Faculty Bibliography

Ulcerative colitis is one of the two main subtypes of inflammatory bowel disease, along with Crohn's disease. Understanding the clinical and endoscopic features of ulcerative colitis is critical in achieving a timely diagnosis. An initial evaluation includes assessing clinical symptoms, inflammatory markers, endoscopic findings, and determination of the presence or absence of extraintestinal manifestations. Initial disease management should consider disease severity at the time of diagnosis as well as prognostication, or the determination of risk factors present with a high likelihood of severe disease in the future. Once appropriate therapy has been initiated, ongoing monitoring is crucial, which may include repeated clinical assessments over time, measuring noninvasive markers of inflammation, and endoscopic and histologic reevaluation. An important aspect of disease monitoring in ulcerative colitis is dysplasia surveillance; there are many patient-specific risk factors which influence surveillance strategies. Utilizing appropriate surveillance techniques is necessary for early detection of dysplasia and colorectal neoplasia.

BACKGROUND/UNASSIGNED:Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity. METHODS/UNASSIGNED:We performed a nationwide study of Swedish women diagnosed with IBD 1990-2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation (1223 and 630 births, respectively). We also examined pregnancy outcomes in 2007-2016 of women with vs. without clinically active IBD (i.e., IBD-related hospitalization, surgery, or medication escalation) <12 months before pregnancy (2110 and 4993 births, respectively). Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth (<37 gestational weeks) and small-for-gestational age (SGA, <10th percentile weight for age). FINDINGS/UNASSIGNED:Of infants to women with vs. without histological inflammation, 9.6% (n = 117) and 6.5% (n = 41) were preterm, respectively (aRR = 1.46; 95%CI = 1.03-2.06). Histological inflammation was associated with preterm birth in ulcerative colitis (UC) (aRR = 1.64; 95%CI = 1.07-2.52), especially extensive colitis (aRR = 2.37; 95%CI = 1.12-5.02), but not in Crohn's disease (aRR = 0.99; 95%CI = 0.55-1.78). Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA (aRR = 1.09; 95%CI = 0.81-1.47). Clinically active disease before pregnancy was linked to preterm birth (aRR = 1.42; 95%CI = 1.20-1.69), but not to SGA birth (aRR = 1.13; 95%CI = 0.96-1.32). Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth (aRR = 1.20; 95%CI = 0.68-2.13). INTERPRETATION/UNASSIGNED:Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity. FUNDING/UNASSIGNED:The Swedish Society of Medicine.

Introduction: Ileocecal resection (ICR) often leads to remission of Crohn's Disease (CD), but relapse is common. Guidelines suggest postoperative biologic prophylaxis in high-risk patients and colonoscopy within 6-12 months of surgery to assess for post-operative recurrence (POR). Guidance on adjunctive disease monitoring modalities such as biomarkers and cross-sectional imaging is lacking. We aimed to describe the real-world surveillance approach for CD patients after ICR in relation to evidence-based guidelines.
Method(s): This was a dual center retrospective study of CD patients who underwent ICR with >=1 year of follow-up. We grouped patients into high- (HR) and low-risk (LR) for POR per guidelines and assessed the use of biomarkers, imaging, and colonoscopy postoperatively. Approaches and recurrence rates in patients who received resection prior to or after 2015, accounting for changing practices with guidelines, were compared. Biomarker, radiographic, and endoscopic POR were defined as high CRP/fecal calprotectin (FC), active inflammation on CT/MRE, and modified Rutgeerts >=i2b, respectively. P-values were calculated using Wilcoxon and Chi squared tests.
Result(s): Of 1026 CD patients who underwent ICR, 798 were HR. For LR patients, median time to first CRP was 244 days (d), FC was 267d, imaging was 579d, and colonoscopy was 392d. For HR patients, median time to first CRP was 183d, FC was 241d, imaging was 460d, and colonoscopy was 352d. 72% of HR patients had at least 1 modality within 1 year compared to 59% of LR. Compared to pre-2015, patients who underwent an ICR in 2015 or later had significantly earlier imaging (543d vs. 379d, p< 0.001) and colonoscopy (404d vs. 292d, p< 0.001). There was no difference in time to first CRP or FC. Timing of ICR was significantly associated with postoperative biologic use and the detection of POR by all methods (p< 0.001).
Conclusion(s): 30% of HR CD patients did not undergo any monitoring within the first year after ICR. Evolving practice patterns suggest earlier disease monitoring with imaging and colonoscopy in more recent years whereas utilization of biomarkers was not changed. These data suggest that while guidelines have changed practice, allowing for the earlier identification of POR and initiation of therapy, many patients remain under-monitored. As earlier monitoring may improve long-term clinical outcomes, additional studies are required to further guide optimal surveillance intervals and use of biomarkers

