Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity

Abstract

Objective The aim of the current study is to determine whether baseline serum adiponectin levels predict the development of rheumatoid arthritis (RA). Method The current report includes 3693 individuals from the Swedish Obese Subjects (SOS) study. The original SOS study is a longitudinal non-randomized controlled study aiming to assess the effect of bariatric surgery on obesity-related mortality and morbidity. Participants included in the present report had adiponectin measurement available at baseline and no prevalent RA. The diagnosis of RA was retrieved through the Swedish National Patient Register. Results During a follow-up for up to 29 years, 82 study participants developed RA. Elevated baseline adiponectin levels were associated with a higher risk of developing RA independently of other factors, including C-reactive protein (CRP) and smoking [hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.12-2.60 for an increase in adiponectin of 10 mg/L, p = 0.01]. After stratifying the population according to adiponectin and CRP median at baseline, study participants with both adiponectin and CRP above the median had a higher risk of developing RA compared to subjects with adiponectin and CRP below the median (HR 2.80, 95% CI 1.25-6.31, p = 0.01). Conclusions In this cohort of subjects with obesity followed up for up to 29 years, high serum adiponectin levels at baseline were associated with an increased risk for RA. Moreover, subjects with both high adiponectin and CRP levels at baseline were at particular risk of developing RA. ClinicalTrials.gov Identifier: NCT01479452. Adiponectin is a relatively abundant adipokine in plasma, with concentrations ranging from 2 to 30 mg/L and accounting for up to 0.05% of total plasma proteins (1, 2). Although mostly produced by the adipose tissue, adiponectin levels are inversely correlated with fat mass and are low in subjects with obesity (3, 4). Low serum adiponectin is associated with an unhealthy metabolic profile, including a higher risk for type 2 diabetes and insulin resistance (5-7). It has been hypothesized that the low adiponectin levels observed in obesity and its comorbidities are a consequence of the chronic low-grade inflammation that affects the adipose tissue under these circumstances (8, 9). However, other studies show that adiponectin levels are elevated in inflammatory and autoimmune diseases (10-12). Indeed, in patients with established rheumatoid arthritis (RA), adiponectin is increased in both serum and synovia, and subjects with early treatment-naïve RA have higher circulating adiponectin levels than controls. Moreover, plasma adiponectin is associated with pro-inflammatory cytokines in a population without RA but at high risk of developing the disease (13), suggesting that adiponectin may play a role in the early phases of disease development (14-17). This

Recombinant Adiponectin Induces the Production of Pro-Inflammatory Chemokines and Cytokines in Circulating Mononuclear Cells and Fibroblast-Like Synoviocytes From Non-Inflamed Subjects

“…Plasma levels of adiponectin have been shown to associate with levels of circulating pro-inflammatory cytokines, i.e., IL-2, IL-6, IL-9, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in relatives of RA patients that had a high-risk autoantibody profile ( 24 ). Together with our finding that an increase in serum adiponectin levels predicts the development of RA, this suggests that adiponectin plays a role in the initiation of the disease ( 16 ). In the current study, we aimed to determine if adiponectin is able to induce pro-inflammatory responses in cells involved in the pathogenesis of RA, but collected from subjects without any known inflammatory disease.…”

“…As a support for this hypothesis, adiponectin has been shown to induce the production of IL-6, TNF, CXCL1, and CXCL8 in human lymphocytes from healthy subjects ( 10 ), and IL-6 and CXCL8 in FLS collected from subjects with RA ( 20 ). We have also recently shown that increased circulating adiponectin levels precede the development of RA in subjects with obesity, suggesting that adiponectin could play a role in the early phases of disease pathogenesis ( 16 ). The current study shows that adiponectin stimulates the production of a wide range of pro-inflammatory chemokines and cytokines in PBMCs and FLS collected from non-inflamed subjects, thus suggesting that adiponectin is able to initiate pro-inflammatory responses in healthy cells.…”

Adipokines and Autoimmunity in Inflammatory Arthritis

“…Interestingly, subcutaneous adipose tissue from RA patients produced more adiponectin compared to OA patients and correlated with disease activity and disease duration in these patients [ 49 ]. Along this line, an increased risk for obese subjects with high serum adiponectin levels at baseline to develop RA, specifically with high adiponectin and CRP levels, was recently described in a study during a follow-up for up to 29 years [ 50 ]. The response to anti-TNF-alpha treatment seems to be associated with better improvement in patients with higher adiponectin levels at baseline [ 51 ].…”

Mini-Review: The Contribution of Adipokines to Joint Inflammation in Inflammatory Rheumatic Diseases

“…Collectively, it was reported that adiponectin is associated with the erosive process ( 49 – 53 ). Finally, in a Swedish cohort of obese subjects, elevated levels of adiponectin were associated with the development of RA, independently of CRP and levels of smoking (hazard ratio: 1.7 [95% CI: 1.12-2.6]) ( 60 ).…”