Faculty Bibliography

OBJECTIVE:We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS:This study utilized a retrospective, multicenter, multinational, consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remission were assessed using time-to-event and clinical predictors were assessed by multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS:A total of 1113 patients (51.8% female, 90% prior anti-TNF exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remission at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naïve patients achieved significantly higher rates of clinical and endoscopic remission at 63% and 55%, respectively. On multivariable analyses, prior anti-TNF (HR, 0.72; 95% CI, 0.49-0.99) and vedolizumab exposure (HR, 0.65; 95% CI, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77/102 (75%) underwent dose optimization, and 44/77 (57%) achieved clinical response. An additional 152/681 (22.3%) patients were dose optimized as a result of primary non- or incomplete response to UST, of whom 40.1% (61/152) responded. Serious infections occurred in 3.4% of patients, while other non-infectious adverse events [lymphoma (n=1), arthralgia (n=6), rash (n=6), headache (n=3), hepatitis (n=3), hair loss (n=3), neuropathy (n=1), and vasculitis (n=1)] occurred in 2.4% of patients. CONCLUSIONS:UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in bio-naive patients, and dose escalation may recapture clinical response.

BACKGROUND:Postoperative recurrence (POR) of Crohn's disease (CD) is common after surgical resection. We aimed to compare biologic type and timing for preventing POR in adult CD patients after ileocecal resection (ICR). METHODS:We performed a retrospective cohort study of CD patients who underwent an ICR at 2 medical centers. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum) and stratified by type and timing of postoperative prophylactic biologic within 12 weeks following an ICR (none, tumor necrosis factor antagonists [anti-TNF], vedolizumab, and ustekinumab). RESULTS:We identified 1037 patients with CD who underwent an ICR. Of 278 (26%) who received postoperative prophylaxis, 80% were placed on an anti-TNF agent (n = 223) followed by ustekinumab (n = 28, 10%) and vedolizumab (n = 27, 10%). Prophylaxis was initiated in 35% within 4 weeks following an ICR and in 65% within 4 to 12 weeks. After adjusting for factors associated with POR, compared with no biologic prophylaxis, the initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61; 95% CI, 0.40-0.93). Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis. CONCLUSION/CONCLUSIONS:Early initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR. Vedolizumab or ustekinumab, at any time following surgery, was not associated with a reduction in POR, although sample size was limited.

BACKGROUND:Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Using a novel electronic reporting tool, we aimed to prospectively describe the onset of tofacitinib efficacy during induction therapy in a real-world study. METHODS:Patient-reported outcome data (PROs) including the simple clinical colitis activity index (SCCAI), PRO Measurement Identification Systems (PROMIS) measures, and adverse events were collected daily for the first 14 days and at day 28 and 56. Paired t tests and P for trend were utilized to compare changes in SCCAI over time. Bivariate analyses and logistic regression models were performed to describe response (SCCAI <5) and remission (SCCAI ≤2) by clinical factors. RESULTS:Of all included patients (n = 96), 67% had failed ≥2 biologics, and 61.5% were on concomitant steroids. Starting at day 3, PROs showed significant and persistent decline of the mean SCCAI (-1.1, P < 000.1) including significantly lower SCCAI subscores for stool frequency (-0.3; P < .003), bleeding (-0.3; P < .0002) and urgency (-0.2; P < .001). Steroid-free remission at day 14, 28, and 56 was achieved in 25%, 30.2%, and 29.2% of patients, respectively. Neither prior biologics nor endoscopic severity were independently predictive of response or remission in multivariate models. Numeric improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through day 56. Rates of discontinuation due to adverse events were low. CONCLUSIONS:In this prospective real-world study, tofacitinib resulted in a rapid and persistent improvement in UC disease activity PROs. The safety findings were consistent with the established safety profile of tofacitinib.

