Treatment of IBD //
Bernstein CN, Crocker E, Nugent Z, Virdi P, Singh H, Targownik LE. Gastroenterologist Consultation is Uncommon but Associated with Improved Care among IBD Patients Presenting to Emergency Departments in Winnipeg Hospitals. Journal of the Canadian Association of Gastroenterology 2020; in press.
We aimed to describe the patterns of care when persons with IBD present to the Emergency Department and post Emergency Department follow-up. We linked the University of Manitoba IBD Epidemiology Database with the Emergency Department Information System of the Winnipeg Regional Health Authority from 01/01/10 to 12/31/12. We then generated a list of all Emergency Department attendances by persons with IBD at 4 of 6 hospitals within the City of Winnipeg (2 academic and 2 community hospitals). The charts were reviewed by 2 investigators extracting data on testing, consulting and treatment undertaken in the Emergency Department as well as post discharge follow up. We focused on outcomes among those attending the Emergency Department but not admitted to hospital. Of 1275 IBD patients with a first visit to the Emergency Department, 523 (41%) were for IBD-specific complaints. 327 (62.5%) were discharged from the Emergency Department without an in-hospital admission. Nearly 80% had an identified gastrointestinal (GI) specialist (either gastroenterologist or GI surgeon) involved in their care. A gastroenterologist was consulted in the Emergency Department 20% of the time. Follow-up post Emergency Department with a gastroenterologist was only documented in 36%. For those who saw a gastroenterologist in the Emergency Department there was more likely to be a change in medications and follow-up arranged with a gastroenterologist. Emergency Department consultation with a gastroenterologist was the only predictor of seeing a gastroenterologist in follow-up post Emergency Department.
We concluded that ED gastroenterology consultation is more likely to effect IBD management change. When discharged from the Emergency Department gastroenterology follow-up should be arranged and documented.
Shen B, Kochhar G, Navaneethan U, Farraye FA, Schwartz DA, Iacucci M, Bernstein CN, Dryden G, Cross R, Bruining DH, Kobayashi T, Lukas M, Shergill A, Bortlik M, Nan L, Lukas M, Tang S-J, Kotze P, Kiran RP, Dulai PS, El-Hachem S, Coelho-Prabhu N, Thakkar S, Mao R, Chen G,González Suárez B, Gonzalez Lam, Silverberg MS, Sandborn WJ. Consensus statement on endoscopic therapy for Crohn's disease strictures: practical guidelines from the Global Interventional Inflammatory Bowel Disease Group. Lancet Gastroenterology and Hepatology 2020; in press.
Stricture formation is a common complication of Crohn’s disease. Stretching open the stricture by balloon dilation through an endoscope is widely used in the management of strictures. However, there are new techniques being used as well including endoscopic electroincision and stenting. This refers to using a heated knife through the endoscope and cutting open the stricture and then placing a stent or bridge across it to keep it open. There is an important need for the standardisation of endoscopic procedures and management strategies around the time of the endoscopy. A consensus group of experts from around the world was convened who reviewed the medical literature and combined with expert opinion based on clinical experience of the consensus group, this report provides guidance on all aspects of the principles and techniques for endoscopic procedures in the treatment inflammatory bowel disease-associated strictures.
Schoenfeld R, Nguyen G, Bernstein CN. Integrated Care Models: Optimizing adult ambulatory care in inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2020; 3: 44-53.
In this article we reviewed the literature on outpatient care models used to treat adults with IBD, and proposed approaches to improve quality of care and reduce costs. A comprehensive review of recent literature on PubMed, Scopus, and Google Scholar databases about care models used to treat IBD was performed. Key terms included “inflammatory bowel disease”, “organizational models”, “patient care team”, and “quality improvement”. Studies showed that an integrated care model decreases hospital admissions, IBD-related surgeries, and comorbidities of IBD, ultimately decreasing direct and indirect costs of IBD compared to a more traditional patient-physician model. A gastroenterologist-led multidisciplinary team, involving comprehensive care by IBD nurses, a surgeon, psychologist, dietician, pharmacist, and other members as needed is recommended.
We concluded that a holistic approach to IBD care delivered by a multidisciplinary team with structured monitoring, active follow-up, patient education, and prompt access to care improves outcomes for IBD patients. More research is needed on the cost-effectiveness of integrated care models to demonstrate long-term value and secure funding for implementation. Future research should compare integrated models of care and assess patient and physician satisfaction in these models of delivering IBD care.
Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2020; 26: 150-57.
