Cynthia H. Seow

Clinical Practice Guidelines for the Medical Management of Nonhospitalized Ulcerative Colitis: The Toronto Consensus

BACKGROUND & AIMS The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS A systematic literature search identified studies on the management of UC. 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 working group of specialists. RESULTS The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Comparative Effectiveness of Immunosuppressants and Biologics for Inducing and Maintaining Remission in Crohn's Disease: A Network Meta-analysis

BACKGROUND & AIMS There is controversy regarding the best treatment for patients with Crohns disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohns disease, based on direct and indirect evidence. METHODS We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohns disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI). RESULTS Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti-tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4-7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6). CONCLUSIONS Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohns disease.

Decreasing Colectomy Rates for Ulcerative Colitis: A Population-Based Time Trend Study

OBJECTIVES:Colectomy rates for ulcerative colitis (UC) have been inconsistently reported. We assessed temporal trends of colectomy rates for UC, stratified by emergent vs. elective colectomy indication.METHODS:From 1997 to 2009, we identified adults hospitalized for a flare of UC. Medical charts were reviewed. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. Logistic regression analysis compared: (i) UC patients responding to medical management in hospital to those who underwent colectomy; (ii) UC patients who underwent an emergent vs. elective colectomy; and (iii) temporal trends of drug utilization.RESULTS:From 1997 to 2009, colectomy rates significantly dropped for elective colectomies with an AAPC of −7.4% (95% confidence interval (CI): −10.8%, −3.9%). The rate of emergent colectomies remained stable with an AAPC of −1.4% (95% CI: −4.8%, 2.0%). Azathioprine/6-mercaptopurine prescriptions increased from 1997 to 2009 (odds ratio (OR)=1.15; 95% CI: 1.09–1.22) and infliximab use increased after 2005 (OR=1.68; 95% CI: 1.25–2.26). A 13% per year risk adjusted reduction in the odds of colectomy (OR=0.87; 95% CI: 0.83–0.92) was observed in UC patients responding to medical management compared with those who required colectomy. Emergent colectomy patients had a shorter duration of flare (<2 weeks vs. 2–8 weeks, OR=5.31; 95% CI: 1.58–17.81) and underwent colectomy early after diagnosis (<1 year vs. 1–3 years, OR=5.48; 95% CI: 2.18–13.79).CONCLUSIONS:From 1997 to 2009, use of purine anti-metabolites increased and elective colectomy rates in UC patients decreased significantly. In contrast, emergent colectomy rates were stable, which may have been due to rapid progression of disease activity.

Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease.

Background  Anti‐Tumour necrosis factor (TNF) therapy is now well established in the treatment of inflammatory bowel disease and the risk of opportunistic infection is recognized. However, specific considerations regarding screening, detection, prevention and treatment of chronic viral infections in the context of anti‐TNF therapy in inflammatory bowel disease are not widely adopted in practice.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

BACKGROUND & AIMS The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohns disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.

Cumulative Incidence of Second Intestinal Resection in Crohn's Disease: A Systematic Review and Meta-Analysis of Population-Based Studies

OBJECTIVES:Approximately 50% of Crohn’s disease patients undergo an intestinal resection within 10 years of diagnosis. The risk of second surgery in Crohn’s disease and the influence of time are not well characterized. We performed a systematic review and meta-analysis to establish the risk of second abdominal surgery in patients with Crohn’s disease among patients who had a previous surgery.METHODS:We searched Medline, EMBASE, PubMed (March 2014), and conference proceedings for terms related to Crohn’s disease and intestinal surgery. We included population-based articles (n=11) and an abstract (n=1) reporting surgical risk for the overall study period and for 5 and 10 years after the first surgery for Crohn’s disease. We stratified studies by year (start year before vs. after 1980) to explore the role of time.RESULTS:For all population-based studies, the overall risk of second surgery was 28.7% (95% confidence interval (CI): 22.6–36.6%). The 5-year risk of second surgery was 24.2% (95% CI: 22.3–26.4%). The 10-year risk of second surgery was 35.0% (95% CI: 31.8–38.6%). A significant difference in the 10-year risk of second surgery was observed over time such that studies conducted after 1980 had a lower risk of second surgery (33.2%; 95% CI: 31.2–35.4%) compared with those that started before 1980 (44.6%; 95% CI: 37.7–52.7%).CONCLUSIONS:Approximately one-quarter of Crohn’s disease patients who have a first surgery also have a second, and the majority of these surgeries occur within 5 years of the first surgery. The 10-year risk of second surgery is significantly decreasing over time.

