Meta-Analysis of Asymmetric Dimethylarginine Concentrations in Rheumatic Diseases

Gian Luca Erre,Ciriaco Carru,Floriana Castagna,Angelo Zinellu,Arduino Aleksander Mangoni,Panagiotis Paliogiannis,Giuseppe Passiu

doi:10.1038/s41598-019-41994-5

Abstract

Raised circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), have been reported in several rheumatic diseases (RDs). However, the strength of this relationship is unclear. Therefore, the aim of this systematic review and meta-analysis was to evaluate the magnitude and the robustness of the association between ADMA concentrations and RDs. We calculated standardized mean differences (SMD, with 95% confidence intervals, CI). Study heterogeneity was evaluated by meta-regressions and sensitivity analyses according to type of RDs, conventional cardiovascular risk factors, inflammatory markers, and type of ADMA assessment methodology. Thirty-seven studies with a total of 2,982 subjects (1,860 RDs patients and 1,122 healthy controls) were included in our meta-analysis. Pooled results showed that ADMA concentrations were significantly higher in patients with RDs than in healthy controls (SMD = 1.27 µmol/L, 95% CI 0.94–1.60 µmol/L; p < 0.001). However, the between-studies heterogeneity was high. Differences in ADMA concentrations between controls and RDs patients were not significantly associated with inflammatory markers, increasing age, lipid concentrations, body mass index, blood pressure, or methodology used to assess ADMA. Furthermore, subgroup analysis showed no difference across RDs. This meta-analysis showed that, in the context of significant between-study heterogeneity, circulating concentrations of ADMA are positively related to RDs.

Highlights

The term “systemic rheumatic diseases” (RDs) encompasses a broad spectrum of chronic inflammatory disorders of joints and internal organs that are characterized by tissue destruction, disability and increased cardiovascular and all-cause mortality
A pre-established protocol, including methods for the analysis, was followed: in particular, we investigated the difference in asymmetric dimethylarginine (ADMA) concentrations stratifying for the following subgroups (i) RD subtype (e.g. rheumatoid arthritis (RA) vs systemic sclerosis (SSc) vs psoriatic arthritis (PsA), etc.) (ii) connective tissue diseases (CTD) vs non-CTD, (iii) autoimmune conditions (SLE, RA, SSc and SSj) vs conditions with mixed features (PsA, ankylosing spondylitis (AS)) and autoinflammatory conditions (BD and Familial Mediterranean Fever, FMF), (iv) biological sample and (v) type of laboratory test
Pooled results showed that ADMA concentrations were significantly higher in patients with RDs (SMD = 1.27 μmol/L, 95% confidence intervals (CIs) 0.94–1.60 μmol/L; p < 0.001)

Summary

Introduction

The term “systemic rheumatic diseases” (RDs) encompasses a broad spectrum of chronic inflammatory disorders of joints and internal organs that are characterized by tissue destruction, disability and increased cardiovascular and all-cause mortality. Compared with the general population, patients with RDs suffer from a significantly reduced life expectancy that is mainly due to atherosclerotic cardiovascular disease[2,3]. This excess of cardiovascular mortality, only partially predicted by conventional risk factors, has been linked to early endothelial dysfunction and accelerated arterial stiffening[2,3,4]. Peripheral and central endothelial dysfunction, a measure of nitric-oxide (NO) availability and vasodilatory function, has been shown to be more prevalent in RDs than in the general population[5,6,7].

Methods

Results

Conclusion