Few data exist about the utilization of combination therapy (anti-tumor necrosis factor [anti-TNF] plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use vs anti-TNF monotherapy in IBD in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005 to 2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. A total of 774 patients met inclusion criteria. 71% had Crohn's disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified; 45.3% received combination therapy, with no difference between Crohn's disease and ulcerative colitis. Crohn's disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%; P = 0.001) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%; P = 0.02). The median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab (Humira) users were as likely as infliximab (Remicade or Inflectra) users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time (P = 0.43). There was substantial variation in combination therapy use between prescribers (P = 0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy.
We concluded that use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.
El-Matary W, Leung S, Tennakoon A, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2020; 26:134-8.
Population-based studies examining the prevalence of anti-tumor necrosis factor (anti-TNF) antagonist utilization in children and young adults with IBD are lacking. We aimed to describe the trend of anti-TNF utilization in pediatric IBD over time. Survival analyses were performed for all patients diagnosed with IBD before age 18 years in the province of Manitoba to determine the time from diagnosis to first anti-TNF prescription in different time eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 with Crohn's disease and 134 with UC over the study period. The likelihood of being initiated on an anti-TNF by 1, 2, and 5 years postdiagnosis was 18.4%, 30.5%, and 42.6%, respectively. The proportion of persons aged <18 years utilizing anti-TNFs rose over time; in 2010, 13.0% of Crohn's disease and 4.9% of UC; by 2016, 60.0% of Crohn's disease and 25.5% of UC. For those diagnosed after 2012, 42.5% of Crohn's disease and 28.4% of UC patients had been prescribed an anti-TNF antagonist within 12 months of IBD diagnosis. Initiating an anti-TNF without prior exposure to an immunosuppressive agent increased over time (before 2008: 0%; 2008-2012: 18.2%; 2012-2016: 42.8%; P < 0.001). There was a significant reduction in median cumulative dose of corticosteroids in the year before anti-TNF initiation (2005-2008: 4360 mg; 2008-2012: 2010 mg; 2012-2016: 1395 mg prednisone equivalents; P < 0.001).
Over a period of 11 years, anti-TNFs are being used earlier in the course of pediatric IBD, with a parallel reduction in the cumulative corticosteroid dose.
Eissa N, Hussein H, Diarra A, Kapoor K, Gounni AS, Bernstein CN, Ghia JE. Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis. Biochemical Pharmacology 2019; 166:264-273.
Semaphorin 3E is a protein that regulates various biological processes including immune responses and apoptosis. However, its role in the pathophysiology of colitis is not fully known. We investigated the role of Semaphorin 3E in intestinal epithelial cells activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of Semaphorin 3E is reduced significantly in patients with UC and demonstrated a negative linear association between Semaphorin 3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e (gene for Semaphorin 3E) resulted in an increase in onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant Semaphorin 3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant Semaphorin 3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes.
Together, these findings identify Semaphorin 3E as a novel regulator in intestinal inflammation that regulates intestinal epithelial cells apoptosis and suggest a potential novel approach to treat UC.
Sexton K, Walker JR, Targownik LE, Graff LA, Haviva C, Beattie B, Petty S, Bernstein MT, Singh H, Miller N, Bernstein CN. The Inflammatory Bowel Disease Symptom Inventory: A patient-report scale for research and clinical application. Inflammatory Bowel Diseases 2019; 25: 1277-1290.
Existing measures of inflammatory bowel disease symptoms are not well suited to self-report, inadequate in measurement properties, insufficiently specific, or burdensome for brief or repeated administration. We aimed to develop a patient-reported outcome measure to assess a broader range of IBD symptoms. The IBD Symptoms Inventory (IBDSI) was developed by adapting symptom items from existing clinician-rated or diary-format inventories; after factor analysis, 38 items were retained on 5 subscales: bowel symptoms, abdominal discomfort, fatigue, bowel complications, and systemic complications. Participants completed the IBDSI and other self-report measures during a clinic visit. A nurse administered the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) or the Powell-Tuck Index (PTI) for ulcerative colitis (UC), and a gastroenterologist completed a global assessment of disease severity (PGA). The 267 participants with CD (n = 142) or UC (n = 125), ages 18 to 81 (Mean = 43.4 years) were 58.1% female, with a mean disease duration of 13.9 years. Confirmatory factor analysis supported the 5 subscales. The total scale and subscales showed good reliability and significant correlations with self-report symptom and IBD quality of life measures, the HBI, PTI, and PGA. The IBDSI showed strong measurement properties: a supported factor structure, very good internal consistency, convergent validity, and excellent sensitivity and specificity to clinician-rated active disease. Self-report HBI and PTI items, when extracted from this measure, produced scores comparable to clinician-administered versions. The 38-item IBDSI, or 26-item short form, can be used as a brief survey of common IBD symptoms in clinic or research settings
Elias E, Targownik LE, Singh H, Bernstein CN. A population-based study of combination versus monotherapy of anti-TNF in persons with IBD. Inflammatory Bowel Diseases 2019; 26: 150-157.
