Citations

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn’s disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Objective Vedolizumab is a gut-selective antibody to α 4 β 7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Conclusions Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. Trial registration number NCT01177228, NCT00619489 , NCT00783718 , NCT00783692 , NCT01224171 , NCT00790933 .

SummaryBackgroundReal‐world comparative benefits and risks of infliximab (IFX) and adalimumab (ADA) in patients with ulcerative colitis (UC) are unclear.AimTo evaluate the comparative effectiveness and safety of IFX and ADA in patients with UC who were new users of anti‐TNF agents.MethodsUsing an administrative claims database (Optum Labs Data Warehouse), we identified patients who received first anti‐TNF (IFX, ADA) prescription after a 12‐month period without any anti‐TNF treatment (baseline), and with a minimum 6‐month follow‐up after anti‐TNF initiation. Primary outcome measures were: all‐cause and UC‐related hospitalisation, abdominal surgery, corticosteroid use >60 days after starting anti‐TNF, and serious infections. We performed 2:1 propensity‐score matched Cox proportional hazard analysis, and inverse probability‐of‐treatment weight (IPTW) analysis, accounting for healthcare utilisation, comorbidities and use of UC‐related medication.ResultsWe included 1400 new users of anti‐TNF agents (age, 43 ± 15 years; 52% males), from 2006 to 2014. On propensity‐score matched analysis, there was no significant difference in the risk of UC‐related hospitalisation [IFX vs. ADA; adjusted hazard ratio (aHR), 1.04; 95% confidence interval (CI) 0.71–1.51], corticosteroid use (aHR, 0.85; 95% CI, 0.68–1.06) and serious infections (aHR, 0.62; 95% CI, 0.29–1.34) between IFX‐ and ADA‐treated patients; the number of surgical events was very small. On IPTW analysis, risk of corticosteroid use was significantly lower in IFX – as compared to ADA – treated patients (aHR, 0.82; 95% CI, 0.68–0.99). Results were stable on multiple sensitivity analyses.ConclusionsIn a large retrospective cohort of patients with UC who were new users of anti‐TNF agents, IFX‐treated patients may have lower corticosteroid use than ADA‐treated patients, but risk of hospitalisation and serious infections were comparable.

OBJECTIVE: To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn’s disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy.METHODS: Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada.RESULTS: Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients.CONCLUSIONS: Adalimumab therapy induced and sustained steroid-free remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.

SummaryBackgroundAzathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount.AimTo provide a comprehensive review focused on pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy inIBD.MethodsA literature search up to July 2015 was performed in PubMed using a combination of relevant MeSHterms.ResultsPre‐treatment thiopurine S‐methyltransferase typing plus measurement of 6‐tioguanine nucleotides and 6‐methylmercaptopurine ribonucleotides levels during treatment have emerged with key roles in facilitating safe and effective thiopurine therapy. Optimal use of these tools has been shown to reduce the risk of adverse effects by 3‐7%, and to improve efficacy by 15–30%. For the introduction of aldehyde oxidase (AOX) into clinical practice, the association betweenAOXactivity andAZAdose requirements should be positively confirmed. Inosine triphosphatase assessment associated with adverse effects also shows promise. Nucleoside diphosphate‐linked moiety X‐type motif 15 variants have been shown to predict myelotoxicity on thiopurines in East Asian patients. However, the impact of assessments of xanthine oxidase, glutathione S‐transferase, hypoxanthine guanine phosphoribosyltransferase and inosine monophosphate dehydrogenase appears too low to favour incorporation into clinical practice.ConclusionsMeasurement of thiopurine‐related enzymes and metabolites reduces the risk of adverse effects and improves efficacy, and should be considered part of standard management. However, this approach will not predict or avoid all adverse effects, and careful clinical and laboratory monitoring of patients receiving thiopurines remains essential.

