Faculty Bibliography

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. The duration of active disease prior to starting treatment may impact treatment effects. We evaluated the association between duration of the latest flare before starting tofacitinib therapy and efficacy outcomes in the tofacitinib UC clinical program.
METHOD(S): Patients (pts) received tofacitinib 10 mg twice daily (BID) or placebo in OCTAVE Induction 1&2 (NCT01465763; NCT01458951) and responders received tofacitinib 5 or 10 mg BID or placebo during OCTAVE Sustain (final efficacy assessment at Wk52; NCT01458574). Pts were stratified by UC flare duration (ie duration of active disease; <3 and >=3 mo) prior to enrollment in OCTAVE Induction 1&2. Differences between the change from baseline Mayo stool frequency subscore (SF), Mayo rectal bleeding subscore (RB), and partial Mayo score (PMS) at Wk2 of OCTAVE Induction 1&2 between flare duration groups were assessed using ANOVA. Associations between flare duration and efficacy endpoints were assessed using the Cochran-Mantel-Haenszel chi-squared test.
RESULT(S): Among the 905 pts who received tofacitinib 10 mg BID in OCTAVE Induction 1&2, 443 and 462 pts had flare durations of <3 and >=3 mo, respectively. A higher proportion of pts with >=3 mo flare duration had pancolitis (53.7%) vs pts with <3 mo flare duration (48.8%); this was also true for prior TNFi failure (60% vs 42%). Mean baseline total Mayo score in both groups was 9.0. In OCTAVE Induction 1&2, a numerically higher proportion of pts with <3 mo flare duration met efficacy endpoints vs pts with >=3 mo, with a significant association. Changes from baseline SF, RB, and PMS at Wk2 were significantly greater in pts with <3 vs >=3 mo flare duration. Among pts who received tofacitinib 5 mg BID in OCTAVE Sustain, a numerically higher proportion with <3 mo flare duration met efficacy endpoints at Wk52 vs pts with >=3 mo; similar proportions of tofacitinib 10 mg BID-treated pts across flare duration groups met efficacy endpoints (Table).
CONCLUSION(S): These post hoc analyses showed that latest flare duration was significantly associated with the efficacy of tofacitinib 10 mg BID induction therapy at Wk8, with shorter duration (,3 mo) associated with greater efficacy, potentially implying that a timely intervention during a new flare may, as expected, lead to a better outcome for induction. During maintenance, flare duration had less impact on efficacy, with similar responses at Wk52 between tofacitinib 10 mg BID groups

BACKGROUND:Ileal pouch-anal anastomosis is a common surgical procedure in patients with an initial diagnosis of ulcerative colitis or indeterminate colitis. Tobacco smoking has been associated with protection from onset of ulcerative colitis. Smoking has been reported to be both a protective factor and a risk factor for the development of pouchitis. AIM/OBJECTIVE:To examine the influence of smoking on the risk of pouchitis. METHODS:We identified 15 studies evaluating smoking as a risk factor for developing pouchitis in ulcerative colitis or indeterminate colitis patients with a history of ileal pouch-anal anastomosis in a systematic search performed from inception through May 4, 2020. A meta-analysis was then performed using a random-effects model to generate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: = 78.5%). CONCLUSIONS:Smoking, past or present, is not associated with an increased risk for the development of pouchitis in patients with ulcerative colitis or indeterminate colitis.