BACKGROUND & AIMS/OBJECTIVE:Postoperative Crohn's disease (CD) surveillance relies on endoscopic monitoring. The role of cross-sectional imaging is less clear. We evaluated the concordance of cross-sectional enterography with endoscopic recurrence and the predictive ability of radiography for future CD postoperative recurrence. METHODS:We performed a multi-institution retrospective cohort study of postoperative adult patients with CD who underwent ileocolonoscopy and cross-sectional enterography within 90 days of each other following ileocecal resection. Imaging studies were interpreted by blinded, expert CD radiologists. Patients were categorized by presence of endoscopic postoperative recurrence (E+) (modified Rutgeerts' score ≥i2b) or radiographic disease activity (R+) and grouped by concordance status. RESULTS:A total of 216 patients with CD with paired ileocolonoscopy and imaging were included. A majority (54.2%) exhibited concordance (34.7% E+/R+; 19.4% E-/R-) between studies. The plurality (41.7%; n = 90) were E-/R+ discordant. Imaging was highly sensitive (89.3%), with low specificity (31.8%), in detecting endoscopic postoperative recurrence. Intestinal wall thickening, luminal narrowing, mural hyper-enhancement, and length of disease on imaging were associated with endoscopic recurrence (all P < .01). Radiographic disease severity was associated with increasing Rutgeerts' score (P < .001). E-/R+ patients experienced more rapid subsequent endoscopic recurrence (hazard ratio, 4.16; P = .033) and increased rates of subsequent endoscopic (43.8% vs 22.7%) and surgical recurrence (20% vs 9.5%) than E-/R- patients (median follow-up, 4.5 years). CONCLUSIONS:Cross-sectional imaging is highly sensitive, but poorly specific, in detecting endoscopic disease activity and postoperative recurrence. Advanced radiographic disease correlates with endoscopic severity. Patients with radiographic activity in the absence of endoscopic recurrence may be at increased risk for future recurrence, and closer monitoring should be considered.

Introduction: As the inflammatory bowel disease (IBD) patient population ages, there will be an increasing number of individuals requiring advanced therapies. Although older age is thought to be associated with immunosenescence, there are data suggesting that older adults may be at higher risk for antibody development as the result of biologic use.
Method(s): Using a large commercial laboratory database (Prometheus Laboratories), we extracted infliximab (IFX) dosing as well as antibody to infliximab (ATI) levels for all individuals using this assay from 2015-2021. Our primary outcome was the presence of ATI (titer >3.1 U/mL). Frequencies were recorded as categorical variables with chi-square analysis used, and multivariable logistic regression was employed to assess the impact of IFX dose, age (< 60 years-old v. >=60 years-old), and IBD subtype on the development of ATI.
Result(s): Overall, there were 22,197 unique specimens, with 3,028 (13.6%) having ATI. When stratified by age, individuals >=60 years-old developed ATI 18.1% (473/2,612) of the time as compared to 15.0% (2,555/17,030) for individuals < 60 years of age (p< 0.01, Figure). Among all individuals with IFX dose < 10mg q8 weeks, older adults (>=60 years of age) were more likely to develop ATI as compared to younger adults (22.8% vs. 16.2%, respectively, p< 0.01); however, when IFX dose was >=10mg/kg q8 weeks, age >= 60 years-old was no longer significantly associated with the development of ATI (9.9% if < 60 years-old vs. 10.6% if >=60 years-old) on univariable analysis. Overall, older adults were less likely to receive IFX doses >=10mg/kg q8 weeks (38.4% in older adults vs. 49.7% in younger adults; p< 0.01). On multivariable analysis, age >=60 years-old (adjOR 1.35, 95%CI 1.20-1.51), IFX dose >= 10mg/kg q8 weeks (adjOR 0.53, 95%CI 0.49-0.57) and having ulcerative colitis as compared to Crohn's disease (adjOR 1.44, 95%CI 1.33-1.57) were independently associated with the development of ATI.
Conclusion(s): Older adults with IBD develop ATI more frequently than younger adults when adjusting for IFX dose and IBD subtype. However, when IFX dose >=10mg/kg q8 weeks, ATI was significantly less likely to develop among older adults, and occurred in a similar proportion of younger individuals. Further education is needed, highlighting that older adults with IBD are more likely to develop ATI as compared to younger adults, particularly when using lower doses of IFX, and that higher doses may decrease this likelihood. (Figure Presented)