Little data exist about the utilization of combination therapy (anti-TNF plus immunosuppressives) in clinical practice. We assessed the prevalence and predictors of combination therapy use versus anti-TNF monotherapy in inflammatory bowel disease in the Canadian province of Manitoba. All 23 prescribers of anti-TNF medications for IBD in Manitoba facilitated chart review of their comprehensive lists of adult anti-TNF patients from 2005-2015. Subjects were stratified by year of first anti-TNF exposure. Patient, disease, and prescriber factors influencing combination therapy use were explored. 774 patients met inclusion criteria. 71.1% had Crohn’s disease, 28.3% had ulcerative colitis, and 0.6% had IBD unclassified. 45.3% received combination therapy with no difference between Crohn’s disease and UC. Crohn’s disease subjects receiving combination therapy were more likely to have penetrating or perianal disease (56.9% vs 42.8%) and less likely to have had previous IBD-related surgeries (36.2% vs 46.2%). Median age at diagnosis and at anti-TNF initiation was lower among combination therapy users. Adalimumab users were as likely as infliximab users to receive combination therapy but persisted with treatment for a shorter time. The proportion of new anti-TNF users receiving combination therapy did not change over time. There was substantial variation in combination therapy use between prescribers (p=0.002). The most frequently encountered reasons for avoiding combination therapy were previous intolerance or ineffectiveness of immunosuppressive monotherapy. We concluded tht the use of combination therapy has remained unchanged over time despite the publication of high-quality data supporting its efficacy over anti-TNF monotherapy.
Singh H, Bernstein CN. Sorting Through the Risks and Benefits of Thiopurine Therapy for Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology 2019; 17: 2171-2.
In this editorial we discuss the merits of thiopurine (azathioprine or 6-mercaptopurine) therapy including as monotherapy viz aviz the potential adverse effects. On balance we feel that thiopurines have animportant role as monotherapy or when used in combination with anti-TNF therapy.
Panaccione R, Steinhart AH, Bressler B, Khanna R, Marshall JK, Targownik L, Afif W, Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C, Bernstein CN. Clinical Practice Guideline for the Management of Luminal Crohn's Disease: The Toronto Consensus. Clinical Gastroenterology and Hepatology 2019; 17: 1680-1713.
Crohn's disease is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. In these guidelines we provide guidance for treatment of ambulatory patients with mild to severe active luminal Crohn’s disease. We performed a systematic review to identify published studies of the management of Crohn’s disease. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent Crohn’s disease. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent.
Steinhart AH, Panaccione R, Targownik L, Bressler B, Khanna R, Marshall JK, Afif W, , Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV Jr, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C. Clinical practice guideline for the medical management of perianal fistulizing Crohn's disease: The Toronto Consensus.
Inflammatory Bowel Diseases 2019 Jan 1;25(1):1-13.
A group of experts in Canada got together to review the literature regarding treatment of perianal fistulizing Crohn’s disease. This review serves as a clinical practice guideline for management of perianal fistulising disease.
Nugent Z, Singh H, Targownik LE, Bernstein CN. Herpes Zoster infection and Herpes Zoster vaccination in a population based sample of persons with IBD: Is there still an unmet need? Inflammatory Bowel Disease 2019 Feb 21;25(3): 532-540.
In this study we aimed to report the rates of herpes zoster infection before and after the introduction of herpes zoster vaccine (HZVac) and to determine the rates of HZVac after it became available in Manitoba in 2009. We used the population-based University of Manitoba IBD Epidemiology Database to identify cases of IBD and controls (1984-2016) who were diagnosed with HZI before and after 2009 and to determine the rate of HZVac in those older than age 50 years. Further, we explored predictors of receipt of HZVac among persons with IBD. Persons with IBD vs matched controls have higher rates of herpes zoster infection before diagnosis and postdiagnosis. Herpes zoster infection rates before 2009 per 1000 person-years were increased in persons with IBD (9.2) vs controls (7.2, P < 0.0001). Persons with IBD compared with controls were more likely to get HZVac (15.5 vs 12 per 1000 person-years). Persons newly diagnosed with IBD after 2009 and of higher socioeconomic status were more likely to get HZVac. Despite the introduction of HZVac, there was a steady rise in herpes zoster infection throughout the study period (annual percent change in infection rates of +0.54, P < 0.0001). The increased risk of herpes zoster infection in IBD may reflect an inherent risk associated with the disease or, in those already diagnosed, an increased risk secondary to the use of immunomodulating drugs. HZVac rates are very low, which may reflect physician and patient knowledge of the vaccine's availability and utility and the fact that it is not covered by the provincially provided health care plan.
