Faculty Bibliography

BACKGROUND:Patients with inflammatory bowel disease (IBD) experience increased rates of sexual dysfunction (SD). This study investigated SD longitudinally in patients initiating a biologic or small molecule therapy. METHODS:Patients with Crohn's disease (CD) or ulcerative colitis (UC) starting biologic or small molecule therapy were surveyed at induction, 2 months, and 6 months. Measures included the IBD-Female and Male Sexual Dysfunction Scales (FSDS, MSDS), PROMIS Sexual Function and Satisfaction Brief Profile, Harvey Bradshaw Index (HBI), Simple Clinical Colitis Activity Index (SCCAI), partial Mayo score, Short IBD Questionnaire (SIBDQ), PHQ-9, and IBD Disability Index (IBDDI). Endoscopic and biomarker data were collected. Correlations, longitudinal changes, and predictors of SD were analyzed. RESULTS:A total of 170 patients (89 males, 81 females) completed baseline surveys, 132 at 2 months, and 115 at 6 months. Median age was 31.5 years; 59% had CD. At baseline, median HBI was 5.5, SCCAI 6, and pMayo 4. SD scores correlated with clinical disease activity (p < 0.05) but not consistently with endoscopic or biomarker measures. SD was associated with impaired quality of life, depression, and disability (p < 0.05). Among responders to therapy, SD, SIBDQ, and IBDDI significantly improved (p < 0.05). Multivariate analysis showed that more severe clinical disease activity predicted worse SD, while time after therapy initiation and improved quality of life were independently associated with better SD. CONCLUSIONS:Advanced therapy can improve SD in IBD. Improvements appear to be mediated by reductions in clinical disease activity and psychosocial factors.

Current therapies for inflammatory bowel disease (IBD) often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects. To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton's jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3⁺ regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.

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.

BACKGROUND:In patients with inflammatory bowel disease (IBD), social determinants of health contribute to health inequalities. We aimed to compare patients with IBD treated at a private nonprofit vs public hospital in New York City. METHODS:We performed a retrospective study of adult patients with Crohn's disease or ulcerative colitis with established IBD care. Patient demographics, disease characteristics, healthcare utilization, treatment modalities, and clinical outcomes were collected. Using a series of linear mixed and logistic models, the differences between care at a private nonprofit vs public hospital were assessed while controlling for factors that differed between them. RESULTS:Our study included 418 patients with IBD, 209 from each hospital. Compared with public hospital patients, private hospital patients were more likely to be White, be non-Hispanic, and have private insurance (all P = .0005) and less likely to face housing instability (P < .0001), face unemployment (P = .0004), be current smokers (P = .03), or be foreign born (P < .0001). Patients at the private hospital were more likely to have multiple anti-tumor necrosis factor (P = .0001) and biologic use (P < .0001). Public hospital patients were less likely to be considered endoscopically adherent (odds ratio [OR], 0.377; P = .001) and more likely to visit the emergency department (OR, 5.01; P < .0001) and be hospitalized (OR, 1.92; P = .05). CONCLUSIONS:Our study is the first to identify significant differences in patient demographics, disease phenotype, treatments and clinical outcomes between patients treated for IBD at a private nonprofit vs public hospital. Our data suggest that social determinants of health drive disparities in the utilization of healthcare facilities.

BACKGROUND:Infliximab (IFX) is commonly used in the management of acute severe ulcerative colitis (ASUC), yet up to 30% of individuals still require colectomy within 1 year. Clinical data characterizing these patients, however, are limited. AIMS/OBJECTIVE:We aimed to determine risk factors for colectomy among patients with ASUC who received in-hospital IFX treatment. METHODS:We performed a retrospective analysis of patients with ASUC who were treated with at least one dose of IFX while admitted between 2014 and 2022. Cox proportional hazards (PH) models were used to assess demographic, clinical, and laboratory risk factors for colectomy within 30 days and 1 year of IFX initiation. RESULTS:Overall, 36/170 (21.2%) patients underwent colectomy within 1 year of IFX initiation, with 22 (12.9%) individuals requiring colectomy within 30 days. On univariable analysis, concomitant Clostridioides difficile infection during admission, a ≤50% decrease in C-reactive protein (CRP) and experiencing 3 or more bowel movements per day within 48 hours after an initial IFX dose were significantly associated with 1-year colectomy. On multivariable Cox PH analysis, C. difficile infection during admission (aHR=2.92, 95% CI: 1.12-7.58) and a higher CRP/albumin ratio on admission (aHR=1.13, 95% CI: 1.01-1.27) were associated with increased colectomy risk within 1 year of IFX initiation. CONCLUSIONS:C. difficile infection and a higher CRP/albumin ratio on admission are associated with decreased time to colectomy within 1 year of IFX among patients presenting with ASUC. These factors may aid in early risk stratification to minimize delays in JAK-inhibitor initiation or surgical referral.

