Faculty Bibliography

INTRODUCTION: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Fecal calprotectin (FCP) levels correlated with clinical and endoscopic outcomes at Week (Wk) 8 in patients (pts) with moderately to severely active UC receiving tofacitinib in a Phase 2 study (1). In these post hoc analyses, we aimed to determine if FCP levels, C-reactive protein (CRP) levels, or partial Mayo score (PMS) can be early predictors of clinical or endoscopic outcomes in a Phase 2, randomized, double-blind, placebo-controlled study (NCT00787202) (2).
METHOD(S): FCP levels and PMS at baseline, Wk 2, and Wk 4, and CRP levels at baseline and Wk 4 were analyzed based on whether pts with moderately to severely active UC treated with tofacitinib 10 mg twice daily (BID) had clinical response, clinical remission, mucosal healing, or endoscopic remission at Wk 8. Univariate logistic regression analyses were used to evaluate if FCP levels (log transformed), CRP levels (log transformed), or PMS were associated with each outcome.
RESULT(S): In pts treated with tofacitinib 10 mg BID (N = 28), numerically greater decreases from baseline were observed in FCP levels and PMS at Wks 2 and 4 in pts who achieved clinical response, clinical remission, mucosal healing, and endoscopic remission at Wk 8 vs those who did not. FCP levels at Wk 2 decreased by>50% from baseline in pts who achieved endoscopic remission. Numerically greater decreases from baseline were observed in CRP levels at Wk 4 in pts who achieved clinical response and mucosal healing at Wk 8 vs those who did not (Table 1). In pts treated with tofacitinib 10 mg BID, logistic regression results (shown as odds ratio [95% confidence interval]) showed that PMS at Wk 2 (0.496 [0.288, 0.856]; P=0.0117) and Wk 4 (0.463 [0.251, 0.853]; P=0.0135), and CRP levels at Wk 4 (0.582 [0.342, 0.990]; P=0.0460), were significantly associated with clinical remission at Wk 8, and that PMS at Wk 4 (0.572 [0.345, 0.948]; P=0.0302) was significantly associated with clinical response at Wk 8.
CONCLUSION(S): These post hoc analyses of a Phase 2 study showed that decreases as early as Wk 2 in FCP levels and PMS, and as early as Wk 4 in CRP levels, may be predictors of improved clinical and endoscopic outcomes in pts with moderately to severely active UC treated with tofacitinib 10 mg BID, although definitive conclusions cannot be drawn due to low pt numbers

INTRODUCTION: Relapse of Crohn's disease (CD) is common after surgical resection. Prior data have demonstrated that postoperative tumor necrosis factor antagonists (anti-TNF) may reduce recurrence, although little is known about the efficacy of other biologic therapies. The aim of this study was to compare biologics for preventing postoperative objective recurrence in adult CD patients.
METHOD(S): We performed a retrospective chart review of CD patients who underwent intestinal resection from 2012 to 2018. Demographics, IBD history, pre- and postoperative course were obtained from the electronic medical record. The primary outcome was postoperative recurrence during follow up, defined as a composite of endoscopic (Rutgeerts grade > i2), biochemical (increase in CRP >5 mg/dL), or radiographic (presence of active inflammation) disease recurrence stratified by postoperative biologic exposure, including anti-TNF, vedolizumab (VDZ), ustekinumab (UST), and no therapy. Student's t-test, Pearson's chi-squared, logistic and Cox regression analyses were used to detect differences in the composite and components of the outcome among these groups.
RESULT(S): 123 patients were included. CD recurrence occurred in 36.6% of patients (13.0% biochemically, 24.4% endoscopically, 16.3% radiographically) at a median of 6.9 months (IQR 3.3-14.1) from surgery (Table 1). The number of patients in the anti-TNF, VDZ, UST, and no therapy groups were 57 (46.7%), 6 (4.9%), 13 (10.7%), and 46 (37.7%), respectively. Biologic therapy was initiated after ileostomy reversal within 3 months for 55 patients (72.4%), between 3-6 months for 11 patients (14.5%), and between 6-12 months for 10 patients (13.2%). Adjusting for prior resection and anti- TNF exposure, any biologic initiation within 6 months of surgery was superior to initiation after 6 months for preventing postoperative endoscopic recurrence (OR 0.24, 0.06-0.92), but not for the composite outcome. There were statistically significant differences among biologics for recurrence (Figure 1). Adjusting for prior resection and anti-TNF exposure, less patients relapsed under anti- TNF exposure compared to UST (HR 3.46, 1.45-8.23) for the composite outcome, and compared to UST (HR 3.95, 1.43-10.9) and VDZ (HR 4.42, 1.02-19.1) for endoscopic recurrence (Figure 2).
CONCLUSION(S): Among CD patients, initiation of biologics within 6 months and anti-TNF agents were superior in preventing postoperative recurrence compared to other management strategies. (Figure Presented)