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: The phase 3 True North (TN) study demonstrated the efficacy and safety of oral ozanimod (OZA) 0.92 mg once daily (equivalent to OZA HCl 1 mg) in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) study is exploring longer-term efficacy and safety of OZA in UC. This interim analysis of the TN OLE evaluated the efficacy and safety of OZA in pts who received 98 weeks of continuous OZA treatment.
Method(s): Pts in clinical response (CRS) after 52weeks of continuous OZAduringTNwho rolled over into theOLE were included (data cutoff: September 30, 2020). Nearly 73% of pts had completed OLEWeek 46 (Week 98 of continuous OZA therapy) at the time of data cutoff when outcomes were measured. Endoscopy was performed annually throughout the OLE and was scored by Mayo endoscopic score. Efficacy data (Clinical Remission [CRM], CRS, Endoscopic Improvement [EI], and Corticosteroid-Free Remission [CFR]) were analyzed using observed cases (OC) and nonresponder imputation (NRI). Safety data were also recorded.
Result(s): Of 131 total pts in CRS at TNWeek 52, 83 (63%) were in CRM and 48 (37%) were in CRS only (but not CRM) on entry to the OLE. Demographic and clinical characteristics at TN baseline were similar for pts in both subgroups, except that a higher proportion of pts with only CRS at OLE entry were exposed to prior immunomodulators or tumor necrosis factor inhibitors at TN baseline. A high proportion of the overall population sustained CRM, CRS, EI, and CFR on OZA at OLE Week 46 in both OC and NRI analyses, with higher rates of CRM, EI, and CFR among pts entering the OLE in CRM (Table). Notably, 97% of all pts sustained CRS through overall Week 98 in OC analysis (64% in NRI analysis). Of the pts in CRS only at OLE entry, 55% achieved CRM by OLE Week 46 in OC analysis (NRI: 32%). Mean partialMayo score over time for the overall population is shown in the Figure. No new safety findings emerged from this extended analysis; 1 sudden death occurred during the OLE and was adjudicated to be unrelated to OZA.
Conclusion(s): This interim analysis of the TN OLE found that pts who achieved CRS or CRM after 1 year of OZA had a high rate of sustaining CRS, CRM, and EI for another year. Pts who after a year of OZA were in CRS could achieve CRM with continued OZA therapy. No additional safety signals were observed. (Figure Presented)

Introduction: Nearly a quarter of older adults with inflammatory bowel disease (IBD) require surgery. Patients with IBD are at risk for complications postoperatively and this risk is increased in older adults. However, little is known about the risk factors leading to these complications.We assessed risk factors associated with adverse postoperative outcomes among older adults who underwent IBD-related surgery, as well as evaluated trends in emergency vs. elective surgery in this population.
Method(s): Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, we identified adults >=60 years of age who underwent an IBD-related intestinal resection from 2005-2019. Our primary outcome included a 30-day composite of mortality, readmission, reoperation, and/or what we identified as serious complications listed in NSQIP.
Result(s): In total, 9,640 intestinal resections were performed among older adults with IBD from 2005-2019, with 48.3% having undergone resection for Crohn's disease (CD), and 51.7% for ulcerative colitis (UC). Nearly 37% experienced an adverse outcome, with the most common complication being infection (20.21%). From 2005 to 2015, there was no decrease in the number of emergent cases among older adults. On univariate analysis, higher rates of adverse postoperative outcomes were seen with increasing age (p< 0.001), with nearly 50% of those >=80 years of age having an adverse outcome. Patients who underwent an emergency surgery had a higher likelihood of postoperative complications (66.86%; p< 0.001). On multivariable analysis, albumin <=3 (aOR 1.99; 95%CI 1.69-2.33), the presence of two or more comorbidities (aOR, 1.50; 95%CI 1.27-1.76), totally dependent functional status as compared to those partially dependent or independent (aOR, 7.28; 95%CI 3.14-21.2), and emergency surgery (aOR, 1.70; 95% CI 1.36-2.11) significantly increased the odds of an adverse outcome. (Figure)
Conclusion(s): Overall 37% of older adults with IBD experienced an adverse outcome as a result of IBD-related surgery. Limited functional health status, low preoperative serum albumin levels, and those undergoing emergent surgery were associated with a significantly higher risk. This is particularly important as the number of older adults with IBD is increasing, with a persisting number of emergency cases over time. Given the high rate of surgery in this population, future research should focus on preoperative rehabilitation, nutritional optimization, and timely surgery to improve outcomes. (Table Presented)

