Ahmed Al-Darmaki

Helminth Regulation of Immunity: A Three-pronged Approach to Treat Colitis.

Abstract:By reputation, the parasite is a pariah, an unwelcome guest. Infection with helminth parasites evokes stereotypic immune responses in humans and mice that are dominated by T helper (Th)-2 responses; thus, a hypothesis arises that infection with helminths would limit immunopathology in concomitant inflammatory disease. Although infection with some species of helminths can cause devastating disease and affect the course of microbial infections, analyses of rodent models of inflammatory disease reveal that infection with helminth parasites, or treatment with helminth extracts, can limit the severity of autoinflammatory disease, including colitis. Intriguing, but fewer, studies show that adoptive transfer of myeloid immune cells treated with helminth products/extracts in vitro can suppress inflammation. Herein, 3 facets of helminth therapy are reviewed and critiqued: treatment with viable ova or larvae, treatment with crude extracts of the worm or purified molecules, and cellular immunotherapy. The beneficial effect of helminth therapy often converges on the mobilization of IL-10 and regulatory/alternatively activated macrophages, while there are reports on transforming growth factor (TGF)-&bgr;, regulatory T cells and dendritic cells, and recent data suggest that helminth-evoked changes in the microbiota should be considered when defining anticolitic mechanisms. We speculate that if the data from animal models translate to humans, noting the heterogeneity therein, then the choice between use of viable helminth ova, helminth extracts/molecules or antigen-pulsed immune cells could be matched to disease management in defined cohorts of patients with inflammatory bowel disease.

Preoperative Ustekinumab Treatment is not Associated with Increased Postoperative Complications in crohn's Disease: A Canadian Multicentre Case–Control Cohort Study

Background Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohns disease (CD). However, it is unclear if patients treated with UST are at increased risk for postoperative complications. Aim To evaluate the postoperative safety outcomes in UST-treated CD patients. Methods A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti-TNF-treated patients over the same time-period. The primary outcome was occurrence of postoperative complications up to six months postoperatively, stratified by timing (early <30 days vs. late complications ≥30 days). Results Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST-treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). Conclusions CD patients receiving preoperative UST did not experience an increase in postoperative complications, despite increased use of concurrent immunosuppression.

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn’s Disease: A Canadian Multi-Centre Observational Cohort Study

Abstract Background Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn’s disease (CD). However, it is unclear if patients treated with UST are at increased risk for postoperative complications. Aim To evaluate the postoperative safety outcomes in UST-treated CD patients. Methods A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti-TNF-treated patients over the same time-period. The primary outcome was occurrence of postoperative complications up to six months postoperatively, stratified by timing (early <30 days vs. late complications ≥30 days). Results Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST-treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). Conclusions CD patients receiving preoperative UST did not experience an increase in postoperative complications, despite increased use of concurrent immunosuppression.

Dyssynergic Defecation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background Inflammatory bowel disease (IBD) patients often continue to experience nonspecific gastrointestinal symptoms despite quiescent disease. Unlike non-IBD patients, IBD patients with dyssynergic defecation (DD) may present with various symptoms such as diarrhea, fecal incontinence, constipation, and rectal discomfort. Despite its importance and treatability, DD in IBD patients is not well recognized in practice. We conducted a systematic review and meta-analysis on the prevalence, diagnosis, and management of DD in IBD patients with ongoing defecatory symptoms. Methods We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (from 1966 through February 2017) to identify relevant studies on the prevalence, diagnostic methods, or management of DD in IBD patients with and without ileal pouch-anal anastomoses (IPAAs). A random effects model was used to calculate the pooled estimates with 95% confidence intervals (CIs). Heterogeneity was assessed with I2 statistics, Cochran Q statistic, and sensitivity analyses. Results Seven studies (n = 442) were included. In patients with ongoing defecatory symptoms, the prevalence of DD without IPAA ranged from 45% to 97%, and in patients with IPAA, it ranged from 25% to 75%. The prevalence of DD in IPAA patients with and without pouchitis ranged from 17% to 67% and 29% to 50%, respectively. The pooled response rate to biofeedback therapy in patients without IPAA was 70% (95% CI, 55%-84%; I2 = 95%; P < 0.01), and it was 86% (95% CI, 67%-98%; I2 = 61%; P = 0.05) in those with IPAA. Conclusions Despite limited data, the current literature suggests that DD is highly prevalent in active or quiescent IBD patients with ongoing defecatory symptoms and is responsive to biofeedback therapy. Although more studies are needed, DD should be considered in IBD patients with persistent defecatory symptoms.

Real-world clinical, endoscopic and radiographic efficacy of vedolizumab for the treatment of inflammatory bowel disease

Vedolizumab is an α4β7 integrin antagonist with proven efficacy for inducing and maintaining clinical response and remission in Crohns disease (CD) and ulcerative colitis (UC).

Clinical Predictors of the Risk of Early Colectomy in Ulcerative Colitis: A Population-based Study

Background: A subset of patients with ulcerative colitis (UC) will require colectomy within a few years of diagnosis. Thus, our aim was to determine the clinical predictors of early colectomy among patients with UC who are hospitalized with an acute flare. Methods: Using population-based surveillance (1996–2009), all adults (≥18 years) hospitalized for UC within 3 years of diagnosis (n = 489) were identified. The primary outcome was a colectomy within 3 years of diagnosis. All medical charts were reviewed. A logistic regression model evaluated clinical variables that predicted colectomy within 3 years of diagnosis, and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Results: Among patients admitted to hospital with UC within 3 years of diagnosis, 57.7% underwent colectomy, with the odds of colectomy decreasing by 12% per year. Early colectomy was more likely among patients aged 35 to 64 years versus 18 to 34 years (OR 2.18 [95% CI, 1.27–3.74]), males (OR 2.03 [95% CI, 1.24–3.34]), those with pancolitis (OR 5.38 [95% CI, 3.20–9.06]), and living in rural areas (OR 2.81 [95% CI, 1.49–5.29]). Prescription of infliximab before hospitalization increased odds of surgery (OR 5.12 [95% CI, 1.36–19.30]). Conclusions: Patients hospitalized for UC have a high risk of early colectomy. This is particularly true in middle-aged men, those living in rural areas, and those without response to infliximab.