Faculty Bibliography

GOALS AND BACKGROUND/OBJECTIVE:Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications. STUDY/METHODS:A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition. RESULTS:Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen. CONCLUSIONS:UST was not associated with an increase in short-term risk of AEs.

BACKGROUND & AIMS:We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC). METHODS:We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017. RESULTS:Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy. CONCLUSIONS:We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

INTRODUCTION: The outbreak of novel severe acute respiratory virus syndrome coronavirus 2 (SARS-CoV 2), the causative virus of coronavirus disease 2019 (COVID-19), has become a global pandemic. In the United States, cases exceed 2 million, with the New York City (NYC) metropolitan area at the epicenter. Patients with inflammatory bowel disease (IBD) are generally considered higher risk of infection due to immunosuppressive therapies, however, data are lacking regarding outcomes of COVID-19 in patients with IBD compared to the general population. We aim to investigate the impact of IBD on COVID-19 outcomes.
METHOD(S): We prospectively collected data on all patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] with confirmed or highly suspected COVID-19 (fever and/or close contact plus respiratory symptoms) and all non-IBD patients with confirmed COVID-19 from March 3 to May 10, 2020 at an academic medical center in NYC. Patient demographics, co-morbidities, and medication history were recorded. The endpoints were severe outcomes of COVID-19, including hospitalization, ventilator requirement, ICU admission and death. Adjusted analyses were performed for predictors of a composite endpoint of ventilator, ICU and death.
RESULT(S): We identified 83 patients with IBD [CD (n = 56, 67%) or UC (n = 27, 33%)] with confirmed or suspected COVID-19 and 8277 non-IBD patients with confirmed COVID-19 (Table 1). IBD patients had a lower median age (34 vs. 53 years; P < 0.001) and a higher proportion of Caucasians (69% vs. 41%; P < 0.001). IBD patients were less likely to have any co-morbidity (29% vs. 52%; P < 0.001), and had higher rates of immunomodulator (IMM) or biologic use. IBD patients with confirmed COVID-19 had lower rates of hospitalizations (14% vs. 51%; P < 0.001) and ICU admissions (2% vs. 13%; P = 0.04; Table 2). On multivariable analysis restricted to confirmed COVID-19, the presence of IBD was not associated with severe outcomes (OR 0.55, 95% CI 0.12-2.44, P = 0.43). Age, male gender, number of comorbidities, thiopurine and steroid use were significant predictors of severe COVID-19 outcomes, while TNF-antagonists had a protective effect (Table 3).
CONCLUSION(S): In this large cohort study, IBD was not a risk factor for severe outcomes of COVID-19. Age, co-morbidities, and exposure to thiopurines and steroids were associated with severe outcomes of COVID-19. TNF-antagonists may be protective from severe outcomes of COVID-19, but this requires further study

INTRODUCTION: Hospitalization for flare of inflammatory bowel disease (IBD) is associated with significant morbidity and healthcare costs. We aimed to examine the relationship between IBD severity at presentation and adverse outcomes in patients hospitalized with flare. Additionally, we aimed to create and validate a predictive model for length of stay (LOS) using markers of disease severity.
METHOD(S): We conducted a retrospective cohort study of IBD patients hospitalized with flare at two urban academic medical centers. We collected demographic and IBD-related data including the presence of Clostridioides difficile and markers of disease severity at presentation. The primary outcome was a composite of adverse inpatient IBD outcomes, including LOS >7 days, anti-TNF administration, and surgery. The data was split into training (70%) and validation (30%) samples. Employing variables of disease severity, models (including logistic regression, Classification and Regression Tree (CART), and Random Forest (RF) modeling techniques) were created to predict LOS >7 days using the training sample. These models were adjusted for surgery and anti-TNF administration, and their performance was subsequently validated.
RESULT(S): A total of 187 IBD patients hospitalized with flare were included (Table 1). The composite primary outcome was achieved in 71 patients (38%) with 51 (27%) hospitalized for >7 days. In univariate analyses, C-reactive protein and C. difficile positivity correlated with anti-TNF administration and surgery (Table 2). Adjusting for anti-TNF administration and surgery, tachycardia (OR 1.07; 95% CI 1.05-1.10), hypotension (1.07; 1.03-1.11), hypoalbuminemia (2.87; 1.81-4.74), leukocytosis (1.17; 1.09-1.27), anemia (1.10; 1.05-1.15) and C. difficile posi-tivity (2.63; 1.27-5.47) were predictive of prolonged LOS (Table 2). In multivariate analyses, tachycardia predicted the primary composite outcome of all adverse effects (OR 1.07; 95% CI 1.03-1.11). C. difficile positivity (OR 4.33; 95% CI 1.36-14.9), hypoalbuminemia (3.25; 1.29-9.01), and tachycardia (1.11; 1.06-1.16) predicted prolonged LOS (.7 days). The CART and RF models had acceptable accuracy, sensitivity, and specificity for predicting LOS >7 days (Table 3).
CONCLUSION(S): C. difficile positivity, hypoalbuminemia, and tachycardia at presentation predicted prolonged length of stay in a multicenter cohort of IBD patients hospitalized with flare. CART and Random Forest models perform well in predicting prolonged length of stay in these patients

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

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