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Production of APRIL is increased in SSc-PBMC and is associated with the presence of anti-topo I antibodies and more severe disease. Targeting the APRIL pathway might represent a therapeutic possibility for treatment of patients with SSc, in particular those with anti-topo I antibodies.

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Widespread vasculopathy and profound fibrosis are key features of the pathogenesis of systemic sclerosis (SSc). We hypothesized that the TNF-like weak inducer of apoptosis (TWEAK), a recently recognized multifunctional cytokine which regulates angiogenesis and tissue remodeling, may play a role in the development of SSc. The production of TWEAK by the peripheral blood mononuclear cells (PBMC) was investigated, by means of ELISA, in 24 SSc patients and 14 healthy subjects. Moreover, production of TWEAK was correlated with clinical features of SSc. PBMC were isolated using density gradient centrifugation on Histopaque and were cultured in FCS supplemented RPMI medium at 37°C under 5% CO 2 . Production of TWEAK by PBMC was significantly diminished in patients with more severe microvascular damage, as indicated by the presence of "active" capillaroscopic pattern, compared with SSc patients with less pronounced microangiopathy ("slow" pattern), and healthy subjects. Moreover production of TWEAK correlated inversely with duration of Raynaud's phenomenon. PBMC from patients with scleroderma-related interstitial lung disease tended to produce lower amounts of TWEAK compared with SSc patients without lung involvement but the difference was not significant. The results of our study suggest that diminished production of TWEAK might play a role in the pathogenesis of vascular injury in SSc patients. Whether TWEAK may represent a new therapeutic target in SSc requires further studies.

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...