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      Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease

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          Abstract

          <p class="first" id="d5541050e319">This cohort study uses 2 large administrative claims databases to examine the incidence of Parkinson disease among patients with inflammatory bowel disease and to assess whether exposure to antitumor necrosis factor therapy among these patients mitigates Parkinson disease risk. </p><div class="section"> <a class="named-anchor" id="ab-noi180020-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e325">Question</h5> <p id="d5541050e327">Among patients with inflammatory bowel disease, what is the incidence of Parkinson disease, and does earlier exposure to anti–tumor necrosis factor therapy mitigate their risk of Parkinson disease? </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e330">Findings</h5> <p id="d5541050e332">In this cohort study analyzing administrative claims from more than 170 million health care–covered lives, patients with inflammatory bowel disease were 28% more likely than matched individuals without inflammatory bowel disease to develop Parkinson disease. Patients with inflammatory bowel disease exposed to antitumor necrosis factor therapy had a 78% reduction in Parkinson disease incidence rates compared with unexposed patients. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e335">Meaning</h5> <p id="d5541050e337">Reducing systemic inflammation in at-risk individuals may decrease the incidence of Parkinson disease. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e341">Importance</h5> <p id="d5541050e343">Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti–tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e346">Objective</h5> <p id="d5541050e348">To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e351">Design, Setting, and Participants</h5> <p id="d5541050e353">This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e356">Main Outcomes and Measures</h5> <p id="d5541050e358">Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy.</p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e361">Results</h5> <p id="d5541050e363">In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44; <i>P</i> &lt; .001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88; <i>P</i> = .03). </p> </div><div class="section"> <a class="named-anchor" id="ab-noi180020-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d5541050e372">Conclusions and Relevance</h5> <p id="d5541050e374">A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk. </p> </div>

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          Most cited references29

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          Neuroinflammation in Parkinson’s disease and its potential as therapeutic target

          Parkinson’s disease (PD), the second most common age-associated neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons and the presence of α-synuclein-containing aggregates in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Post-mortem analyses of human PD patients and experimental animal studies indicate that activation of glial cells and increases in pro-inflammatory factor levels are common features of the PD brain. Chronic release of pro-inflammatory cytokines by activated astrocytes and microglia leads to the exacerbation of DA neuron degeneration in the SNpc. Besides, peripheral immune system is also implicated in the pathogenesis of PD. Infiltration and accumulation of immune cells from the periphery are detected in and around the affected brain regions of PD patients. Moreover, inflammatory processes have been suggested as promising interventional targets for PD and even other neurodegenerative diseases. A better understanding of the role of inflammation in PD will provide new insights into the pathological processes and help to establish effective therapeutic strategies. In this review, we will summarize recent progresses in the neuroimmune aspects of PD and highlight the potential therapeutic interventions targeting neuroinflammation.
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            Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

            A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.
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              Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management

              Tumor necrosis factor-α (TNFα) antagonists have advanced the management of inflammatory bowel diseases patients leading to an improvement of patient's quality of life with the reduction of number of surgeries and hospitalizations. Despite these advances, many patients do not respond to the induction therapy (primary non-response—PNR) or lose response during the treatment (secondary loss of response—LOR). In this paper we will provide an overview of the definition, epidemiology and risk factors for PNR and LOR, as well as discuss the therapeutic options for managing LOR.
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                Author and article information

                Journal
                JAMA Neurology
                JAMA Neurol
                American Medical Association (AMA)
                2168-6149
                August 01 2018
                August 01 2018
                : 75
                : 8
                : 939
                Affiliations
                [1 ]Department of Genetics and Genomic Sciences, ISMMS (Icahn School of Medicine at Mount Sinai), New York, New York
                [2 ]Division of Gastroenterology, Department of Medicine, ISMMS, New York, New York
                [3 ]Department of Neurology, ISMMS, New York, New York
                [4 ]AbbVie Inc, North Chicago, Illinois
                Article
                10.1001/jamaneurol.2018.0605
                6142934
                29710331
                91defd2b-b6e6-4232-bcb8-85fea04c40a9
                © 2018
                History

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