Metaflammation, PEDF and Chemerin: Potential Systemic Factors Which Link Obesity To Response To Therapy In Early Rheumatoid Arthritis.

Background/Purpose: Obesity per se is a systemic, low-grade inflammatory state and the adipose tissue is an endocrine organ that releases bioactive substances, including pro-inflammatory cytokines, like TNFα and IL6, and specific adipokines. There are only few data about early RA (ERA), suggesting that obesity associates with disease outcomes. In this work we aimed to evaluate whether the body weight, and its metabolic (PEDF) and meta-inflammatory parameters (Chemerin), could be associated with the outcomes in terms of disease remission and treatment in ERA patients (symptoms duration <12 months). Methods: 346 ERA patients, treated according to a treat-to-target strategy, were enrolled. At each visit the ACR/EULAR core data set was registered. Baseline BMI was collected and baseline PEDF and Chemerin plasma levels were evaluated by ELISA’s methods. Adipose tissue PEDF gene expression was evaluated in overweight and obese subjects (24 ERA and 6 healthy controls). Logistic regression models were applied to determine the influence of independent variables reaching a pvalue<0.25 at the univariate analysis, on the dependent variables “DAS remission at 12th month and anti-TNF therapy at 12th month”. Results: Of the 346 ERA patients (76.3% female, age 54.6±14.0 years, 32.9% very ERA, 70.2% seropositive, baseline DAS 3.6±1.1), 168 (48.6%) were normal weight, 135 (39%) overweight and 43 (12.4%) obese. BMI values correlated with baseline PEDF (r=0.33, p<0.001) and chemerin (r=0.31, p<0.001) plasma levels. Moreover, BMI values correlated with age (r=0.23, p<0.001), baseline inflammatory markers (ESR: r=0.14, p=0.009, CRP: r=0.19, p<0.001), DAS (r=0.18, p<0.001) and HAQ (r=0.17, p<0.001). PEDF relative gene expression was 1.55 times higher in ERA patients compared to healthy subjects. Overweight and obese patients reached a lower remission rate at 6 and 12 month follow-up visits (DAS remission at 6th month: 52.1% in normal, 41.2% in overweight, 28.1% in obese, p=0.03; sustained DAS remission at 12th month: 51.0% in normal, 28.8% in overweight, 34.4% in obese, p=0.004). Moreover, an higher percentage of obese and overweight ERA patients were under anti-TNF treatment after 12 months of follow-up (27.3% of obese, 30.2% of overweight, 11.4% of normal weight, p=0.003). At the multivariate analysis, the independent baseline variables associated with the risk of “not obtaining DAS remission at 12th month follow-up” were duration of symptoms >3 months (OR: 2.3 (1.0–5.3)), baseline CRP>5.0 mg/l (OR: 2.4 (1.1–5.6)) and baseline chemerin plasma levels>99.5ng/ml (OR: 2.4 (1.1–5.6)). The independent variables associated with the probability of being in anti-TNF therapy at 12th month follow-up were age <55 years (OR: 2.70 (1.41–5.34)), baseline DAS>3.7 (OR: 2.27 (1.19–4.34) and BMI>25 (OR: 2.36 (1.21–4.59)). Conclusion: In ERA patients, not only obesity, but also overweightness, are associated with worst outcomes, like higher disease activity, lower remission rates, and greater use of anti-TNF therapy. PEDF and chemerin seem to be biomarkers of metaflammation.