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: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.

INTRODUCTION/BACKGROUND:It is uncertain whether the risk of major congenital anomalies (mCAs) is increased in children of women with inflammatory bowel disease (IBD). METHODS:We aimed to determine the risk of mCAs in a Swedish nationwide cohort of 13,131 singleton live births from 1997 to 2020 to women with IBD and 61,909 matched children to women without IBD from the general population. We additionally examined mCAs according to periconceptional histological inflammation (vs remission: 1,124 and 646 births, respectively) or clinically active IBD (vs quiescent: 3,380 and 6,603 births, respectively). Adjusted risk ratios (aRRs) for overall and organ-specific mCAs were estimated using generalized linear models. These models adjusted for maternal sociodemographics, comorbidities, body mass index, and smoking. RESULTS:There were 38.0 (n = 499) mCAs per 1,000 births to women with IBD vs 33.9 (n = 2,101) in matched comparators and a risk difference of 1 extra mCA per 246 births to women with IBD (aRR 1.11; 95% confidence interval [CI] 1.01-1.23). Risks of heart defects and mCAs of the urinary system partly drove estimates. The risk of mCAs was similar in children of women with ulcerative colitis and Crohn's disease. Periconceptional histological inflammation (vs remission) or clinically active (vs quiescent) IBD did not further influence the risk of mCA in the child (aRR 0.87 [95% CI 0.55-1.40] and aRR 1.04 [95% CI 0.85-1.27], respectively). DISCUSSION/CONCLUSIONS:Children of women with IBD had a heightened susceptibility to mCAs, although absolute and relative risks were lower than previously reported. IBD activity was not linked to mCA risks, but those analyses included relatively few events.

BACKGROUND AND AIMS/OBJECTIVE:PredictSURE IBD is a prognostic blood test that classifies newly diagnosed, treatment-naïve Inflammatory Bowel Disease (IBD) patients into 'IBDhi' (high-risk) or 'IBDlo' (low-risk) groups (risk of future aggressive disease). We evaluated this assay in a multinational cohort and explored the effect of concomitant corticosteroids on its discrimination. METHODS:One hundred thirty-six (71 Ulcerative colitis [UC], 65 Crohn's Disease [CD]) and 41 (15 UC, 26 CD) patients with active IBD were 'unexposed' and 'exposed', respectively, to corticosteroids at baseline blood sampling. The number of treatment escalations, time to first escalation, and need for repeated escalations were compared between the biomarker subgroups. Another 20 patients (13 UC, 7 CD) were longitudinally sampled over 6 weeks after commencing corticosteroids. RESULTS:In corticosteroids-naïve UC and CD patients, all bowel surgeries (n = 6) and multiple therapy escalations (n = 10) occurred in IBDhi patients. IBDhi UC patients required significantly more treatment escalations, had a shorter time to first escalation, and a greater need for multiple escalations than IBDlo patients. No statistically significant differences were observed among CD patients. In corticosteroid-exposed patients, 66.6% of 'misclassifications' were IBDlo patients who required escalations. Among corticosteroid-treated patients with longitudinal sampling, 81.3% of those classified as IBDhi before steroids switched to IBDlo during therapy. CONCLUSIONS:No significant differences in treatment escalations were observed between biomarker-defined subgroups in CD. However, IBDhi UC patients required significantly earlier and more frequent therapy escalations, highlighting the need to further investigate PredictSURE IBD in UC. Notably, the discrimination ability of the biomarker was unreliable in patients receiving corticosteroid therapy.