Venner JM, Bernstein CN. Immunomodulators: Still having a role? Gastroenterology Reports (Oxf). 2022 Nov 8:10.

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Immunomodulators, particularly the thiopurines and to a lesser extent methotrexate, were standard-of-care for inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, for over 40 years. While there has been a renaissance in available therapies with the advent of biologics and small molecules, an impetus remains for the ongoing use of thiopurines and methotrexate. This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies. This article summarizes the data behind immunomodulator use in Crohn’s disease, focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.

 

 

Ma C, Hanzel J, Panaccione R, Sandborn WJ, D’Haens GR, Ahuja V, Atreya R, Bernstein CN, Bossuyt P, Bressler B, Bryant RV, Cohen B, Colombel JF, Danese S, Dignass A, Dubinsky MC, Fleshner PR, Gearry RB, Hanauer SB, Hart A, Kotze PG, Kucharzik T, Lakatos PL, Leong RW, Magro F, Panes J, Peyrin-Biroulet L, Ran Z, Regueiro M, Singh S, Spinelli A, Steinhart AH, Travis SP, van der Woude CJ, Yacyshyn B, Yamamoto T, Allez M, Bemelman WA, Lightner AL, Louis E, Rubin DT, Scherl EJ, Siegel CA, Silverberg MS, Vermeire S, Parker CE, McFarlane SC, Guizzetti L, Smith MI, Vande Casteele N, Feagan BG, Jairath V. CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease. Gastroenterology 2022; 163: 950-964.

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End points to determine the efficacy and safety of medical therapies for Crohn's disease and ulcerative colitis are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in IBD. Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists.  Results: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for ulcerative colitis. In Crohn’s disease, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In ulcerative colitis, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. Conclusions: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of Crohn’s disease and ulcerative colitis.

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Li L, Aviña-Zubieta JA, Bernstein CN, Kaplan GG, Tremlett H, Xie H, Peña-Sánchez JN, Marrie RA, Etminan M. The Risk of Multiple Sclerosis Among Users of Anti-tumor Necrosis Factor Alpha in four Canadian provinces: A Population-Based Study. Neurology 2023; 100: e558-e567.

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Antitumor necrosis factor α (TNFα) agents are a class of biologic drugs used for the treatment of several immune-mediated conditions. An increased risk of multiple sclerosis with their use has been suggested, but studies have been limited. Relevant population-based epidemiologic data linking anti-TNFα to multiple sclerosis are scarce. The objective was to compare the risk of multiple sclerosis in anti-TNFα users with nonusers among patients with rheumatic disease or IBD. A nested case-control study was conducted. Population-based health care-linked databases from 4 Canadian provinces were used. All patients with rheumatic diseases or IBD residing within a participating province between January 2000 and March 2018 were identified by validated case definitions. Any anti-TNFα dispensation in the 2 years before the index date (Multiple sclerosis onset) was identified. Incident onset multiple sclerosis cases were ascertained using a validated algorithm. Up to 5 controls were matched to each multiple sclerosis case based on birth year ±3 years, disease duration, and health authority (based on region of residence). Conditional logistic regressions were used to calculate the incidence rate ratio after adjusting for potential confounders. A meta-analysis was conducted to provide pooled estimates across provinces using random-effects models. Results: Among 296,918 patients with rheumatic diseases patients, 462 multiple sclerosis cases (80.1% female, mean [SD] age, 47.4 [14.6] years) were matched with 2,296 controls (59.5% female, mean [SD] age, 47.4 [14.5] years). Exposure to anti-TNFα occurred in 18 multiple sclerosis cases and 42 controls. After adjusting for matching variables, sex, and the Charlson Comorbidity Index, the pooled incidence rate ratio was 2.05 (95% CI, 1.13-3.72). Among 84,458 patients with IBD, 190 multiple sclerosis cases (69.5% female, mean [SD] age, 44.3 [12.3] years) were matched with 943 controls (54.1% female, mean [SD] age, 44.2 [12.2] years). Exposure to anti-TNFα occurred in 23 multiple sclerosis cases and 98 controls. The pooled adjusted IRR was 1.35 (95% CI, 0.70-2.59). Conclusions: The use of anti-TNFα was associated with an increased risk of multiple sclerosis compared with nonusers, especially among patients with RD. These findings could help clinicians and patients with rheumatic diseases to make more informed treatment decisions. Further studies are needed to validate these results for patients with IBD.