INTRODUCTION: The treatment paradigm for inflammatory bowel disease (IBD) has become increasingly complex with more treatment options available. We evaluated treatment sequence and duration in recent real-world (RW) patients with ulcerative colitis (UC) or Crohn's disease (CD) in a large US IBD registry.
METHOD(S): We conducted a retrospective analysis of patients enrolled in the Corrona IBD Registry from 5/3/17 to 12/31/18 with a diagnosis of UC or CD on 1/1/2014 or later. Demographics, clinical characteristics, and prior treatment history were obtained at enrollment. Prescribed therapies were divided into the following categories: biologics (BIO; adalimumab, certolizumab, golimumab, infliximab, natalizumab, ustekinumab, vedolizumab), immunosuppressants (IST; methotrexate, 6-mercaptopurine, azathioprine, tacrolimus, cyclosporine), 5-aminosalicylic acids (ASAs), corticoste-roids (CSs), or a combination of 2 or more of the above. Following a stepwise approach, once patients' treatments graduated to IST or BIO, use of ASA therapy was not considered a change in therapy state. Median (Q1, Q3) duration of treatment for each therapy, across all lines of treatment, was reported.
RESULT(S): 196 UC and 124 CD patients were included in the analysis. Demographics at enrollment are summarized (Table 1). Among UC patients, 81% of first-line (1L) therapy was ASA (38.8%), ASA 1 CS (31.6%), or CS (10.7%), followed by BIO 1 CS (8.2%) and BIO (5.6%; Table 2). Among the 45% of patients with UC who received second-line (2L) therapy, BIO and BIO 1 CS were most common Fewer than 30% of patients were prescribed $3L of therapy. Overall, the longest median duration of treatment was BIO 1 IST (27.6 months [mo]) and BIO 1 IST 1 CS (11.0 mo; Table 3). Among CD patients, 51% of 1L therapy was ASA (21.0%), ASA 1 CS (17.7%), or CS (12.1%), followed by BIO (20.2%; Table 2). 2L therapy was received by 41% of CD patients and 20% were prescribed $3L of therapy. 1L treatment with ASA had a short treatment duration. Longer median durations of treatment were seen for combination treatment such as BIO 1 IST 1 CS (17.8 mo) and BIO 1 IST (10.5 mo; Table 3).
CONCLUSION(S): This RW registry provides insight into treatment sequencing. BIO was commonly a 2L therapy for UC patients, and had higher use as a 1L therapy for CD patients. Although a combination of therapies was not commonly used in practice as 1L or 2L therapy, it had the longest treatment duration. Use of 1L ASA treatment in CD was high despite treatment guidelines, which may explain short treatment durations

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Following 8 weeks of tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2, modest and reversible increases in serum lipid levels were reported in patients with UC, which were associated with reduced C-reactive protein (CRP) levels [1].
METHOD(S): OCTAVE Induction 1&2 (NCT01465763; NCT01458951) were 2 identical, 8-week, Phase 3 studies in which patients with moderately to severely active UC received tofacitinib 10 mg BID or placebo (total n = 1,139). In this post hoc analysis of the pooled induction studies, we assessed changes from baseline (CFB) in lipid levels (total cholesterol [total-c], high-density lipo-protein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c]) at Week 8 by responder and remitter status in patients who received tofacitinib 10 mg BID or placebo; analysis of variance was performed to estimate differences for responders or remitters vs non-responders. The association between CFB in lipid levels and CFB in CRP levels (log-transformed), by responder and remitter status, was assessed using a linear regression model at Week 8 in patients who received tofacitinib 10 mg BID.
RESULT(S): Increases in lipid levels from baseline to Week 8 were observed in responders, non-responders, and remitters (Table), which were greater with tofacitinib 10 mg BID vs placebo. There were significantly greater increases from baseline in total-c, HDL-c, and LDL-c for responders vs non-responders (all P < 0.0001), and in total-c and HDL-c for remitters vs non-responders (both P # 0.0001) in patients who received tofacitinib 10 mg BID (Table). Significant differences in lipid levels by responder and remitter status were not reported with placebo (data not shown). In patients who received tofacitinib 10 mg BID, linear regression modeling showed a significant association between CFB in total-c, HDL-c, and LDL-c and CFB in CRP in responders and non-responders, and between CFB in total-c and HDL-c and CFB in CRP in remitters (all P < 0.01) (Table).
CONCLUSION(S): These data suggest an association between increases in lipid levels and tofacitinib responder and remitter status. Further research is necessary to determine if increases in lipid levels can be used as a surrogate marker of reduced inflammation, and to establish lipid levels as potential predictors of patient outcomes to tofacitinib treatment

