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Genetic risk factors for serious infections in inflammatory bowel diseases.

ABSTRACT: Immunosuppression, the cornerstone of management of Crohn's disease (CD) and ulcerative colitis (UC) (inflammatory bowel diseases; IBD) is associated with an increased risk of serious infections that is inadequately predicted by clinical risk factors. The role of genetics in determining susceptibility to infections is unknown.From a prospective-consented patient registry, we identified IBD patients with serious infections requiring hospitalization. Analysis was performed to identify IBD-related and non-IBD related immune response loci on the Immunochip that were associated with serious infections and a genetic risk score (GRS) representing the cumulative burden of the identified single nucleotide polymorphisms was calculated. Multivariable logistic regression used to identify effect of clinical and genetic factors.The study included 1333 IBD patients (795?CD, 538 UC) with median disease duration of 13 years. A total of 133 patients (10%) had a serious infection requiring hospitalization. Patients with infections were more likely to have CD and had shorter disease duration. The most common infections were skin and soft-tissue, respiratory and urinary tract infections. Eight IBD risk loci and two other polymorphisms were significantly associations with serious infections. Each one point increase in the infection GRS was associated with a 50% increase in risk of infections (OR?=?1.53, 95% CI?=?1.37-1.70) (p?=?1?×?10-14), confirmed on multivariable analysis. Genetic risk factors improved performance of a model predicting infections over clinical covariates alone (p?

SUBMITTER: Sasidharan S

PROVIDER: S-EPMC5642969 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetic risk factors for serious infections in inflammatory bowel diseases.

Sasidharan Saranya S Yajnik Vijay V Khalili Hamed H Garber John J Xavier Ramnik R Ananthakrishnan Ashwin N AN

Scandinavian journal of gastroenterology 20170205 5

<h4>Introduction</h4>Immunosuppression, the cornerstone of management of Crohn's disease (CD) and ulcerative colitis (UC) (inflammatory bowel diseases; IBD) is associated with an increased risk of serious infections that is inadequately predicted by clinical risk factors. The role of genetics in determining susceptibility to infections is unknown.<h4>Methods</h4>From a prospective-consented patient registry, we identified IBD patients with serious infections requiring hospitalization. Analysis w ...[more]

PMID: 28162010

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Project description:Background & aimsWe performed a systematic review and meta-analysis to evaluate the comparative risk of serious infections with tumor necrosis factor (TNF) antagonists, non-TNF targeted biologics, tofacitinib, and immunosuppressive agents in patients with inflammatory bowel diseases (IBDs).MethodsIn a systematic search of publications, through March 18, 2018, we identified 15 observational studies (>500 person-years) of patients with IBD treated with TNF antagonists, non-TNF targeted biologics, tofacitinib, and/or immunosuppressive agents (thiopurines, methotrexate) that reported risk of serious infections. Only studies with active comparators were included, to allow appropriate comparative synthesis. We performed random-effects meta-analysis and estimated relative risk (RR) and 95% CIs.ResultsCompared with anti-TNF monotherapy, risk of serious infection increased with the combination of anti-TNF and an immunosuppressive agent (in 6 cohorts: RR, 1.19; 95% CI, 1.03-1.37), with anti-TNF and a corticosteroid (in 4 cohorts: RR, 1.64; 95% CI, 1.33-2.03), or with all 3 drugs (in 2 cohorts: RR, 1.35; 95% CI, 1.04-1.77); there was minimal heterogeneity among studies. In contrast, monotherapy with an immunosuppressive agent was associated with a lower risk of serious infections than monotherapy with a TNF antagonist (7 cohorts: RR, 0.61; 95% CI 0.44-0.84) or a TNF antagonist with an immunosuppressive agent (2 cohorts: RR, 0.56; 95% CI, 0.39-0.81). Infliximab-based therapy was associated with a lower risk of serious infections compared with adalimumab-based therapy in patients with ulcerative colitis (4 cohorts: RR, 0.57; 95% CI, 0.33-0.97), but not Crohn's disease (4 cohorts: RR, 0.91; 95% CI, 0.49-1.70). Few data were available on the comparative safety of biologic agents that do not inhibit TNF and tofacitinib.ConclusionsCombination therapies for IBD that include TNF antagonists, especially with corticosteroids, are associated with a higher risk of serious infection, whereas monotherapy with an immunosuppressive agent is associated with a lower risk, compared with monotherapy with a TNF antagonist. Studies are needed to evaluate the comparative safety of non-TNF targeted biologics and small molecules for treatment of IBD.

Project description:The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn's disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.

Project description:ObjectiveTo investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections.DesignNationwide register based propensity score matched cohort study.SettingDenmark, 2002-12.ParticipantsThe background cohort eligible for matching comprised 52,392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses.Main outcome measuresThe main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period.ResultsWithin the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12).ConclusionsThis nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment.

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Genetic risk factors for serious infections in inflammatory bowel diseases.

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Genetic risk factors for serious infections in inflammatory bowel diseases.

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