Bernstein CN. Past time for doctors to lessen their dependence on corticosteroids in the treatment of IBD. American Journal of Gastroenterology 2018; 113:418-420.
This editorial reviews the risks of using corticosteroids in treatment of IBD. Corticosteroids are effective treatment for both Crohn’s disease and UC but they are often overused.
Targownik LE, Leung S, Lix L, Singh H, Bernstein CN. Persistence with immunomodulator monotherapy use and incidence of therapeutic ineffectiveness among users of immunomodulator monotherapy in IBD. American Journal of Gastroenterology 2018; 113: 1206-12.
Immunomodulator-based monotherapy with thiopurines or methotrexate is being increasingly supplanted in the management of moderate-to-severe IBD by more efficacious biologic agents. However, given their low cost, Immunomodulators may still have a selective role in this setting. We used the population-based dataset of the University of Manitoba IBD Epidemiology Database spanning from 1996 until 2014 to assess the initiation and continued use of immunomodulator monotherapy, the incidence of outcomes associated with ineffectiveness (defined as IBD-related hospitalization, IBD-resective surgery, systemic corticosteroid use, or the need for biologic therapy), and the demographic and disease-related characteristics associated with persistence on IM monotherapy and IBD-associated adverse outcomes. We found that there were 3312 persons diagnosed with IBD (1480 CD, 1832 ulcerative colitis (UC)) in the study period. The cumulative incidence of immunomodulator monotherapy use at 5 years was 46 % for CD and 24.9% for UC. Approximately one-third remained on immunomodulator monotherapy continuously for 5 years or more. Roughly three-quarters of immunomodulator users with a history of corticosteroid use had at least a 50% reduction in corticosteroid exposure in the year following immunomodulator initiation. 35% of those with CD and 30% with UC had not developed evidence of therapeutic ineffectiveness within 5 years of immunomodulator initiation; people with no history of prior corticosteroid use, no IBD hospitalizations, and persons with CD initiating immunomodulator therapy after age 40 were less likely to have an episode of therapeutic ineffectiveness while on immunomodulator monotherapy We concluded that although the majority of persons who are initiated on immunomodulator monotherapy discontinue medications and/or have evidence of therapeutic ineffectiveness a significant minority remain free of these outcomes over many years of therapy.
Ben Horin S, Andrews JM, Katsanos KH, Reider F, Steinwurz F, Karmiris K, Cheon JS, Moran GW, Cesarini M, Stone CD, Schwartz D, Protic M, Roblin X, Roda G, Chin MH, Har-Noy O, . Combination of corticosteroids and 5-aminosalicylaes or corticosteroids alone for patients with moderate-severe ulcerative colitis: A global survey of physicians’ practices. 2017; 23:2995-3002.
We aimed to understand gastroenterologists opinions about using 5ASA when more intensive therapy with corticosteroids is required. We pursued an international questionnaire exploring physicians' attitudes toward 5ASA + corticosteroid combination therapy vs corticosteroid alone. The questionnaire was distributed to gastroenterology experts in 12 countries in 5 continents. There were 349 questionnaires received (52.6% response rate). 65% said they would continue 5ASA in a patient hospitalized for intravenous corticosteroid treatment due to a moderate-severe UC flare, while 32% would stop the 5ASA (P < 0.001), and 3% were undecided. 62% would continue 5ASA in an out-patient starting oral corticosteroids. However, only 41% would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + corticosteroids were positively associated with the decision to continue 5ASA with corticosteroids. Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + corticosteroids for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.
Bernstein CN. The impact of the placebo effect in Crohn’s disease. Alimentary Pharmacology and Therapeutics 2017; 45(11):1471-1472.
This editorial discusses the role of placebo in Crohn’s disease treatment trials.
Bernstein CN and Kornbluth A. Yes, we are still talking about cyclosporin versus infliximab in steroid resistant acute severe ulcerative colitis. American Journal of Gastroenterology 2017;112(11):1719-1721.
This editorial discusses the use of cyclosporine as a useful drug to treat persons with acute severe UC in hospital.