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

Siddharth Singh,Niels Vande Casteele,Jeffrey R Curtis,Abha G Singh,Larry J Prokop,Antonio Facciorusso,Amir Zarrinpar,William J Sandborn,Eduardo L Grunvald,Michael Nurmohamed

doi:10.1371/journal.pone.0195123

Abstract

ObjectivesWe sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis.MethodsThrough 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).ResultsBased 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;I2 = 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/m2 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.ConclusionsObesity 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.

Highlights

The global prevalence of obesity is rising, with one in 10 people across the world being classified as obese.[1, 2] In the United States, over 35% adults are obese, and increased healthcare spending on this population is estimated to account for nearly a third of the growth in healthcare expenditure.[3]
Obesity is an under-reported predictor of inferior response to anti-tumor necrosis factor-α (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

Summary

Introduction

The global prevalence of obesity is rising, with one in 10 people across the world being classified as obese.[1, 2] In the United States, over 35% adults are obese, and increased healthcare spending on this population is estimated to account for nearly a third of the growth in healthcare expenditure.[3] Obesity may contribute to increased risk of developing select immunemediated inflammatory diseases (IMIDs) such as rheumatoid arthritis (RA), psoriasis and Crohn’s disease (CD), and approximately 10–50% of patients with IMIDs are obese.[4,5,6,7,8,9] Obesity has been associated with more severe disease activity, inferior quality of life and higher burden of hospitalization in patients with these immune-mediated diseases.[5, 6, 10,11,12,13,14]. Clinical response to these agents is seen in 40–80% patients with select IMIDs.[15,16,17,18,19] Population pharmacokinetic studies of different anti-TNF agents have consistently shown that high body weight is associated with accelerated clearance, resulting in lower trough concentrations.[20,21,22] obesity, visceral fat, independently contributes to higher systemic inflammatory burden.[23, 24] Several observational studies have shown that obesity may be a negative prognostic marker in patients with rheumatic diseases,[11, 25] and variably and inconsistently shown an inferior response to biologic agents in obese patients.[26,27,28,29,30,31,32,33]

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