Background Cytokine production and release are key events in the pathogenesis of systemic sclerosis (SSc) as they are involved in T and B cell activation leading to inflammation, auto-antibody production, microvascular damage and fibrosis.
Objectives To investigate the potential role of different cytokines (IL-6, IL-7, IL-8, CCL 2, CCL 4, TNFα and TGFβ) in bronchoalveolar lavage fluid (BALF) and the serum of SSc patients at baseline and during follow-up (FU) period. We aimed to explore the relationship of cytokine levels in BALF and serum with clinical items and outcome.
Methods Serum cytokines were measured with bioplex analysis in 153 SSc patients fulfilling the ACR criteria, levels of both BALF and serum cytokines were measured in 25 of these. SSc patients were classified according to the presence/absence of internal organ involvement at first visit, in which cytokine expression was measured, and during the FU period [mean period 66.16 (26.38) months]. Cross sectional analysis focused on cytokine levels in serum and BALF and a possible correlation with clinical manifestations as well as mortality. FU investigations of clinical data were performed to identify the role of cytokines to predict prognosis and disease deterioration. Multivariate analysis was performed with items showing significant values in the univariate analysis (p<0.1).
Results In lung fibrosis patients at baseline higher levels of serum IL-6 and TGFß (p=0.002 and p=0.022; respectively) and lower levels of serum CCL4 (p=0.002) were observed compared to the group without lung fibrosis. Serum IL-8 concentrations were significantly correlated to the BALF levels of IL-8 and TNFα (Rho=0.52, p=0.009; Rho=0.45, p=0.03; respectively). In follow-up investigations, patients with decline in predicted FVC>20% revealed higher initial serum IL-10 concentrations compared to those with stable disease (p=0.02). In patients with lung fibrosis during FU period, significantly higher serum IL-6 concentrations (p=0.001) and lower serum CCL4 and IL-8 levels were detected (p=0.039 and p=0.009; respectively). Finally, serum CCL2 levels of patients with initial pulmonary arterial hypertension (PAH) and PAH developed during FU period were lower compared to the patients without PAH (p=0.006 and p=0.016; respectively). In SSc patients who died during FU, serum IL-6 levels were significantly higher than in surviving patients (p=0.005). Serum IL6>30 pg/ml, muscle atrophy, developed PAH at FU, and decline in FVC>10% predicted mortality (p=0.004, OR 32.79, CI 3.14-342.40; p=0.02, OR 23.40, CI 1.57-348.72, p=0.003, OR 20.74, CI 2.77-155.17, p 0.03, OR 8.11, CI 1.13-57.97, respectively). Furthermore, serum CCL4>300 pg/ml, TGFβ>200 pg/ml and anti-Scl 70 level predicted decline in FVC>20% (p=0.003, OR 0.005, CI 0.000-0.16; p 0.008, OR 18.78, CI 2.17-162.59, p=0.03, OR 0.06, CI 0.005-0.84, respectively). IL6>2 pg/ml and IL8>10 pg/ml predicted decline in DLCO>20% (p=0.04, OR 2.25, CI 1.02-4.97; p=0.03, OR 0.42, CI 0.19-0.94).
Conclusions Association of serum cytokines with clinical manifestations and survival suggests a possible role of several cytokines in SSc pathogenesis. Serum cytokine levels correlate with some BALF cytokine levels in SSc patients. They might serve as marker for survival and disease deterioration in SSc patients.
Disclosure of Interest: None Declared