SAT0024 Increased production of leukotrienes by peripheral blood mononuclear cells is associated with more severe disease and worse prognosis in patients with systemic sclerosis

Abstract

Background Leukotrienes (LTs) are a group of pro-inflammatory and pro-fibrotic, arachidonic acid-derived lipid mediators. We have shown that LTs are increased in the lungs of patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc). Objectives Since leukocytes are considered a major source of LTs in humans and since inflammatory infiltrates consisting of mononuclear cells are found in the skin and internal organs in early SSc, we undertook this study to investigate the relationship between the synthesis of LTs by peripheral blood mononuclear cells (PBMC) and clinical features of SSc. Methods Leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs) were measured by ELISA in the supernatants from ionophore-stimulated PBMC of 39 patients with SSc and 24 age- and sex-matched healthy controls (HC). Only patients, who had not received immunosuppressive drugs, aspirin or other NSAIDs for at least 6 months, 1 month and 7 days respectively before the study, were included. Follow-up data were available in 25 SSc patients (mean ± SD follow-up time: 34±18 months). Disease progression was defined as death due to SSc-related organ complication, development of a new or progression of pre-existing SSc-related organ involvement (>10% decrease in FVC, increase by at least one WHO class, increase by ≥120% of upper normal limit in serum creatinine and/or loss of >10% of weight after excluding other causes). Results Concentration of LTB4 was significantly higher in PBMC cultures from patients with SSc (640±518 pg/mL/105cells) as compared with HC (353±216 pg/mL/105cells, p<0.05). Higher LTB4 levels were associated with the presence of diffuse SSc, restrictive ILD (FVC<80% predictive and FEV1/FVC >0.8), pulmonary hypertension (PASP>45 mmHg by echo), and more severe microangiopathy in capillaroscpy. Mean concentration of LTB4 was higher in 7/25 SSc patients who experienced subsequent progression of the disease (918±665 pg/mL/105cells) compared with the remaining 18/25 with stable disease (569±549 pg/mL/105cells), but the difference was not significant (p=0.1). We did not find significant differences in the synthesis of CysLTs between SSc patients (313±162 pg/mL/105cells) and HC (266±138 pg/mL/105cells, p>0.05), nor significant associations of CysTLs concentration and SSc-related organ involvement. However, concentration of CysLTs was significantly higher in PBMC cultures from SSc patients with subsequent progression of the disease (452.0±197.3 pg/mL/105cells) as compared with those with stable SSc (275.6±138.9 pg/mL/105cells, p<0.05). Conclusions The results of our study indicate that increased synthesis of LTs might be involved in the pathogenesis and progression of SSc. Consequently, inhibition of LTs synthesis or action might represent a new, promising target in the treatment of SSc. Disclosure of Interest A. Lapinska: None Declared, M. Bielecki: None Declared, O. Distler Grant/Research support from: PD Dr. O. Distler has consultancy relationship and/or has received research funding from Actelion, P...

The role of leukotrienes in the pathogenesis of systemic sclerosis

“…Studies performed in SSc revealed that neutrophils and mononuclear cells from the peripheral blood of SSc patients synthesize higher amounts of leukotrienes than cells obtained from healthy individuals [26,27]. In SSc patients, higher levels of LTB4 in the peripheral blood mononuclear cells (PBMC) cultures were associated with more severe disease as indicated by the presence of diffuse skin involvement, restrictive SSc-ILD, pulmonary hypertension, and greater vascular injury in capillaroscopy [28]. Moreover, higher concentrations of leukotrienes in PBMC cultures were associated with subsequent progression of the disease.…”