Waqqas Afif

Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.

OBJECTIVES:Human anti-chimeric antibodies (HACAs) and subtherapeutic infliximab concentrations are associated with decreased duration of response. We evaluated the clinical utility of measuring HACA and infliximab concentrations.METHODS:The medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured were reviewed to determine whether the result affected clinical management.RESULTS:One hundred fifty-five patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). HACAs were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of 17%. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86% of patients whereas changing to another anti-TNF agent had a response of 33%. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76% of the time and had no evidence of active inflammation by endoscopic/radiographic assessment 62% of the time.CONCLUSIONS:Measurement of HACA and infliximab concentration impacts management and is clinically useful. Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent.

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.

Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab†

Background: The aim of this study was to assess the clinical benefit and tolerability of adalimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF), in patients with ulcerative colitis (UC). Methods: Patients with active UC, including those who had lost response or developed intolerance to the chimeric anti‐TNF antibody infliximab, were enrolled in a 24‐week uncontrolled trial. Patients were treated with subcutaneous adalimumab 160 mg at week 0, 80 mg at week 2, and 40 mg every other week starting at week 4. After week 8 the dose could be escalated to 40 mg weekly for incomplete response. Outcome measures included clinical response and remission and mucosal healing. Results: Twenty patients were enrolled, of whom 13 had previously received infliximab. Seven patients had dose escalation of adalimumab between weeks 8 and 16, from 40 mg every other week to 40 mg weekly, due to incomplete response. The rates of clinical response were 25% at week 8 and 50% at week 24. The rates of clinical remission were 5% at week 8 and 20% at week 24. The rate of mucosal healing was 30% at week 8. The rates of clinical response and remission and mucosal healing were similar in infliximab‐naïve and previously exposed patients. None of the patients experienced hypersensitivity reactions during treatment with adalimumab. Conclusions: Adalimumab is well tolerated and appears to be a clinically beneficial option for patients with UC, including those who have previously lost their response to or cannot tolerate infliximab. (Inflamm Bowel Dis 2009)

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease

Tumour necrosis factor (TNF)‐antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti‐drug antibodies (ADAs) may decrease their efficacy.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease—The McGill experience

BACKGROUND Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohns disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS A retrospective observational open-label study. Clinical response was defined by physicians global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Small bowel capsule endoscopy in the management of established Crohn's disease: clinical impact, safety, and correlation with inflammatory biomarkers.

Background:Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohns disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD. Methods:A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. Results:The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-to-severe inflammation in 45% of the patients (median Lewis score, 662; range, 0–6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). Conclusions:VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor.

Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn's disease: A systematic review and meta-analysis

BACKGROUND AND AIMS Combination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohns disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial. The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature. METHODS We performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1 year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed. RESULTS Eighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n=1984) showed that ADA monotherapy was inferior to combination therapy [OR=0.78 (0.64-0.96), p=0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR=1.08 (0.79-1.48), p=0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR=1.13 (0.69-1.85), p=0.62]. CONCLUSIONS Combination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1 year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials.

Safety profile of IBD therapeutics: infectious risks.

Over the last decade, the medical treatment of inflammatory bowel disease (IBD) has been revolutionized, with increasing use of both immunomodulatory and biologic medications. Corticosteroids have increasingly been associated with an elevated risk of serious and opportunistic infections, both independently and in combination with immunomodulator and biologic agents. There are limited data on the infectious risk of immunomodulators. It is unclear if anti-tumor necrosis factor agents increase overall infectious risk in patients with IBD, but the available literature has demonstrated an increased risk of opportunistic infections, particularly in terms of tuberculosis and histoplasmosis. Combination therapy likely increases the risk of opportunistic infections in patients with IBD but this has not yet been conclusively proved.

Risk of Lymphoma, Colorectal and Skin Cancer in Patients with IBD Treated with Immunomodulators and Biologics: A Quebec Claims Database Study

Background:Immunomodulatory medications in patients with inflammatory bowel disease (IBD) have been associated with an increased risk of developing certain malignancies. The aim of this study was to evaluate the risk of melanoma, nonmelanoma skin cancer, colorectal cancer and lymphoma associated with immunomodulators and biologics in patients with IBD. Methods:A nested case–control study was carried out using the provincial health insurance database of Québec, Canada (RAMQ/MedECHO). Results:A total of 41,176 patients with IBD were identified of whom 19,582 patients were eligible for inclusion in the study. Treatment with thiopurine for more than 5 years was associated with a significantly increased risk of nonmelanoma skin cancer (odds ratio: 1.78; 95% confidence interval, 1.25–2.54). Immunomodulator treatment was not associated with an increased risk of non-Hodgkins lymphoma (odds ratio: 0.87; 95% confidence interval, 0.53–1.41). Neither immunomodulators nor anti-TNF-&agr; agents were associated with an increased risk of melanoma or colorectal cancer. Conclusions:In a large provincial IBD cohort, treatment with immunomodulators for more than 5 years was associated with an increased risk of non-melanoma skin cancer, whereas the risk of lymphoma, melanoma, and colorectal cancer was not increased. No association was found between the risk of the evaluated malignancies and anti-TNF-&agr; medications.

Predictors of inappropriate utilization of intravenous proton pump inhibitors

Background  Inappropriate use of intravenous proton pump inhibitors is prevalent.