Shane M. Devlin

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

BACKGROUND & AIMSnThe 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.nnnMETHODSnA 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnOptimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy.

There are limited therapeutic options available for patients with autoimmune hepatitis in whom conventional treatment fails. A case series of five patients unresponsive to or unable to take azathioprine, 6-mercaptopurine or corticosteroids who were treated with mycophenolate mofetil (MMF) is reported. While on MMF, alanine aminotransferase normalized or remained normal in all patients. MMF had a steroid-sparing effect and histological remission was demonstrated in one patient after seven months of MMF. One patient experienced an uncomplicated episode of pyelonephritis. In conclusion, MMF can effectively induce and maintain remission in refractory autoimmune hepatitis patients.

Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease.

Background:Cannabinoids are used by patients with inflammatory bowel disease (IBD) to alleviate their symptoms. Little is known on patient motivation, benefit, or risks of this practice. Our aim was to assess the extent and motives for Cannabis use in patients with IBD and the beneficial and adverse effects associated with self-administration of Cannabis. Methods:Consecutive patients with IBD (n = 313) seen in the University of Calgary from July 2008 to March 2009 completed a structured anonymous questionnaire covering motives, pattern of use, and subjective beneficial and adverse effects associated with self-administration of Cannabis. Subjects who had used Cannabis specifically for the treatment of IBD or its symptoms were compared with those who had not. Logistic regression analysis was used to identify variables predictive of poor IBD outcomes, specifically surgery or hospitalization for IBD. Results:Cannabis had been used by 17.6% of respondents specifically to relieve symptoms associated with their IBD, the majority by inhalational route (96.4%). Patients with IBD reported that Cannabis improved abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%), and diarrhea (28.6%), although side effects were frequent. The use of Cannabis for more than 6 months at any time for IBD symptoms was a strong predictor of requiring surgery in patients with Crohns disease (odds ratio = 5.03, 95% confidence interval = 1.45–17.46) after correcting for demographic factors, tobacco smoking status, time since IBD diagnosis, and biological use. Cannabis was not a predictor for hospitalization for IBD in the previous year. Conclusions:Cannabis use is common in patients with IBD and subjectively improved pain and diarrheal symptoms. However, Cannabis use was associated with higher risk of surgery in patients with Crohns disease. Patients using Cannabis should be cautioned about potential harm, until clinical trials evaluate efficacy and safety.

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti–Tumor Necrosis Factor Therapy for Crohn’s Disease: A Meta-analysis of Placebo-controlled Trials

BACKGROUND & AIMSnThere is debate over whether patients with Crohns disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy.nnnMETHODSnWe performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohns disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents.nnnRESULTSnOverall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.)nnnCONCLUSIONSnOn the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

The Appropriateness of Concomitant Immunomodulators With Anti–Tumor Necrosis Factor Agents for Crohn's Disease: One Size Does Not Fit All

BACKGROUND & AIMSnThere is no consensus on the appropriateness of concomitant immunomodulators with anti-tumor necrosis factor (TNF) therapy for Crohns disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohns disease.nnnMETHODSnA literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohns disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index.nnnRESULTSnConcomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios.nnnCONCLUSIONSnThe appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohns disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.

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.

Systematic review: the short‐term and long‐term efficacy of adalimumab following discontinuation of infliximab

Backgroundu2002 Therapy with adalimumab has been shown to be effective in Crohn’s disease (CD) patients who have lost response or are intolerant to infliximab.

Optimizing the safety of biologic therapy for IBD

The introduction of biologic therapy for the treatment of IBD has substantially changed its management. The safety concerns associated with biologic therapies include the increased risk of infection, autoimmunity, development of lymphoma and demyelinating disease, and the risk of worsening heart failure. There are several strategies for minimizing the risks associated with biologic therapies. Pretreatment strategies include taking a proper history from the patient, physical examination of the patient, screening for latent tuberculosis and ruling out sepsis. Vaccination of patients against vaccine preventable diseases is also recommended. During treatment, patients should be closely monitored and any symptoms that develop should be dealt with early. Education of physicians and patients is also important to allow the early detection of any adverse events.