INTRODUCTION: Previous studies have demonstrated that exposure to anti-TNFalpha and/or immunomodulators for inflammatory bowel disease (IBD) following a diagnosis of cancer was not associated with an increased risk of new or recurrent cancer. There is little data regarding the use of newer biologics, vedolizumab and ustekinumab, after a diagnosis of cancer. We aimed to investigate whether patients with IBD and a history of cancer who were subsequently exposed to vedolizumab or ustekinumab have an increased risk of developing new or recurrent cancer.
METHOD(S): We reviewed the medical records of 5062 patients with IBD and cancer from an academic medical center between January 2013 and November 2018 to identify IBD patients who received vedolizumab or ustekinumab following a diagnosis of cancer. We collected demographic, IBD and cancer-related data. Our primary outcome was the development of new or recurrent cancer. Results were compared to historical data regarding the risk of new or recurrent cancer in patients exposed to anti-TNFalpha, an immunomodulator or no therapy for IBD following a diagnosis of cancer.
RESULT(S): We identified IBD patients who received vedolizumab (n = 59) or ustekinumab (n = 18) monotherapy following a diagnosis of cancer (Table 1). The median age at cancer diagnosis was 51 years (IQR 43-65) for vedolizumab and 57 years (IQR 55-66) for ustekinumab. During a median follow-up of 68 months (IQR 21-132) for vedolizumab and 48 months (IQR 12-96) for ustekinumab, 3 (5%) and 3 (17%) patients developed subsequent cancer, respectively. Compared to historical data, there were differences in subsequent cancer risk between exposure groups (Figure 1; log-rank 0.001). However, when adjusted for stage of prior cancer, compared to no therapy, there was no difference in risk of new or recurrent cancer between patients exposed to vedolizumab (HR 0.01, 0.01-7.58), ustekinumab (HR 0.85, 0.11-6.50), anti-TNFalpha (HR 0.60, 0.34-1.07) or immunomodulators (HR 1.01, 0.58-1.75) following a diagnosis of cancer.
CONCLUSION(S): In this single-center study, exposure to vedolizumab or ustekinumab in patients with IBD and a history of cancer conferred a low risk of new or recurrent cancer. Exposure to vedolizumab or ustekinumab monotherapy was not associated with an increased risk of subsequent cancer compared to historical data of exposure to anti-TNF, immunomodulators or no immunosuppression following a diagnosis of cancer. Larger studies are needed to confirm these findings. (Figure Presented)