Introduction: Infliximab (IFX) has been efficacious in reducing colectomy rates among patients with moderate-to severe ulcerative colitis, but predictors of colectomy within 30 days of IFX among patients with acute severe ulcerative colitis (ASUC) are less established.
Method(s): We performed a single-center retrospective analysis of patients who received at least one dose of IFX while admitted between 2011-2022. We assessed demographic, clinical and laboratory predictors of colectomy within 30 days of first IFX dose. Multivariable and time-to-event analysis using Kaplan-Meier with log-rank statistics were used to assess risk factors for colectomy within 30 days.
Result(s): A majority of the 172 patients hospitalized with ASUC who received IFX received 10 mg/kg (87.79%). Overall, 22/172 patients (12.79%) underwent colectomy within 30 days of first IFX dose. On univariable analysis, age, sex, race, ethnicity, BMI and smoking status were not associated with risk of colectomy. Higher initial CRP was significantly associated with 30-day risk of colectomy (106.17 vs. 65.10 mg/dL among patients who did not undergo colectomy; p< 0.01), as was a decrease of CRP <=50% prior to discharge (p< 0.01). Lower initial albumin [< 3 (36.36%), 3.0-3.5 (40.91%), >3.5 g/dL (22.73%)] was associated with our primary outcome (p=0.046), as was a higher number of bowel movements in a 24-hour period prior to discharge (5.6 vs. 3.9 among patients who did not undergo colectomy; p=0.0256). On multivariable analysis, higher initial CRP (aOR 1.01, 95% CI 1.00 - 1.02), <=50% change in CRP after first dose of IFX (aOR 9.00, 95% CI 2.43 - 33.29) and higher number of bowel movements in a 24-hour period prior to discharge (aOR 1.24, 95% CI 1.01- 1.52) remained significantly associated with risk of colectomy when adjusting for relevant covariables (Table). On Kaplan-Meier analysis, initial CRP >100 mg/ dL, albumin < 3 g/dL and change in CRP <=50% prior to discharge were significantly associated with decreased time to colectomy (Figure).
Conclusion(s): Among patients with ASUC, higher CRP, decrease of CRP <=50% and higher number of bowel movements prior to discharge were associated with increased risk of colectomy within 30-days of receiving IFX. Initial CRP >100 mg/dL, albumin < 3 g/dL and decrease of <=50% in CRP prior to discharge were associated with decreased time to colectomy. These results can identify patients at highest risk and impact clinical decision-making regarding need for and timing of colectomy in patients with ASUC receiving IFX. (Table Presented)

Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease^1-7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium^8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.

Introduction: Obesity is associated with an increased risk of colorectal neoplasia, but this relationship has not been studied in patients with inflammatory bowel disease (IBD). Both IBD and obesity induce a chronic inflammatory state, so the combination of the two could have an additive or synergistic effect on risk of colorectal neoplasia. Given the increased baseline incidence of dysplasia among IBD patients, identifying modifiable risk factors, such as obesity, could have a significant impact on long term cancer-related outcomes.
Method(s): We performed a retrospective case-control study of IBD colitis patients at an academic IBD Center between January 2006 and February 2022. Demographic and disease-related data, known risk factors for dysplasia, and median BMI during the follow-up period were obtained. Only patients with at least 5 years of colonoscopy reports were included. A case was defined as any patient with biopsy proven dysplasia-indefinite, low-grade, or high-grade-during the study period. A control was defined as any patient with absence of biopsy-proven dysplasia. Obesity was defined as BMI of 30 or greater. Univariate analysis was performed using T-test for continuous variables and chi-square for categorical variables. Multivariate analysis was performed using logistic regression to model dysplasia risk.
Result(s): 106 cases had biopsy-proven colorectal dysplasia (64 IND, 36 LGD, 10 HGD); 125 controls had no dysplasia. Number of colonoscopies (p < 0.001) IBD subtype ulcerative colitis (p = 0.016), maximum histologic severity (p = 0.127), pseudopolyps (p = 0.162), IBD duration (p = 0.098), sex (p = 0.18), age (p < 0.001), smoking history (p = 0.048), prior dysplasia (p < 0.001), and obesity (p < 0.001) were associated with dysplasia on univariate analysis. On multivariable regression, number of colonoscopies (OR 1.26, 95% CI 1.08 - 1.48, p = 0.004), prior dysplasia (OR 3.98, 95% CI 1.23 - 12.86, p = 0.021), and obesity (OR 2.90, 95% CI 1.21 - 6.95, p = 0.017) were each independently associated with increased dysplasia risk. (Figure)
Conclusion(s): Patients with IBD have an increased risk of colorectal neoplasia, but a variety of comorbid states may exacerbate this risk. Notably, we identified obesity as an independent risk factor for dysplasia. Further research is needed to determine whether this risk functions synergistically with IBD or just as an independent risk factor. Furthermore, targeted weight-loss interventions may reduce the incidence of dysplasia among patients with IBD. (Table Presented)