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Heron V, Panaccione N, Restellini S, Germain P, Candido K, Bernstein CN, Bessissow T, Bitton A, Chauhan UK, Lakatos PL, Marshall JK, Michetti P, Seow CH, Rosenfeld G, Panaccione R, Afif W. Efficacy of intravenous ustekinumab reinduction in patients with Crohn’s disease with a loss of response. Journal of the Canadian Association of Gastroenterology 2022; 5: 208-213.

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In patients receiving ustekinumab for treatment of Crohn's disease, there is no proven strategy to enhance or re-capture response. We assessed the utility of ustekinumab intravenous (IV) reinduction (~6 mg/kg) to achieve clinical, biochemical and endoscopic response or remission, in patients with partial or loss of response to ustekinumab maintenance therapy. A multicentre, retrospective cohort study was performed. Adults who received an IV reinduction dose of ustekinumab for either partial response or secondary loss of response to ustekinumab were assessed. The primary outcome was clinical remission off corticosteroids (Harvey Bradshaw Index less than 5), with biochemical response (defined as at least 50% decrease of CRP or fecal calprotectin and/or endoscopic response (defined as a decrease in Simple Endoscopic Score-CD greater than 50%). Secondary outcomes included clinical, biomarker and endoscopic response/remission, as well as safety. Results: 65 patients (median age 38 years, 54.7% women) underwent IV ustekinumab reinduction between January 2017 and April 2019. Most patients (88.3%) were already on escalated maintenance dosing of ustekinumab 90 mg subcutaneous every 4 weeks. Clinical outcomes were assessed at a median of 14 weeks (IQR: 12-19) post-reinduction. The primary outcome of clinical remission off corticosteroids with biochemical and/or endoscopic response was achieved in 31.0% (n = 18). Pre-reinduction ustekinumab concentrations were ≥1 μg/mL in 88.6% (mean 3.2 ± 2.0 μg/mL). No serious adverse events were reported. Conclusions: Ustekinumab IV reinduction can be effective in patients with Crohn's disease with partial or loss of response to ustekinumab maintenance therapy. Further studies evaluating this strategy are warranted.

 

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Targownik LE, Bernstein CN, Benchimol EI, Kaplan GG, Singh H, Tennakoon A, Nugent Z, Coward SB, Kuenzig ME, Murthy SK. Earlier Anti-TNF initiation leads to long term lower health care utilization in Crohn’s disease but not in ulcerative colitis. Clinical Gastroenterology and Hepatology 2022: in press.

 

The timing of initiating biologic therapy in persons with Crohn’s disease and ulcerative colitis is an area of ongoing controversy. In particular, there is concern that delaying the initiation of biologic therapy may lead to more treatment resistant disease, which can result in more complications and hospitalizations. We used the University of Manitoba IBD Epidemiologic Database derived from health administrative data to identify all persons with a new diagnosis of IBD between 2001 and 2018 who received anti-TNF therapy and had at least one year of post anti-TNF initiation follow-up. We measured the rates of hospitalization, surgery, and outpatient visits, prior to and for up to 5 years following anti-TNF initiation. We compared the rates of these health care utilization outcomes between persons receiving anti-TNFs at less than 2 years following diagnosis and those receiving anti-TNFs at more than 2 years following IBD diagnosis. We used inverse probability treatment weighting (IPTW) to adjust for baseline differences in risk between the two groups. In persons with Crohn’s disease, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy. Incidence of resective surgery was also lower in earlier anti-TNF initiators with Crohn’s disease if the first year following initiation was excluded from the analysis. There was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery for persons with ulcerative colitis.

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Earlier administration of anti-TNF therapy is associated with reduced downstream health care resource utilization in Crohn’s disease, though these impacts are not as evident in ulcerative colitis.

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Shen B, Kochhar GS, Kariv R, Rex DR, Sugita A, Rubin DT, Navaneethan U, Hull TL, Ko HM, Liu X, Kachnic LA, Strong S, Iacucci M, Bemelman W, Fleshner P, Safyan RA, Kotze PG, D'Hoore A, Faiz O, Lo S, Ashburn JH, Spineli A, Bernstein CN, Kane SV, Cross RK, Schairer J, McCormick JT, Farraye FA, Chang S, Scherl E, Schwartz DA, Bruining DH, Philpott J, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sandborn WJ, Silverberg MS, Pardi DS, Church J, Kiran RP. Management of Pouch Neoplasia: A Consensus Guideline from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022; in press.

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Shen B, Kochhar GS, Rubin DT, Kane SV, Navaneethan U, Bernstein CN, Cross RK, Sugita A, Schairer J, Kiran RP, Fleshner P, McCormick JT, D'Hoore A, Shah SA, Farraye FA, Kariv R, Liu X, Rosh J, Chang S, Scherl E, Schwartz DA, Kotze PG, Bruining DH, Philpott J, Abraham B, Segal J, Sedano R, Kayal M, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sehgal P, Picoraro JA, Vermeire S, Sandborn WJ, Silverberg MS, Pardi DS. Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022 Jan;7(1):69-95. 

