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      Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: A systematic review and meta-analysis

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          Abstract

          Objectives

          We sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis.

          Methods

          Through a systematic search through January 24, 2017, we identified randomized controlled trials (RCTs) or observational studies in adults with select immune-mediated inflammatory diseases–inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathies (SpA), psoriasis and psoriatic arthritis (PsA)–treated with anti-TNF agents, and reporting outcomes, stratified by body mass index (BMI) categories or weight. Primary outcome was failure to achieve clinical remission or response or treatment modification. We performed random effects meta-analysis and estimated odds ratios (OR) and 95% confidence interval (CI).

          Results

          Based on 54 cohorts including 19,372 patients (23% obese), patients with obesity had 60% higher odds of failing therapy (OR,1.60; 95% CI,1.39–1.83;I 2 = 71%). Dose-response relationship was observed (obese vs. normal BMI: OR,1.87 [1.39–2.52]; overweight vs. normal BMI: OR,1.38 [1.11–1.74],p = 0.11); a 1kg/m 2 increase in BMI was associated with 6.5% higher odds of failure (OR,1.065 [1.043–1.087]). These effects were observed across patients with rheumatic diseases, but not observed in patients with IBD. Effect was consistent based on dosing regimen/route, study design, exposure definition, and outcome measures. Less than 10% eligible RCTs reported outcomes stratified by BMI.

          Conclusions

          Obesity is an under-reported predictor of inferior response to anti-TNF agents in patients with select immune-mediated inflammatory diseases. A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy.

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          Most cited references68

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          Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.

          In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013. We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19,244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m(2) or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4-29·3) to 36·9% (36·3-37·4) in men, and from 29·8% (29·3-30·2) to 38·0% (37·5-38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9-24·7) of boys and 22·6% (21·7-23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7-8·6) to 12·9% (12·3-13·5) in 2013 for boys and from 8·4% (8·1-8·8) to 13·4% (13·0-13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Bill & Melinda Gates Foundation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.

            Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. Ulcerative colitis long-term remission and maintenance with adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti-TNF-α) and randomly assigned to groups given adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. Overall rates of clinical remission at week 8 were 16.5% on adalimumab and 9.3% on placebo (P = .019); corresponding values for week 52 were 17.3% and 8.5% (P = .004). Among anti-TNF-α naïve patients, rates of remission at week 8 were 21.3% on adalimumab and 11% on placebo (P = .017); corresponding values for week 52 were 22% and 12.4% (P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (P = .559); corresponding values for week 52 were 10.2% and 3% (P = .039). Serious adverse events occurred in 12% of patients given adalimumab or placebo. Serious infections developed in 1.6% of patients given adalimumab and 1.9% given placebo. In the group given adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.

              The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor α (TNF), for the induction of clinical remission in anti-TNF naïve patients with moderately to severely active ulcerative colitis. This 8-week, multicentre, randomised, double-blind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of ≥ 6 points and endoscopic subscore of ≥ 2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score ≤ 2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. At week 8, 18.5% of patients in the ADA160/80 group (p = 0.031 vs placebo) and 10.0% in the ADA80/40 group (p = 0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 May 2018
                2018
                : 13
                : 5
                : e0195123
                Affiliations
                [1 ] Division of Gastroenterology, University of California San Diego, La Jolla, California, United States of America
                [2 ] Division of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America
                [3 ] Gastroenterology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy
                [4 ] Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, United States of America
                [5 ] Institute for Diabetes and Metabolic Health, University of California, San Diego, La Jolla, California, United States of America
                [6 ] VA San Diego Health Systems, La Jolla, California, United States of America
                [7 ] Department of Library Services, Mayo Clinic, Rochester, Minnesota, United States of America
                [8 ] Weight Management Program, Department of Medicine, University of California San Diego, La Jolla, California, United States of America
                [9 ] Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                VU University Medical Center, NETHERLANDS
                Author notes

                Competing Interests: Dr. Singh has received research support from Pfizer and AbbVie. Dr. Zarrinpar has consulted for Takeda and Illumina. Dr. Sandborn has served as a consultant and received research funding from Janssen, Abbvie, UCB Pharma, Takeda, and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to share.

                Author information
                http://orcid.org/0000-0002-2640-7269
                Article
                PONE-D-17-42198
                10.1371/journal.pone.0195123
                5957395
                29771924
                bcaf454a-8a1e-441a-a484-895366826a39
                © 2018 Singh et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 December 2017
                : 17 March 2018
                Page count
                Figures: 7, Tables: 2, Pages: 26
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100007827, American College of Gastroenterology;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100001063, Crohn's and Colitis Foundation of America;
                Award Recipient :
                Dr. Singh is supported by the American College of Gastroenterology and the Crohn’s and Colitis Foundation, and has received research support from Pfizer and AbbVie. Dr. Zarrinpar received support from NIH K08 DK102902, AASLD Liver Scholar Award, and American Heart Association Beginning Grant-in-Aid (16BGIA27760160), and has consulted for Takeda and Illumina. Dr. Curtis is supported by the Patient Centered Outcomes Research Institute (PCORI). Dr. Sandborn has served as a consultant and received research funding from Janssen, Abbvie, UCB Pharma, Takeda, and Pfizer. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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