Prednisolone and Budesonide for Short- and Long-Term Treatment of Microscopic Colitis: Systematic Review and Meta-analysis

BACKGROUND & AIMS The incidence of microscopic colitis and its disease burden are increasing, yet there is limited systematic information addressing the use of conventional corticosteroids and budesonide in microscopic colitis. We performed a systematic review and meta-analysis on the short- and long-term efficacy of corticosteroids in treatment of microscopic colitis. METHODS Randomized controlled trials that met predetermined selection criteria were included. Articles were identified through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, proceedings of major gastroenterology meetings, and reference lists of trials and review articles. RESULTS Eight randomized trials were identified. A total of 248 patients were randomized to corticosteroid versus placebo. The intervention was budesonide in 7 trials and prednisolone in 1 trial. Budesonide was significantly more effective than placebo for short-term clinical response (risk ratio [RR], 3.07; 95% confidence interval [CI], 2.06-4.57) and long-term clinical response (RR, 3.22; 95% CI, 1.05-9.89). Prednisolone was not superior to placebo for short-term clinical response (RR, 2.00; 95% CI, 0.38-10.58). Histologic improvement was seen with both short- and long-term budesonide (RR, 3.76; 95% CI, 2.00-7.06, and RR, 2.50; 95% CI, 1.25-4.98, respectively). Symptom relapse occurred in 46%-80% of patients within 6 months of treatment cessation. Withdrawal because of adverse effects occurred in 4.4% of patients, with no difference between study groups (P = .55). CONCLUSIONS Both short- and long-term treatment with budesonide is effective and well-tolerated for microscopic colitis. However, the rate of symptom relapse once budesonide is discontinued is high. Further studies are needed to determine optimal treatment duration, dose, and withdrawal procedure.

Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.

With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the skin. Dermatological adverse events may be confused with extra‐intestinal manifestations of IBD.

C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) or both? A systematic evaluation in pediatric ulcerative colitis

BACKGROUND There has not been an extensive comparison of CRP and ESR in ulcerative colitis (UC), and thus, we aimed to explore their utility in UC. METHODS Four previously enrolled cohorts of 451 children with UC were utilized, all including laboratory, clinical and endoscopic data. A longitudinal analysis was performed on prospectively collected data of 75 children. Disease activity was captured by both global assessment and pediatric UC activity index (PUCAI). RESULTS The best thresholds to differentiate quiescent, mild, moderate and severe disease activity, were <23, 23-29, 30-37, >37 mm/h for ESR, and <2.5, 2.5-5, 5.01-9, >9 mg/L for CRP (area under the ROC curves 0.70-0.81). Correlation of endoscopic appearance with CRP and ESR were 0.55 and 0.41, respectively (P<0.001). Both CRP and ESR may be completely normal in 34% and 5-10% of those with mild and moderate-severe disease activity, respectively. Elevated CRP in the presence of normal ESR or vice versa was noted in 32%, 38%, 30% and 17% of those with quiescent, mild, moderate and severe disease activity. Over time, the utility of CRP and ESR in reflecting disease activity remained stable in 70-80% of cases. CONCLUSION In ~2/3 of children, both CRP and ESR values reflect disease activity to a similar degree and in the remaining, either CRP or ESR may be sufficient, with slight superiority of CRP. CRP is more closely correlated with endoscopic appearance. When either CRP or ESR performs well for a given patient, this is likely to remain so over time. Therefore, it may not be justified to routinely test both ESR and CRP in monitoring disease activity.

Phenotypic features of Crohn's disease associated with failure of medical treatment.

BACKGROUND & AIMS There is conflicting evidence on the effects of thiopurines (azathioprine or mercaptopurine) and anti-tumor necrosis factor (TNF) therapies on rates of surgery among patients with Crohns disease (CD). We aimed to identify factors that identify patients who are unlikely to respond to medical therapy and will therefore require surgery. METHODS We performed a retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry to identify 425 patients diagnosed with CD who received a prescription of a thiopurine and/or an anti-TNF agent from a referral center, from July 1, 1975, through September 13, 2012. We collected data on CD-related abdominal surgery after therapy and disease features when therapy was instituted. Cox proportional regression models were used to associate disease features with outcomes after adjusting for potential confounders. Risk estimates were presented as hazard rate ratios (HRRs) with 95% confidence intervals (CIs). RESULTS Among patients given thiopurines, stricturing disease (adjusted HR, 4.63; 95% CI, 2.00-10.71), ileal location (adjusted HR, 6.20; 95% CI, 1.64-23.42), and ileocolonic location (adjusted HR, 3.71; 95% CI, 1.08-12.74) at the time of prescription were associated significantly with the need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with patients prescribed only a thiopurine (adjusted HR, 0.41; 95% CI, 0.22-0.75). Among patients given anti-TNF agents, stricturing (adjusted HR, 6.17; 95% CI, 2.81-13.54) and penetrating disease (adjusted HR, 3.39; 95% CI, 1.45-7.92) at the time of prescription were associated significantly with surgery. Older age at diagnosis (17-40 y) reduced the risk for abdominal surgery (adjusted HR, 0.41; 95% CI, 0.21-0.80) compared with a younger age group (≤16 y). Surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines (adjusted HR, 0.33; 95% CI, 0.13-0.68) or anti-TNF agents (adjusted HR, 0.49; 95% CI, 0.25-0.96). Terminal ileal disease location was not associated with a stricturing phenotype. CONCLUSIONS Based on a retrospective database analysis, patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages; delayed treatment increases rates of treatment failure.