INTRODUCTION: Ileal pouch-anal anastomosis (IPAA) is a common surgical procedure in patients with an initial diagnosis of ulcerative colitis (UC), indeterminate colitis (IC), or familial adenomatous polyposis syndrome (FAP). Tobacco smoking has been associated with protection from onset of UC. Smoking has been reported to be both a protective factor and a risk factor for the development of pouchitis. In this systematic review and meta-analysis, we examine the influence of smoking on the risk of pouchitis.
METHOD(S): We identified 16 studies evaluating smoking as a risk factor for developing pouchitis in patients with a history of IPAA in a systematic search performed from inception through May 2020. A meta-analysis was then performed using a random-effects model to generate risk ratios.
RESULT(S): A total of 2,389 IPAA patients were included in the systematic review and meta-analysis. In the included studies, the percentage of patients with a diagnosis of pouchitis ranged from 22% to 72%. The percentage of patients with a history of smoking ranged from 7% to 63%. In total, 919 patients had pouchitis (330 current or former smokers; 589 non-smokers), and 1,470 patients did not have pouchitis (485 current or former smokers; 985 non-smokers). A history of smoking compared with never smoking was not associated with an increased risk of developing pouchitis (RR = 0.96, 95% CI 0.78-1.17, I² 5 68.6%). There was also no significant risk of pouchitis when comparing current smokers versus non-smokers (RR = 1.09, 95% CI 0.93-1.28, I² 5 0%) and former smokers versus non-smokers (RR = 0.95, 95% CI 0.70-1.28, I² 5 79.8%).
CONCLUSION(S): Smoking, past or present, is not associated with an increased risk for the development of pouchitis. This is important to consider when counseling patients on the risks of smoking and pouchitis

INTRODUCTION: Ustekinumab has been recently approved for the treatment of moderately to severely active ulcerative colitis (UC). The registry trials for ustekinumab in UC demonstrated efficacy and safety, but data on the effectiveness and safety in the real world are limited. We describe the effectiveness and safety of ustekinumab in patients with UC from two US tertiary IBD centers.
METHOD(S): Patients with moderately to severely active UC treated with ustekinumab at NYU Langone Medical Center (New York, NY) and University of Chicago Medical Center (Chicago, IL) between January 2016 and March 2020 were retrospectively included. The primary outcome was clinical remission at 3 and 12 months, defined as a partial Mayo score of 2, with a combined rectal bleeding and stool frequency subscore of #1.
RESULT(S): Sixty-six UC patients were included (Table 1). 61% of patients had extensive colitis and overall mean total Mayo score was 6.5 +/- 2.4. 92% of patients had prior exposure to biologics or tofacitinib. 43% and 45% of patients achieved clinical remission by 3 and 12 months, respectively (Figure 1). Anti-TNF non-response and endoscopic Mayo score of 3 were negative predictors of clinical remission at 3 months (Table 2). At 1 year, 50% of patients achieved endoscopic remission and 33% achieved mucosal and histo-endoscopic healing. The achievement of histo-endoscopic healing was significantly associated with lower partial Mayo score (0.5 +/- 0.6 vs. 3.5 +/- 1.7; P < 0.01) and lower stool frequency (0.3 +/- 0.5 vs. 1.4 +/- 0.7; P = 0.02). Serious adverse events occurred in 4 (6%) patients (3 UC exacerbations, 1 vasculitis).
CONCLUSION(S): In this cohort of mostly biologic-refractory UC patients, treatment with usteki-numab achieved remission in nearly half of them at 12 months, and was associated with an overall favorable safety profile. These results are modestly better than the pivotal trials