Overview of Subsequent Entry Biologics for the Management of Inflammatory Bowel Disease and Canadian Association of Gastroenterology Position Statement on Subsequent Entry Biologics

The advent of biologic molecules is one of the most important therapeutic advances to have occurred in the medical management of inflammatory bowel disease (IBD). From a Canadian perspective, the monoclonal antibodies directed against tumour necrosis factor-alpha (TNF-α), namely infliximab (Remicade, Johnson & Johnson, USA) and adalimumab (Humira, AbbVie Corporation, USA), are the only approved and commercially available biologics for the treatment of either Crohn disease (CD) or ulcerative colitis (UC) in Canada. n nThese molecules have a large and complex structure and are generated with the aid of DNA recombination technology. This complexity makes the development of biologically similar substitutes – as is common with smaller, less complex molecules – a challenge. However, following the expiry of the patent on Remicade, a biosimilar infliximab has been developed (CT-P13, Remsima [Celltrion, South Korea], Inflectra [Hospira Inc, USA]). In addition, another biosimilar infliximab has been developed by an Indian pharmaceutical company, Reliance Life Sciences. n nStandard, small-molecule pharmaceuticals are significantly different from their complex biological counterparts (Figure 1). Most synthesized pharmaceuticals have a molecular size of only a few hundred Daltons (Da) (eg, omeprazole is 345 Da). In comparison, infliximab is 149,000 Da. Moreover, monoclonal antibodies have a complex structure that is influenced by the vector and post-translational modification, among other factors (1–3). In addition, although the overall structure of a monoclonal antibody may be known, the manufacturing platform used by the manufacturer of the reference biologic drug (RBD) is not, due to the proprietary nature of the information. As such, a different biological system that is used to produce a biosimilar agent will likely translate into subtle differences that could be difficult to characterize. Such differences have the potential to translate into clinically relevant differences in efficacy, safety and immunogenicity. Therefore, it will be extremely challenging to ensure that a subsequent entry biologic (SEB) is, in fact, ‘equivalent’ to the RBD. Clinical equivalence can only be proven in clinical trials. n n n nFigure 1) n nComparison between a biologic monoclonal antibody and an acetylsalicylic acid molecule. From Kozlowski S, Woodcock J, Midthun K, Behrman Sherman R. Developing the Nation’s Biosimilars Program. N Engl J Med 2011;365:385–8. Reprinted with ... n n n nIt is important for the Canadian gastroenterology community to gain a full understanding of the important issues in the context of the development and entry into the marketplace of such biologic agents. n n nThe objectives of the present document are to: n n nProvide a brief primer on the terminology germane to this issue. n n nDescribe the current state of SEBs and the existing guidelines from Health Canada and other jurisdictions. n n nProvide perspective on the potential opportunity in the Canadian marketplace for SEBs in the arena of IBD. n n nProvide a brief overview of the existing data, generated from two trials conducted in rheumatoid arthritis and ankylosing spondylitis, for infliximab-Celltrion (Remsima). n n nIdentify areas that will require careful thought and attention moving forward. n n nProvide a current position statement from the Canadian Association of Gastroenterology (CAG) regarding SEBs.

Combination of Innate and Adaptive Immune Alterations Increased the Likelihood of Fibrostenosis in Crohn’s Disease

Background: Mutations in the nucleotide oligomerization domain‐2 (NOD2) gene and positive antibodies to microbial antigens have been found to be associated with the Crohns disease (CD) phenotype, fibrostenosis. The aim of this study was to confirm these relationships in a large cohort of CD patients and to determine the correlation between the presence of NOD2 variants and antibodies to oligomannan, CBir, outer membrane porin‐C (OmpC), and I2 in CD patients with fibrostenosis. Methods: Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)‐like as well as other clinical features. Results: The presence of NOD2 allelic variants was primarily associated with fibrostenosis, secondarily with small bowel disease and small bowel surgery, and was inversely associated with UC‐like disease. This association was present in patients with a fibrostenosis only (Vienna B2) and those with both stricturing and penetrating disease. The presence and level of antibodies to microbial antigens was also associated with the fibrostenosis phenotype. In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy. Conclusions: Defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype. (Inflamm Bowel Dis 2009;)