGD. Personalized surveillance strategies based on risk factors are critical for preventing advanced CRN.

Recent developments in organoid technology have enabled the creation of patient-derived intestinal organoids (PDIOs) that recapitulate the structural, functional, genetic, and epigenetic features of their original tissues. However, conventional passage-derived organoids inevitably yield heterogeneous populations in size and number, leading to inconsistent results even under identical conditions. To address this, a standardized approach, referred to here as "single cell-seeded PDIOs," was established. In this method, mature PDIOs were enzymatically dissociated into single cells and seeded at a defined number into individual wells of a 96-well plate. This controlled seeding normalized the size and number of PDIOs. Compared with passage-derived organoids, single cell-seeded PDIOs displayed reduced inter-well variability in organoid numbers and intra-well variability in organoid sizes, which enables the determination of generation efficiency and improves the reproducibility of viability assays. Moreover, this platform is compatible with downstream analysis, including transcriptomic analysis and protein expression profiling. Collectively, this approach may enhance experimental consistency and provide a practical foundation for reproducible PDIO-based studies.

BACKGROUND:We aimed to assess the risk of serious infections in patients with inflammatory bowel disease (IBD) exposed to different advanced therapies. METHODS:We linked nationwide registers and compared rates of incident serious infections in patients with Crohn's disease (CD) and ulcerative colitis (UC) exposed to medical therapies versus matched general population comparators during 2007 to 2023. We 1:1 propensity score-matched individuals with IBD to compare infection risk across therapies. RESULTS:We identified 55,866 patients with IBD naïve to immunomodulators (IMM) and advanced therapies, 20,392 exposed to IMM, 15,973 to anti-TNF, 9035 to IMM with anti-TNF, 3948 to vedolizumab, 2926 to ustekinumab, 659 to tofacitinib, 987 to upadacitinib, 262 to filgotinib, and 163 to risankizumab with 987,366 matched comparators with up to 18 years of follow-up. Compared to the general population [incidence rate range 0.39-1.13 per 100 person-years (PY)], patients with IBD had a higher incidence of serious infections [naïve 2.31 per 100 PY; adjusted hazard ratio (aHR) 1.89, 95% Confidence Interval (CI) 1.84-1.94], IMM 3.27 per 100 PY (aHR 4.45 95% CI 4.24-4.66), advanced therapies range 3.14-8.10 per 100 PY (aHRs range 3.45-10.55, 95% CI range 3.04-26.65). Relative risks were elevated in the pediatric population, and for opportunistic and gastrointestinal infections. No differences in infection rates were observed in propensity score-matched comparisons of different advanced therapies. CONCLUSION/CONCLUSIONS:Patients with IBD were at an increased risk of infections, even among those naïve to IMM and advanced therapies. There was no significant difference in risk of infections across advanced therapy exposures.