INTRODUCTION: Patients with inflammatory bowel disease (IBD) frequently receive stool testing for exacerbations in gastrointestinal symptoms. Multiplex polymerase chain reaction-based gastrointestinal pathogen panels (GI PCR) offer significant benefits in sensitivity over conventional tests such as culture and ova and parasites exam. However, it is unclear how additional pathogen positive findings by GI PCR affect further clinical management. In this study we compared the downstream healthcare utilization of IBD patients who received GI PCR to conventional stool testing.
METHOD(S): We reviewed outpatients presenting to an academic medical center with an acute episode of diarrhea from September 2015 to February 2019 to identify patients with IBD who received stool testing with a FilmArray GI PCR or stool culture and ova and parasite exam (conventional testing). All patients received isolated PCR testing for Clostridium difficile. Each GI PCR patient was randomly matched with a conventional testing patient based on age, sex, and date of testing. Post-visit endoscopy, abdominal radiology, antibiotic therapy, and escalation in IBD medical therapy defined as an increase in the dose of a prior medication or prescription of a new medication were recorded. Long-term outcomes including emergency room (ER) visits, hospitalizations, and abdominal surgery were recorded as well. Ttest and Chi-square analysis were used to compare outcomes between groups.
RESULT(S): Among 1,104 patients receiving stool testing, we identified 120 outpatients with IBD, of whom 26 (22%) received conventional stool testing and 94 (78%) GI PCR testing. Of 26 patients with conventional testing, 1 (4%) had a pathogen identified on testing while 36 (38%) of 94 GI PCR patients had positive tests (Table 2). There were no significant differences in demographics, IBD characteristics, rates of C. difficile infection, and behavioral risk factors between groups (P > 0.05). GI PCR patients were less likely to receive any endoscopic exam in the 30-day period after their initial visit (20% vs. 42%, P = 0.021). There were no significant differences in exposure to radiology, antibiotics, escalation of IBD therapy, or long-term IBD outcomes (P > 0.05).
CONCLUSION(S): Testing with GI PCR was associated with lower rates of post-visit endoscopywith no differences in long-term outcomes in outpatients with IBD. This study suggests that in certain populations of patients, GI PCR testing has the potential to reduce downstream healthcare utilization andmanagement burden

INTRODUCTION: Currently, endoscopic remission in ulcerative colitis (UC) is defined using the Mayo Endoscopic subscore (MES), with a score of 0 (normal mucosa) or 1 (erythema, decreased vascular pattern, mild friability) representing mucosal healing. However, it is not clear if clinical outcomes differ between patients with a MES of 0 and 1. The aim of our study was to evaluate differences in relapse rates between patients with MES of 0 and 1.
METHOD(S): UC patients who underwent colonoscopy at 2 IBD referral centers from 2012 to 2017 were identified. Inclusion criteria consisted of patients with a MES score of 0 or 1, no prior colectomy, and outpatient follow up for a minimum of 1 year after colonoscopy. Data was collected for demographics, disease characteristics, medications, time from last disease flare and inflammatory biomarkers. The primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and colectomy. Chi Square, Fisher's exact and logistic regression modeling were used in statistical calculations.
RESULT(S): 446 UC patients were identified, with 228 (51%) and 218 (49%) having a MES of 0 and 1 respectively. 78% were Caucasian, 52% were female and mean age was 40 +/- 15 years. 20, 34, and 46% had proctitis, left sided colitis and extensive or pancolitis, respectively. 46% of patients were on either a 5-ASA alone or no medical therapy, while 46% were on biologics and 27% were on biologic therapy with an immune suppressant. Within 1 year from colonoscopy, 97 (22%) had a change in medical therapy and 66 (15%) were prescribed steroids. Only 8 and 4 patients were hospitalized for UC or underwent colectomy, respectively. UC patients with a MES of 1 were more likely to experience a relapse (P < 0.01) (Table 1). After adjusting for race, disease extent, and medication use, a MES of 1 was the only factor associated with an increased the risk of relapse (aOR 2.54, 1.61-4.01) (Table 2).
CONCLUSION(S): Patients with mild endoscopic activity by MES were at increased risk for relapse compared to patients with no endoscopic activity. In this population of UC patients, MES score was the only variable that predicted future relapse. Future studies are needed to classify low and high risk patients with mild endoscopic activity through evaluation of novel biomarkers and histology. Gastroenterologists should consider enhanced monitoring and/or changes in medical therapy based on the presence of even mild inflammation. (Figure Presented)

