ABSTRACT
Body fat has regulatory functions through producing cytokines and adipokines whose role in the pathogenesis of Systemic Sclerosis (SSc) is currently emerging. Changes in body mass, either overweight or underweight status, entail a dysregulation of the cytokines/adipokines network that may impact on SSc disease activity. We evaluated serum levels of adipokines and cytokines in SSc patients and correlated them to clinical features and body mass index (BMI) categories.
The study included 89 SSc patients and 26 healthy donors (HD). Serum levels of adiponectin, leptin, resistin, visfatin, TNFα, IFNγ, IL-2, IL-10, and IL-17A were measured by Multiplex Immunoassay, and correlated to BMI, waist to hip ratio, and disease specific features. Mann-Whitney U-test or t-Student for unpaired data, Kruskal-Wallis test or ANOVA, were used for comparisons between groups. Spearman’s or Pearson’s test were used for correlation analysis.
Serum levels of TNFα, IL-2, leptin, and resistin, were significantly higher in SSc than in HD. The highest levels of IL-17A, IL-2, IL-10, leptin and visfatin were detected in obese SSc patients (p <0.01 ). Conversely, underweight SSc patients showed the highest TNFα levels (p<0.05 ), which were negatively correlated with BMI (p=0.05 ). No correlation between adipokines/cytokines and clinical characteristics was found.
Adipokines, IL-2, IL-10 and IL-17A were found to be increased in obese SSc patients, but whether they play a role in the pathogenesis of the disease remains to be investigated. Intriguingly, underweight patients had higher TNFα levels, suggesting a potential role of TNFα in inducing the cachexia observed in long-lasting disease.
Introduction
Systemic sclerosis (SSc) is a connective tissue disease characterized by small vessels vasculopathy associated with fibrosis of multiple organs. The pathogenesis is unclear, but an autoimmune dysregulation and an abnormal inflammatory response seem to be involved in the early stage of the disease. Emerging evidence suggests that white adipose tissue (WAT), besides having the role of energy storage, is now acknowledged as a pleiotropic organ with endocrine functions and regulating immune and inflammatory responses, being a source of cytokines and adipokines (leptin, adiponectin, visfatin, resistin) (1). Indeed, obesity may have an impact on disease activity as well as on clinical response of patients with rheumatoid arthritis and psoriatic arthritis (2,3). In obese subjects, leptin induces the expression of adhesion molecules on endothelial cells and activates macrophages, while hindering adiponectin production by adipocytes, contributing to the “low-grade inflammatory state” associated with obesity (1).
Recently, the role of cytokines/adipokines in the pathophysiology of SSc has become a matter of investigation but studies correlating them with the clinical subsets or particular organ involvement were not always consistent. Serum leptin levels were found to be positively correlated with body mass index (BMI), negatively with disease activity in SSc patients, but not increased in comparison with healthy controls (4,5). Conversely, serum levels of leptin, resistin and TNFα were higher in a small cohort of 16 SSc patients than in control subjects but no correlation with skin involvement, disease duration and disease activity was seen (6). A newly discovered adipokine, adipsin, was significantly higher in limited cutaneous SSc (lcSSc) than in diffuse cutaneous SSc (dcSSc) and was strongly associated with pulmonary arterial hypertension (7). Interestingly, adiponectin seems to play a protective role in SSc, as the levels were found to be low in dcSSc patients and inversely correlated with the extension of skin fibrosis, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (5,8-10). However, the interweave among body mass, cytokines/adipokines and SSc clinical phenotypes has been poorly investigated.
In this study, we aimed at evaluating serum levels of adipokines (leptin, resistin, visfatin, adiponectin) and cytokines (TNFα, Interferon-gamma (IFNγ), IL-2, IL-10, IL-17A) in SSc patients according to BMI categories and disease specific characteristics.