The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

No abstract

The capillaroscopic score was found to be a sensitive tool to quantify and monitor the SSc microvascular damage. Furthermore, the microangiopathy evolution score might be used to survey the evolution of the microvascular damage, as the relative scores increase during the progression of the SSc.

Sex hormones seem to play an important role as modulators of the autoimmune disease onset/perpetuation. Generally, steroid hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immunosuppressors. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female rheumatoid arthritis (RA) patients, as compared to controls, which is most probably due to increase of local enzymatic aromatase activity. Serum levels of estrogens have been found altered in RA patients, particularly estradiol in man. Thus, available steroid prehormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e., TNFalpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular, 16alpha-hydroxyestrone, showing a mitogenic tumor growth stimulating role. Altered serum hydroxylated estrogens have been found also in serum of systemic lupus erythematosus (SLE) patients. As a matter of fact, our recent studies indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase of markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on immune/inflammatory response is exerted by activating the NFkB complex pathway. In conclusion, locally increased estrogens (i.e., synovial tissue in RA or skin in SLE) might exert activating effects on cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in autoimmunity.

No abstract

NVC is an appropriate tool for differential diagnosis between primary and secondary RP through the clear recognition of the early NVC scleroderma pattern. This study confirms, in a large number of SSc patients, the existence of three distinct NVC patterns that might reflect the evolution of SSc microangiopathy. The presence of anti-Scl70 antibodies seems be related to earlier expression of the active and late NVC patterns of SSc microvascular damage. The presence of ACA seems to be related to delayed expression of the late NVC pattern.

No abstract

Microvascular damage and dysfunction represent the earliest morphological and functional markers of systemic sclerosis (SSc), a progressive connective tissue disease characterized by vascular abnormalities and diffuse fibrosis in the skin and internal organs. These early microvascular changes are clinically mirrored by Raynaud phenomenon, which can be primary (idiopathic) or secondary to several different conditions including SSc. Morphological and functional assessment of the cutaneous microvasculature have crucial implications for diagnosis, prognosis and therapy in SSc and secondary Raynaud phenomenon. Most importantly, imaging with nailfold videocapillaroscopy (NVC) enables the early differentiation between primary and secondary Raynaud phenomenon by identifying morphological patterns specific to various stages of SSc ('early', 'active' and 'late' patterns); the inclusion of these NVC patterns could increase the sensitivity of classification criteria for SSc. Findings on NVC are also markers of SSc severity and progression, as reduced capillary density has been associated with a high risk of developing digital skin ulcers and pulmonary arterial hypertension. Laser Doppler imaging and thermal imaging demonstrate the dysfunctional cutaneous blood flow in response to cold stimuli. Therapies targeting underlying vascular disease in SSc have been successfully designed to improve the symptoms of Raynaud phenomenon and to reduce ischemic injury to involved organs, and NVC patterns have been found to improve following targeted therapy; however, treatment of later fibrosis remains a challenge.