INTRODUCTION: Gut microbial dysbiosis and impaired mucosal immunity play a major role in the pathogenesis of inflammatory bowel disease (IBD). Previous research has shown that IBD patients experience greater disease burden from gastrointestinal infections. The increasing availability of gastrointestinal multiplex polymerase chain reaction stool panels (GI PCR) has allowed for the rapid and accurate identification of viral, bacterial, and parasitic pathogens not readily diagnosable with conventional stool testing. We aimed to characterize the burden and risk factors for gastrointestinal infections on outpatients with and without inflammatory bowel disease presenting with symptoms of acute gastroenteritis.
METHOD(S): We performed a cross-sectional review of outpatients presenting with gastroenteritis to an academic medical center from September 2015 to March 2019 who received a FilmArray GI PCR. Baseline demographics, presence of IBD and disease characteristics, risk factors including travel history, sexual activity, HIV status, and symptoms on initial presentation were recorded. The primary outcome was the detection of an enteric pathogen. Secondary outcomes include the class of pathogen detected, i.e., viral, bacterial, parasitic. T-test and Chi-square analysis were used to compare outcomes between groups.
RESULT(S): We reviewed 815 outpatients who received GI PCR testing, of whom 94 (12%) were diagnosed with IBD. Patients with IBD were more likely to present to the initial visit with bloody diarrhea (46% vs. 8%, P < 0.001), hematochezia (15% vs. 6%, P = 0.001), and fever (23% vs. 9%, P < 0.001; Table 1). Of outpatients with IBD, 33 (35%) had a gastrointestinal pathogen detected compared to 216 (30%, P = 0.190) of non-IBD outpatients. Patients with IBD were more likely to have viral (28% vs. 18%, P = 0.044) or multiple pathogens (11% vs. 6%, P = 0.028) and less likely to have bacterial (61% vs. 73%, P = 0.920) and parasitic infections (0 vs. 6%, P = 0.382) on GI PCR (Table 2). There were no statistically significant differences in gender, race, travel history, sexual activity, HIV status, or rate of pathogen detection between patients with and without IBD.
CONCLUSION(S): Enteric infections were common in outpatients with and without IBD. IBD patients presented with more viral and multiple pathogens on GI PCR testing compared to non-IBD controls. Further studies are needed to investigate the impact of these different enteric pathogens on clinical management and disease burden. (Figure Presented)

Products derived from bacterial members of the gut microbiota evoke immune signalling pathways of the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. We recently demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities following depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and interleukin (IL)-22-producing innate lymphoid cells, which in turn promote pSTAT3 signalling in intestinal epithelial cells and protection from intestinal injury. In addition, we demonstrate that MNV provides a striking IL-22-dependent protection against early-life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.

Background/UNASSIGNED:Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. Methods/UNASSIGNED:This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. Results/UNASSIGNED:A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). Conclusions/UNASSIGNED:Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI.

Background:Vedolizumab is now widely available for the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). We sought to quantify the rates of postoperative complications with preoperative vedolizumab compared with anti-tumor necrosis factor (anti-TNF) therapy. Methods:A multicenter retrospective review of adult inflammatory bowel disease (IBD) patients who underwent an abdominal operation between May 20, 2014, and December 31, 2015, was performed. The study cohort was comprised of patients who had received vedolizumab within 12 weeks of their abdominal operation, and the control cohort was IBD patients who had received anti-TNF therapy. Results:A total of 146 patients received vedolizumab within 12 weeks before an abdominal operation (64% female; n = 93; median age, 33 years; range, 15-74 years), and 289 patients received anti-TNF therapy (49% female; n = 142; median age, 36 years; range, 17-73 years). Vedolizumab-treated patients were younger (P = 0.015) and were more likely to have taken corticosteroids (P < 0.01) within the 12 weeks before surgery. Vedolizumab-treated patients had a significantly increased risk of any postoperative surgical site infection (SSI; P < 0.01), superficial SSI (P < 0.01), deep space SSI (P = 0.39), and mucocutaneous separation of the diverting stoma (P < 0.00) as compared with patients taking anti-TNF therapy. On multivariate analysis, after adjusting for body mass index, steroids at the time of operation, and institution, exposure to vedolizumab remained a significant predictor of postoperative SSI (P < 0.01). Conclusions:We observed that vedolizumab-treated patients were at significantly increased risk of postoperative SSIs after a major abdominal operation, as compared with anti-TNF-treated patients.