INTRODUCTION: Current guidelines recommend preoperative risk stratification to guide postoperative prophylactic biologic therapy for the prevention of Crohn's disease (CD) recurrence1. Few data have corroborated the quantified risk of postoperative recurrence (POR) and validated the proposed risk stratification. We aimed to assess the impact of biologic therapy on POR based on guideline-recommended risk stratification.
METHOD(S): CD patients who underwent an ileocolic resection from 1992-2019 were identified at two tertiary referral centers. Patients were stratified into cohorts with high-risk features (smoking, age < 30 years, and >=2 prior surgeries) and low-risk features (nonsmokers, age >50 years, resection length < 10 cm, and disease duration < 10 years). POR, defined as endoscopic (Rutgeerts . i1) or radiographic evidence of disease at least >6 months after surgery, was compared between groups. Recurrence-free survival analysis using Cox proportional hazard modeling and Kaplan-Meier curves were used to estimate POR and the impact of biologic prophylaxis.
RESULT(S): A total of 950 patients with ileocolic resection for CD were included (mean age 37.9, 47%): 785 (82.6%) high-risk and 165 (17.4%) low-risk patients. In the high-risk group, the majority (58.2%) received biologic prophylaxis (43.4% anti-TNF, 7.1% vedolizumab, and 7.8% ustekinumab) while 41.8% had no therapy. In contrast, 60% of low-risk patients had no therapy while 40% received biologic prophylaxis (32.7% anti-TNF, 8% vedolizumab, and 2.4% ustekinumab). In the high-risk group, biologic prophylaxis was significantly associated with earlier POR compared to no therapy (P < 0.001). In the low-risk group, there was no significant difference between biologic and no therapy in time to POR (P = 0.10; Figure 1). When assessing specific risk factors on multivariable analysis, >=2 prior surgeries was the only independent risk factor for POR (P < 0.05) (Table 1).
CONCLUSION(S): The risk stratification proposed for POR in current guidelines may have limited utility in predicting disease recurrence. Low-risk individuals are unlikely to benefit from postoperative biologic prophylaxis. Multiple prior surgeries is the strongest risk factor for POR and these patients may benefit from postoperative biologic prophylaxis

INTRODUCTION: Tofacitinib is a Janus kinase inhibitor approved for moderate to severe ulcer-ative colitis (UC). Prospective real-world data on tofacitinib in UC patients are limited. Using an electronic system to evaluate patient reported outcomes (PROs) in real time, we measured clinical response and PROs during the induction phase of tofacitinib.
METHOD(S): An initial 65 patients initiating tofacitinib were recruited from 13 academic and community gastroenterology practices. Demographic information, disease and medication histories were obtained. Patients completed PRO surveys on days 1-14, and at week 6, 10 and 14. Outcome data included the simple clinical colitis activity index (SCCAI), and PRO measurement information system (PROMIS) measures of depression, anxiety and social satisfaction. A score of < 4 with a decrease by >1.5 points is considered response. PROMIS measures are calibrated using a T score (mean of the US population equal to 50, standard deviation (SD) of 10). A higher PROMIS score equates to more of the measure (higher scores worse for depression, anxiety and better for social satisfaction).
RESULT(S): A total of 62/65 (95%) completed electronic PRO data through week 6. Mean age was 38.4 (SD 14.9), 61.5% were male, mean disease duration was 9.6 years and 58.5% were on concomitant steroids at baseline. Mean disease activity at baseline (n = 65) was active (SCCAI of 5.6 (SD 3.2)), with reductions in mean disease activity to SCCAI 3.1 on day 14, 2.7 on week 14 (Figure 1). At the time of first in-person clinical visit (week 2-6), only 18.2% remained on steroids. Among patients initiating tofacitinib without concomitant corticosteroid use (n = 27), early reductions in SCCAI were seen (mean SCCAI 5.4 at baseline, reduced to SCCAI 3.8 by day 4). Improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through week 14 (Figure 2). A total of 54.2% met criteria for response at day 14, with 52.2% at week 6.
CONCLUSION(S): Real time electronic PRO data capture provided the ability to assess cessation of steroids and time to response to tofacitinib via important PRO outcomes. Tofacitinib was associated with a rapid response in this ongoing prospective multi-center real-world cohort, independent of steroid use. Continued enrollment and long-term data, planned through week 30, will enhance our understanding of UC