SummaryBackgroundTemporary faecal diversion is sometimes used for management of refractory perianal Crohn's disease (CD) with variable success.AimsTo perform a systematic review with meta‐analysis to evaluate the effectiveness, long‐term outcomes and factors associated with success of temporary faecal diversion for perianal CD.MethodsThrough a systematic literature review through 15 July 2015, we identified 16 cohort studies (556 patients) reporting outcomes after temporary faecal diversion. We estimated pooled rates [with 95% confidence interval (CI)] of early clinical response, attempted and successful restoration of bowel continuity after temporary faecal diversion (without symptomatic relapse), and rates of re‐diversion (in patients with attempted restoration) and proctectomy (with or without colectomy and end‐ileostomy). We identified factors associated with successful restoration of bowel continuity.ResultsOn meta‐analysis, 63.8% (95% CI: 54.1–72.5) of patients had early clinical response after faecal diversion for refractory perianal CD. Restoration of bowel continuity was attempted in 34.5% (95% CI: 27.0–42.8) of patients, and was successful in only 16.6% (95% CI: 11.8–22.9). Of those in whom restoration was attempted, 26.5% (95% CI: 14.1–44.2) required re‐diversion because of severe relapse. Overall, 41.6% (95% CI: 32.6–51.2) of patients required proctectomy after failure of temporary faecal diversion. There was no difference in the successful restoration of bowel continuity after temporary faecal diversion in the pre‐biological or biological era (13.7% vs. 17.6%, P = 0.60), in part due to selection bias. Absence of rectal involvement was the most consistent factor associated with restoration of bowel continuity.ConclusionsTemporary faecal diversion may improve symptoms in approximately two‐thirds of patients with refractory perianal Crohn's disease, but bowel restoration is successful in only 17% of patients.

SummaryBackgroundCertolizumab pegol (CZP) is Food and Drug Administration (FDA)‐approved to treat Crohn's disease (CD). However, the efficacy and safety of CZP outside clinical trials are not well established.AimTo report the efficacy, safety and predictors of response to CZP in CD patients treated during a 6‐year period since FDA‐approval at a tertiary care centre.MethodsAll CD patients who received CZP at our institution between 2008 and 2013 were evaluated through retrospective medical record‐based review of steroid‐free complete response (SCR), loss of response and safety.ResultsA total of 358 patients were included. One hundred twelve patients (31.3%) and 189 (52.8%) received CZP as their second and third biological agent, respectively. The probability of SCR at 26 week was 19.9% (95% CI, 15.9–24.5). The probability of survival free of loss of response at 2 year was 45.7% (95% CI, 32.5–59.5). A predictor of SCR was age at CD diagnosis of >40 years old (hazard ratio, HR relative to those <17, 4.69; 95% CI, 1.75–12.61). Negative predictors included present perianal fistula (HR, 0.39; 95% CI, 0.16–0.98) and prior primary nonresponse to adalimumab (ADA; HR relative to secondary loss of response, 0.18; 95% CI, 0.04–0.76). Twenty‐three patients (6.4%) experienced serious adverse events and 19 patients (5.3%) discontinued CZP due to adverse events.ConclusionsCertolizumab pegol was both effective and well tolerated for the treatment of Crohn's disease in this large tertiary care centre enriched with biologics‐exposed patients. It may be more effective in patients without early‐aged Crohn's disease diagnosis, prior primary nonresponse to adalimumab and present perianal fistula.

SummaryBackgroundCytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4) has an important role in T‐cell regulation, proliferation and tolerance. Anti‐CTLA‐4 agents, such as ipilimumab and tremelimumab, have been shown to prolong overall survival in patients with metastatic melanoma, and their use is being investigated in the treatment of other malignancies. Their novel immunostimulatory mechanism, however, predisposes patients to immune‐related adverse effects, of which gastrointestinal effects such as diarrhoea and colitis are the most common.AimsTo discuss the existing literature and summarise the epidemiology, pathogenesis and clinical features of anti‐CTLA‐4‐associated colitis, and to present a management algorithm for it.MethodsWe searched PubMed for studies published through October 2014 using the terms ‘anti‐CTLA,’ ‘ipilimumab,’ ‘tremelimumab,’ ‘colitis,’ ‘gastrointestinal,’ ‘immune‐related adverse effect,’ ‘immunotherapy,’ ‘melanoma,’ and ‘diarrhoea.’ResultsWatery diarrhoea is commonly associated with anti‐CTLA‐4 therapy (27–54%), and symptoms occur within a few days to weeks of therapy. Diffuse acute and chronic colitis are the most common findings on endoscopy (8–22%). Concomitant infectious causes of diarrhoea must be evaluated. Most cases may be successfully managed with discontinuation of anti‐CTLA‐4 and conservative therapy. Those with persistent grade 2 and grade 3/4 diarrhoea should undergo endoscopic evaluation and require corticosteroid therapy. Corticosteroid‐resistant cases may respond to anti‐tumour necrosis factor‐alpha therapy such as infliximab. Surgery is reserved for patients with bowel perforation or failure of medical therapy.ConclusionGiven the increasing use of anti‐CTLA‐4 therapy, clinicians must be aware of related adverse events and their management.