Faculty Bibliography

Introduction: Previous studies have demonstrated that exposure to anti-TNFa medications or immunomodulators (IMM) does not increase the risk of new or recurrent cancer in patients with inflammatory bowel disease (IBD) and a previous history of cancer. There is little data regarding this risk after the use of newer biologics such as ustekinumab and vedolizumab. In this study, we assessed whether patients with IBD and a history of previous cancer who are exposed to these newer agents have an increased risk of developing subsequent cancer.
Method(s): We performed a retrospective cohort study of patients with IBD and cancer from a single academic medical center between January 2013 and December 2020. We recorded information on demographics, cancer type and treatment, and IBD characteristics and drug exposures. The primary exposure was type of IBD monotherapy after a cancer diagnosis. The primary outcome was development of new or recurrent cancer.
Result(s): Of 401 patients with IBD and a history of cancer, 37 subsequently received vedolizumab, 14 ustekinumab, 31 IMM, 41 anti-TNF, 11 combination anti-TNF with an IMM, and 267 were not exposed to any immunosuppression following a cancer diagnosis (Table 1). There were no differences in duration of IBD, median age at cancer diagnosis, or smoking history. During a total median follow-up of 52 months, 81 (20%) patients developed incident cancer including 6 (16%) exposed to vedolizumab, 2 (14%) to ustekinumab, 3 (10%) to IMM, 12 (29%) to anti-TNF, 2 (18%) to combination anti-TNF with an IMM, and 56 (21%) with no immunosuppression (P = 0.41). Sensitivity analyses assessing any history of exposure to vedolizumab or ustekinumab, inclusive of both single and multiple biologic exposures, also did not reveal an increased rate of incident cancer.
Conclusion(s): In this single-center study, vedolizumab or ustekinumab monotherapy in patients with IBD and a history of cancer was not associated with an increase in new or recurrent cancer compared with anti-TNF, IMM, or no immunosuppression. Prospective studies are needed to confirm this conclusion

Introduction: With an aging population, management of biologic therapy in IBD patients with active or recent cancer is challenging. We evaluated the comparative safety of non-tumor necrosis factor (TNF)-a directed therapy vs. TNFa antagonists vs. immunomodulator monotherapy (IMM) in IBD patients with active or recent cancer (<=5 years).
Method(s): Through the collaborative REACH-IBD (Rising Educators Academics and Clinicians Helping IBD) research initiative, we conducted a retrospective, multi-center cohort study. We included IBD patients from 12 centers with active cancer (Cohort A) or recent cancer within = years (Cohort B) who were treated with non-TNFa biologics vs. TNFa antagonists (reference) after cancer diagnosis.We excluded patients with nonmelanoma skin cancer. Primary outcomes were cancer progression (Cohort A) or new/recurrent cancer (Cohort B). We performed Cox proportional hazard analysis to compare the safety of different biologics.
Result(s): (Cohort A)We included 107 patients with active cancer (5416y, 62% male, 72% solid cancer, 400 person-year follow-up), of whom 35 were treated with non-TNFa biologics (29 vedolizumab, 6 ustekinumab), 45 with TNFa antagonists and 27 with IMM (Table 1). Overall, 19 patients had progression of cancer, 13 died and 20 were hospitalized for serious infection (Figure 1A). After adjusting for age and type of active cancer, there was no difference in the risk of cancer progression (non-TNFa biologics vs. TNFa antagonists: HR, 1.55; 95% CI, 0.48-5.03), mortality (HR, 2.74; 95% CI, 0.25-30.5) and serious infections (HR, 1.90; 95% CI, 0.15-24.0) between patients treated with non-TNFa biologics vs. TNFa antagonists. (Cohort B) We included 141 patients with recent prior cancer (5214y, 51% male, 86% solid cancer; duration of remission prior to starting biologics, 1719m) of whom 54 were treated with non-TNFa biologics (40 vedolizumab, 14 ustekinumab), 63 with TNFa antagonists and 24 with IMM (Table 1). Overall, 14 patients had recurrence of cancer (or developed new incident cancer) and 6 died (Figure 1B). After adjusting for age, type of prior cancer and duration of remission, there was no difference in the risk of cancer recurrence between non-TNFa biologics vs. TNFa antagonists (HR, 0.97; 95% CI, 0.16-5.75).
Conclusion(s): In IBD patients with active or recent cancer (within = years), non-TNFa-directed biologics and TNFa antagonists have comparable safety. Choice of biologic should be dictated by IBD disease severity, in collaboration with an oncologist

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:We aimed to characterize patients with inflammatory bowel disease (IBD) and novel coronavirus disease 2019 (COVID-19). METHODS:We performed a case series of patients with IBD and confirmed or highly suspected COVID-19 to assess rates of severe outcomes. RESULTS:We identified 83 patients with IBD with confirmed (54%) or highly suspected (46%) COVID-19. The overall hospitalization rate was 6%, generally comprising patients with active Crohn's disease or older men with comorbidities, and 1 patient expired. DISCUSSION/CONCLUSIONS:In this series of patients with IBD, severe outcomes of COVID-19 were rare and comparable to similarly aged individuals in the general population.