INTRODUCTION: Guidelines recommend testing inflammatory bowel disease (IBD) patients hospitalized with flare for Clostridioides difficile infection (CDI), though little is known about whether a delay in testing for CDI is related to adverse outcomes. We examined the relationship between time to C. difficile PCR test order, collection, and result with adverse IBD outcomes.
METHOD(S): We performed a retrospective cohort study of IBD patients hospitalized with flare through the emergency department (ED) between 2013 and January 2020 at an urban academic medical center. The time from ED presentation to CDI test order (time-to-order), sample collection (time-to-collection), and test result (time-to-result) were collected. Time-to-result was stratified by within+/-hours, 6-24 hours, and 24 hours or longer. The primary outcome was length of stay (LOS). Secondary outcomes were inpatient anti-TNF administration and surgery. Separately, we used initial hemodynamic and laboratory values to create an IBD hospitalization severity score for evaluation against LOS and time-dependent variables.
RESULT(S): We identified 122 IBD patients hospitalized with flare. There were no significant differences in baseline characteristics among time-to-result groups. There was no difference in time-toorder between the+/-hours and 6-24 hours groups (Table 1). Despite a shorter time-to-result, the average LOS in the+/-hours group was 7.3 days, longer compared to the 6-24 hours group (4.3 days, P=0.018) and the 24 hours group (4.2 days, P=0.035Table 1). There were no differences in inpatient anti-TNF administration (P=0.10) or surgery (P=0.08) among time-to-result groups. Markers of disease severity correlated with longer LOS and earlier time-to-result (Table 2). A composite of these markers was used to stratify patients by disease severity. Those with more severe disease had earlier times-to-result (12.8 hours vs. 32.2 hours, P=0.014) and had a longer LOS (7.9 vs. 3.4 days, P=0.007) with no difference in time-to-order compared to patients with less severe disease (P=0.09Table 3).
CONCLUSION(S): Earlier time-to-result for CDI is associated with longer LOS in IBD patients hospitalized with flare. This inverse relationship is confounded by disease severity at presentation. Patients with more severe disease have a shorter time-to-result and a longer LOS without any difference in time-to-order. Delay in testing was not associated with higher rates of inpatient anti- TNF administration or surgery

PURPOSE/OBJECTIVE:For more than half of Crohn's disease patients, strictures will cause bowel obstructions that require surgery within 10 years of their initial diagnosis. This study utilizes computed tomography imaging and clinical data obtained at the initial emergency room visit to create a prediction model for progression to surgery in Crohn's disease patients with acute small bowel obstructions. METHODS:A retrospective chart review was performed for patients who presented to the emergency room with an ICD-10 diagnosis for Crohn's disease and visit diagnosis of small bowel obstruction. Two expert abdominal radiologists evaluated the CT scans for bowel wall thickness, maximal and minimal luminal diameters, length of diseased segment, passage of oral contrast, evidence of penetrating disease, bowel wall hyperenhancement or stratification, presence of a comb sign, fat hypertrophy, and small bowel feces sign. The primary outcome was progression to surgery within 6 months of presentation. The secondary outcome was time to readmission. RESULTS:Forty patients met the inclusion criteria, with 78% receiving medical treatment alone and 22% undergoing surgery within 6 months of presentation to the emergency room. Multivariable analysis produced a model with an AUC of 92% (95% CI 0.82-1.00), 78% sensitivity, and 97% specificity, using gender, body mass index, and the radiographic features of segment length, penetrating disease, and bowel wall hyperenhancement. CONCLUSIONS:The model demonstrates that routine clinical and radiographic data from an emergency room visit can predict progression to surgery, and has the potential to risk stratify patients, guide management in the acute setting, and predict readmission.