 

Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of IBD in patients with pouches are similar to those in patients without pouches.

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Targownik LE, Bernstein CN, Lakatos PL, Murthy SK, Benchimol EI, Bitton A, Huang JG, Kuenzig ME, Jones JL, Kaplan GG, Lee K, Mukhtar MS, Tandon P, Windsor JW, Panaccione R. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Risk Factors and Medications. Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S40-S45.

 

IBD is a disease that results from dysregulation of the immune system and frequently requires medications that can affect the immune response to infections; therefore, it was imperative to quickly understand the risk of COVID-19 infection on persons living with IBD and how that risk may be increased by commonly used IBD medications. The IBD research community in Canada and beyond quickly established collaborative efforts to better understand the specific risk posed by COVID-19 on persons with IBD. We learned that IBD itself was not a risk factor for death or serious complications of COVID-19, and that most commonly used drug classes (with the notable exception of corticosteroids) do not increase the risk of COVID-19-related adverse outcomes. The risk factors for serious complications and death from COVID-19 appear to be similar to those identified in the wider population; those being advanced age, having pre-existing heart or lung disease, and smoking. We recommend that persons with IBD do not alter their course of therapy to avoid complications of COVID-19, though the indiscriminate use of corticosteroids should be avoided. Persons with IBD should follow the same public health recommendations as the general population to reduce their personal risk of acquiring COVID-19.

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Murthy SK, Kuenzig ME, Windsor JW, Ghia JE, Griffiths AM, Panaccione R, Seow CH, Benchimol EI, Bernstein CN, Bitton A, Huang JG, Jones JL, Lee K, Kaplan GG, Mukhtar MS, Tandon P, Targownik LE Gibson D. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: COVID-19 Vaccines-Biology, Current Evidence and Recommendations. Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S54-S60.

 

The COVID-19 pandemic has ushered a globally focused vaccine development program that produced multiple successful vaccines within a year. Four SARS-CoV-2 vaccines have been approved for use in Canada, using two different technologies, all of which have shown excellent efficacy in reducing the rate of symptomatic COVID-19 infection and 100% efficacy in preventing death from COVID-19. People with IBD, like many others with immune-mediated chronic diseases, were excluded from the pivotal trials of these vaccines, leading to early hesitancy by regulatory bodies to endorse administering the vaccines to these groups. However, recent data has shown that the adverse event rate to SARS-CoV-2 vaccine among people with IBD is similar to the general population. Early data have further shown that people with IBD are capable of mounting a robust immune response to SARS-CoV-2 vaccines, particularly following a second dose, whereas the response to the first dose is blunted in those receiving anti-TNF therapy or conventional immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Based on these data and evidence from previous vaccine programs among people with IBD, multiple national and international expert panels have recommended that individuals with IBD receive complete vaccination against SARS-CoV-2 as soon as possible.

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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 2021; 4: 57-64.

 

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.

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Singh A, Mahajan R, Kedia S, Dutta AK, Anand A, Bernstein CN, Desai D, Pai CG, Makharia G, Tevethia HV, Mak JW, Kaur K, Peddi K, Ranjan MK, Arkkila P, Kochhar R, Banerjee R, Sinha SK, Ng SC, Hanauer S, Verma S, Dutta U, Midha V, Mehta V, Ahuja V, Sood A. Use of thiopurines in inflammatory bowel disease: an update. Intestinal Research 2021; in press.

 

This is a review of thiopurine use to treat IBD in India. IBD, once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

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Targownik LE, Bernstein CN, Benchimol EI, Kaplan GG, Singh H, Tennakoon A, Nugent Z, Coward SB, Kuenzig ME, Murthy SK. Trends in Corticosteroid Use During the Era of Biologic Therapy: A Population Based Analysis. American Journal of Gastroenterology 2021; 116:1284-1293. 

 

Corticosteroids are effective for inducing clinical remission in IBD, but not for maintaining remission. Reducing corticosteroid use and dependence is an important treatment goal since their use is associated with adverse events. The extent to which the improvements in IBD therapy have led to less corticosteroid use in the modern era remains unclear. We used the University of Manitoba Inflammatory Bowel Disease Epidemiologic Database to assess the cumulative annual dosing of corticosteroids on a per-patient basis for all persons with IBD in the province of Manitoba between 1997 and 2017. Joinpoint analysis was used to assess for trends in corticosteroid use and to look at variation in the trends over time. The mean annual exposure to corticosteroids decreased from 419 mg/yr (1997) to 169 mg/yr (2017) for Crohn's disease (annual decline: 3.8% per year, 95% confidence interval 3.1-4.6) and from 380 to 240 mg/yr in ulcerative colitis (annual decline: 2.5% per year, 95% confidence interval 2.1-2.8). In Crohn's disease there was an acceleration in the rate of decline after 2007 (pre-2007, 1.9% decline per year; after 2007, 5.7% per year); there was no corresponding acceleration in the rate of decline in ulcerative colitis.