Background: 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 real-world outcomes are limited. We describe the effectiveness and safety of ustekinumab in patients with UC from 2 US tertiary inflammatory bowel disease centers. Methods: Patients with moderately to severely active UC treated with ustekinumab at NYU Langone Health (New York, New York) and University of Chicago Medical Center (Chicago, Illinois) 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. Results: Sixty-six UC patients were included. Ninety-two percent of patients had prior exposure to biologics or tofacitinib. Forty-three percent and 45% of patients achieved clinical remission by 3 and 12 months, respectively. Anti-TNF nonresponse and endoscopic Mayo score of 3 were negative predictors of clinical remission. Thirty-three percent of those followed for a year achieved concurrent endoscopic and histologic healing, which was significantly associated with lower partial Mayo score (P < 0.01) and lower stool frequency (P = 0.02). Serious adverse events occurred in 4 (6%) patients (3 UC exacerbations, 1 vasculitis). Conclusions: In this cohort of mostly biologic-refractory UC patients, treatment with ustekinumab 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.

The incidence and prevalence of inflammatory bowel disease (IBD) is rising in the elderly population. Compared with patients with onset during their younger years, patients with elderly onset IBD have a distinct clinical presentation, disease phenotype, and natural history. Genetics contribute less to pathogenesis of disease, whereas biological changes associated with aging including immunosenescence, dysbiosis, and frailty have a greater impact on disease outcomes. With the advent of an increasingly wider array of biologic and small-molecule therapeutic options, data regarding efficacy and safety of these agents in elderly IBD patients specifically are paramount, given the unique characteristics of this population.

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: 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: Gastrointestinal symptoms of SARS-CoV-2 infection common, but usually mild in severity. We describe a case of severe gastrointestinal bleeding (GIB) in a patient with a COVID-19 associated hyperinflammatory response. CASE DESCRIPTION/METHODS: A 25-year-old man with no significant medical history presented with 2 weeks of fevers, cough, dyspnea, and diarrhea. He tested positive for COVID-19 on nasopharyngeal PCR and imaging showed multifocal pneumonia. Initial labs were notable for markedly elevated CRP and ferritin, pancytopenia and acute kidney injury. He was treated for suspected COVID-19 associated hyperinflammatory syndrome with anakinra (5 mg/kg twice daily) and hydroxychloroquine. He became anuric requiring hemodialysis and renal biopsy complicated by retroperitoneal bleeding and emergent embolization of the left renal artery. He was intubated for worsening acute respiratory distress syndrome (ARDS) and developed hematemesis and melena leading to hemorrhagic shock. EGD showed diffuse inflammation, erosions and oozing from the esophagus to the proximal duodenum, non-bleeding gastric ulcers and petechiae (Figure 1A, B). Given clinical suspicion for COVID-19 associated macrophage activation syndrome (MAS)/ secondary hemophagocytic lymphohistiocytosis (sHLH), anakinra was restarted and intravenous immunoglobulin (IVIG, 1mg/kg) was given with clinical improvement. The patient continued to have melena. Repeat EGD showed severe esophagitis with large clots and sloughing mucosa, a focal 3-4 cm area of necrosis in the fundus, unresolved non-bleeding stomach ulcers and improved duodenitis from prior (Figure 1C, D). DISCUSSION: We describe a case of a young adult who developed catastrophic GIB as a complication of COVID-19. The pathogenesis of SARS-CoV2 infection is incompletely understood, but there is mounting evidence that it can induce a MAS/sHLH-like hyperinflammatory response. Several laboratory hallmarks of COVID-19 infection are also seen in MAS/sHLH including elevated CRP, ferritin, IL-1, and IL-6. This hyperinflammatory response can manifest in a variety of ways, including a Kawasaki-like presentation in pediatric patients responsive to IVIG and IL-1 antagonism. GIB is rare in COVID-19, occurring in 4% of cases, but can occur in up to 20% of MAS/sHLH cases. Clinicians should recognize that COVID-19 can provoke a MAS/sHLH-like hyperinflammatory syndrome with gastrointestinal involvement

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