Background. The phase 3 True North (TN) study demonstrated the efficacy and safety of oral ozanimod 0.92 mg once daily (equivalent to ozanimod HCl 1 mg) in patients with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) study is exploring longer-term efficacy and safety of ozanimod in the treatment of UC. This interim analysis of the TN OLE evaluated the efficacy and safety of ozanimod in patients who received 98 weeks of continuous ozanimod treatment.
Method(s): Patients in clinical response after 52 weeks of continuous ozanimod therapy during TN who rolled over into the OLE were included (data cutoff: September 30, 2020). Endoscopy was performed annually throughout the OLE and was scored by Mayo endoscopic score. Efficacy data (clinical remission, clinical response, endoscopic improvement, and corticosteroid-free remission) were analyzed using observed cases (OC) and nonresponder imputation (NRI). Safety data were also recorded.
Result(s): Of 131 patients in clinical response at TN Week 52, 83 (63%) were in clinical remission and 48 (37%) were in clinical response only (but not clinical remission) upon entry to the OLE. Nearly 73% of the overall population of clinical responders, including 69% of patients who achieved clinical remission and 79% of patients who achieved clinical response only, completed Week 46 of the OLE (ie, Week 98 of continuous ozanimod therapy) at the time of data cutoff when outcomes were measured (NRI group). Baseline demographic and clinical characteristics were similar for patients in clinical remission and in clinical response only, except more patients with clinical response only at OLE entry were exposed to prior immunomodulators or tumor necrosis factor inhibitors at TN baseline. A high proportion of the overall population sustained clinical remission (67%), clinical response (97%), endoscopic improvement (74%), and corticosteroid-free remission (63%) on ozanimod at OLE Week 46 (OC analysis); NRI values were 44%, 64%, 58%, and 42%, respectively. There were higher rates of clinical remission (73% vs 55%), endoscopic improvement (82% vs 58%), and corticosteroid-free remission (71% vs 50%) among patients entering the OLE in clinical remission versus clinical response only (OC analysis). In the overall population of clinical responders, the mean partial Mayo score stabilized by Week 18 (mean, 1.3 points; range, 0-6 points) of the maintenance period and was maintained through OLE Week 46 (mean, 0.9 points; range, 0-4 points) in patients treated with continuous ozanimod. No new safety findings emerged from this extended analysis; 1 sudden death occurred during the OLE and was determined to be unrelated to ozanimod. Conclusion(s): This interim analysis of the TN OLE found that patients who achieved clinical response or clinical remission after 52 weeks of ozanimod had a high rate of sustaining clinical response, clinical remission, and endoscopic improvement for another year with continued use of ozanimod. Patients who were in clinical response after 52 weeks of ozanimod could achieve clinical remission with continued ozanimod therapy. No additional safety signals were observed

Introduction: The care of inflammatory bowel disease (IBD) has become increasingly complex and specialized. IBD education of gastroenterology (GI) trainees needs improvement and standardization. IBD 101, an annual course designed to introduce first-year GI fellows to various clinical topics in the management of IBD, was held on September 14, 2019. In this inaugural program, a select group of fellows (N=55 from 32 different programs) participated in a one-day course involving small group didactic sessions and Group Observed Structured Clinical Examinations (OSCEs) led by expert faculty members in seven clinical topics.
Method(s): To assess the long-term impact of IBD 101, email surveys were administered in May 2022 (the graduating year of the inaugural IBD 101 cohort) to all third-year GI fellows from participating programs, inclusive of both attendees and non-attendees. The primary outcome was comfort level discussing the 7 topics addressed at IBD 101, graded using a Likert scale (15 "strongly disagree" to '45 "strongly agree"). Information regarding each fellow's exposure to IBD education was collected.
Result(s): Thirty-six fellows completed surveys, of whom 21 (58%) were IBD 101 attendees and 15 (42%) were non-attendees. Overall, attendees reported equivalent or higher levels of comfort in each of the 7 topics than did non-attendees (Figure). In particular, a higher proportion of attendees strongly agreed with comfort in discussing pregnancy and IBD (43% vs. 13%; P=0.04) and loss of response to biologics (62% vs. 27%; P=0.13) than non-attendees. When assessing overall confidence, 76% of attendees reported comfort in all 7 categories, compared with 53% of non-attendees (P=0.15). Attending IBD 101 was associated with overall confidence (OR 5.21 [95% CI 0.91-29.9]; P=0.06) even after adjusting for presence of an IBD specialist at a fellow's home institution, number of IBD patients seen per month (<=5 vs. >5) and rotating through an IBD-only clinic or inpatient service (Table).
Conclusion(s): IBD 101, a primer for first-year GI trainees, was associated with increased comfort in the management of IBD, with more pronounced impact on challenging topics. IBD 101 is a valuable learning opportunity for first-year GI fellows with a durable benefit independent of individual access to IBD education, and we plan continued development, expansion and assessment of this program in collaboration with the ACG to further enhance the IBD education of the pipeline of GI trainees. (Figure Presented)