Introduction: Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections leading to prolonged hospitalization and significant morbidity. Only a few prior studies have developed predictive risk models for CDI and all but one have utilized logistic regression (LR) models to identify risk factors. Automated machine learning (AutoML) programs consistently outperform standard LR models in non-medical contexts. This study aims to investigate the utility of AutoML methods in developing a model for post-operative CDI prediction.
Method(s): We used an AutoML system developed by Amazon, Autogluon v0.3.1, to evaluate the prediction accuracy of post-surgical CDI using the 2016-2018 ACS NSQIP database. A total of A total of 3,049,617 patients and 79 pre-operative features were included in the model. Post-operative CDI was defined as CDI within 30 days of surgery. Models were trained for 4 hours to optimize performance on the Brier score, with lower being better. Validation of all performance metrics was done using the 2019 NSQIP database.
Result(s): 0.36% of the patients (n = 11,001) developed post-operative CDI. Brier scores were calculated for each model with the top performing model being an ensembled neural net model having a Brier score of 0.0027 on the test set. The corresponding AUROC and AUC-PR was 0.840 and 0.015 respectively (Figure).
Conclusion(s): The models generated via AutoML to predict post-operative CDI had discriminatory characteristics greater than or equal to those models reported in the literature. Future post-operative CDI models may benefit from automated machine learning techniques

Introduction: Inflammatory bowel disease (IBD), comprised of Ulcerative Colitis (UC) and Crohn's Disease (CD), is caused by a combination of environmental factors, immune dysregulation, and genetic susceptibility. Other immune-mediated phenomena, like hypothyroidism, have also been observed in this population. Thus, we sought to explore clinical characteristics and outcomes among IBD patients with hypothyroidism compared to IBD patients without hypothyroidism.
Method(s): In a retrospective chart review from a large, tertiary, academic medical center, baseline demographics and clinical data were extracted for patients diagnosed with either UC or CD and having at least one thyroid stimulating hormone (TSH) measurement from prior to 2016. Based on the presence of a documented hypothyroidism ICD-10 code, patients were then divided into two groups, those with IBD alone and those with both IBD and hypothyroidism, as described in Figure. Individual charts were then further examined for disease characteristics, biomarkers, healthcare utilization, medication use, and other comorbidities from 2016 to 2022. Demographic and clinical variables were then compared between the two groups, as seen in Table.
Result(s): We identified 166 adult IBD patients (CD 53%, UC 47%). The mean age was 62.9 years. Among these patients, 116 patients (69.9%) had IBD and hypothyroidism. The most common causes of hypothyroidism were Hashimoto, subclinical, and acquired hypothyroidism. No differences were noted in race, smoking status, or BMI. IBD disease location, behavior, and prevalence of extra-intestinal manifestations did not significantly differ between the two study groups. Both groups had similar number of colonoscopies, hospitalizations, as well as comparable medication use (SSRI/SNRI, steroids, 5-ASA, immunomodulators, biologics). However, patients with IBD and hypothyroidism had higher rates of anemia (p=0.03), hypoalbuminemia (p=0.007), and CRP elevations (p=0.002). Furthermore, patients with both IBD and hypothyroidism had a greater median number of emergency department visits (p=0.039) and axial radiography (p=0.002).
Conclusion(s): IBD patients with hypothyroidism experience a more severe disease course with higher biomarkers of inflammation and healthcare utilization than those without hypothyroidism despite similar IBD phenotype and therapy exposures. This highlights a potential subgroup of IBD patients who may be at risk for increased disease severity and associated poor outcomes. (Table Presented)