 

We concluded that corticosteroid use has decreased in both Crohn's disease and ulcerative colitis over the past 2 decades, becoming more pronounced after 2007 in Crohn's disease. Potential explanations include introduction and increasing penetrance of biologic therapy in Crohn's disease and greater awareness of corticosteroid-related adverse events in IBD. Further work is required understand the drivers of persistent corticosteroid use in IBD and how this can be further reduced.

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Dolovich C, Bernstein CN, Singh H, Nugent Z, Tennakoon A, Shafer LA, Marrie RA, Sareen J, Targownik L. Anxiety and Depression Leads to Anti-Tumor Necrosis Factor Discontinuation in Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology. 2021;19(6):1200-1208. 

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Anxiety and mood disorders are common among persons with inflammatory bowel diseases (IBD) and are associated with increased health care use and lower quality of life. We assessed the effects of anxiety and mood disorders on persistence on anti-tumor necrosis factor (anti-TNF) therapy in patients with IBD, and risk of IBD-related adverse outcomes after therapy initiation. We identified all persons with IBD in Manitoba who were dispensed an anti-TNF agent from 2001 through 2016 and then identified those with a validated administrative definition of anxiety and mood disorders in the 2 years before initiation of therapy. Survival analysis was used to assess the association between active anxiety and mood disorders and anti-TNF discontinuation and the first occurrence of an IBD-related adverse outcome (defined as IBD-related hospitalization or surgery, new or recurrent corticosteroid use, switching to an alternative anti-TNF, or death). We identified 1135 persons with IBD who began anti-TNF therapy; 178 of these patients (15.7%) met the diagnostic criteria for an anxiety and mood disorder. Anxiety and mood disorders significantly increased risk of discontinuation of anti-TNF therapy (adjusted hazard ratio, 1.28; 95% CI, 1.03-1.59) and discontinuation in the 1 year following anti-TNF initiation (hazard ratio, 1.50; 95% CI, 1.15-1.94). There was no association between AMDs and subsequent risk of IBD-related adverse events.

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We concluded that patients with IBD and an AMD within 2 years before starting anti-TNF therapy are at increased risk of discontinuing therapy, compared to patients with IBD without anxiety and mood disorders. Studies are needed to determine if treatment of anxiety and mood disorders increases compliance with treatment.

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Murthy SK, Begum J, Benchimol EI, Kaplan GG, Targownik LE, Singh H, Bernstein CN, McCurdy JD, Taljaard. Introduction of anti-TNF therapy has not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study. Gut 2020; 69: 274-282.

 

We evaluated the effect of introduction of infliximab in Ontario on the population rates of major health events and direct costs in persons with IBD. We studied all adult patients with Crohn’s disease (CD) and ulcerative colitis (UC) living in Ontario, Canada between July 1, 1995 and March 31, 2012 using population-level health administrative data. Marketplace introduction of infliximab in CD did not have a significant immediate  or gradual impact on the rate of IBD-related hospitalizations, nor an immediate or gradual impact on the rate of intestinal resections. Marketplace introduction of infliximab in UC was not associated with an immediate effect but was associated with a gradual decrease in IBD-related hospitalization rates. There were no significant persistent effects of infliximab availability on colectomy rates among UC patients nor on the rates of non-IBD hospitalizations or other major abdomino-thoracic surgeries (control outcomes) among CD or UC patients. We concluded that robust market penetration of infliximab among CD patients has not resulted in a meaningful reduction in the population rates of IBD-related hospitalizations or intestinal resections. Despite the absence of UC-related colectomies there was a reduction in UC-related hospitalization rates. Since we know these drugs can have dramatic effects in a substantial number of patients we believe that the absence of an impact of infliximab on key outcomes likely relates to underuse of this agent in the target populations.

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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; 5(4): 393-405.

 

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.

 

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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.

 

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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.

 

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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).

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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.

 

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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.

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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.

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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.

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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

 

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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.

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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.

 

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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.

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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.

 

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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.

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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.

 

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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.

 

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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.

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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.

 

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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.

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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. 

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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.

 

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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.

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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.

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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.

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