Introduction: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, is approved in the US and Europe for the treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3, randomized, double-blind, placebocontrolled True North study (NCT02435992), ozanimod led to statistically significant improvements in clinical, endoscopic, and histologic outcomes at Weeks 10 and 52 compared to placebo in patients with moderately to severely active UC. Aims & Methods: The aims of this analysis were to describe the characteristics of patients who did not achieve clinical response at Week 10 of ozanimod induction in True North, and to determine the proportion of patients who benefited from additional ozanimod treatment. In True North, patients were randomized 2:1 to receive double-blind ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo (Cohort 1) or open-label ozanimod 0.92 mg (Cohort 2). Those who did not have clinical response at Week 10 were eligible to receive ozanimod in an open-label extension (OLE). This analysis examined patients in Cohort 1 who were treated with double-blind ozanimod but did not achieve clinical response at Week 10 and subsequently continued ozanimod in the OLE (n=150). Demographics and disease characteristics were assessed at induction baseline, and disease activity was assessed at induction baseline and Week 10 (baseline for OLE entry). Symptomatic clinical response, defined as a reduction from induction baseline in the partial Mayo score of >=1 point and >=30% with at least 1 point decrease in rectal bleeding subscore (RBS) or absolute RBS <=1, during the OLE was determined using nonresponder imputation.
Result(s): A total of 150 patients who received ozanimod in Cohort 1 did not achieve clinical response at Week 10 of the induction period and entered the OLE. These patients had a mean age of 38.6 years, 66.0% were men, 44.0% had extensive disease, and the mean total Mayo score at baseline was 9.2 points. Despite not achieving clinical response at Week 10, these patients had a mean total Mayo score that improved from 9.2 at baseline to 8.5 at Week 10, with a larger percentage of patients having an RBS of 0 at Week 10 (23.3%; 35/150) than at baseline (0.7%; 1/150). Almost half of the patients who did not achieve clinical response at Week 10 had symptomatic clinical response at OLE Week 10 (48.7%; 73/150), with 44% (66/150) achieving symptomatic clinical response at OLE Week 5.
Conclusion(s): This analysis of the True North OLE found that approximately half of the patients who failed to achieve a clinical response after 10 weeks of ozanimod treatment benefited from an additional 5 to 10 weeks of ozanimod therapy

Background/UNASSIGNED:Inflammatory bowel disease (IBD) is not associated with worse coronavirus disease 2019 (COVID-19) outcomes. However, data are lacking regarding the long-term impact of severe acute respiratory syndrome coronavirus 2 infection on the disease course of IBD. Objectives/UNASSIGNED:We aimed to investigate the effect of COVID-19 on long-term outcomes of IBD. Design/UNASSIGNED:We performed a multicenter case-control study of patients with IBD and COVID-19 between February 2020 and December 2020. Methods/UNASSIGNED:Cases and controls were individuals with IBD with presence or absence, respectively, of COVID-19-related symptoms and confirmatory testing. The primary composite outcome was IBD-related hospitalization or surgery. Results/UNASSIGNED: = 0.24) and on multivariate Cox regression, COVID-19 was not associated with increased risk of adverse IBD outcomes [adjusted hazard ratio (aHR): 0.84, 95% confidence interval [CI]: 0.44-1.42]. When stratified by infection severity, severe COVID-19 was associated with a numerically increased risk of adverse IBD outcomes (aHR: 2.43, 95% CI: 1.00-5.86), whereas mild-to-moderate COVID-19 was not (aHR: 0.68, 95% CI: 0.38-1.23). Conclusion/UNASSIGNED:In this case-control study, COVID-19 did not have a long-term impact on the disease course of IBD. However, severe COVID-19 was numerically associated with worse IBD outcomes, underscoring the continued importance of risk mitigation and prevention strategies for patients with IBD during the ongoing COVID-19 pandemic.