An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.

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Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations.

Higher sRANKL levels and sRANKL/OPG ratio in patients with SSc are likely to be a consequence of altered bone microenvironment. We show a dissociation between the well established marker of endothelial activation/injury, sVCAM, and the alleged marker of vascular damage, OPG, in patients with SSc. Further studies are needed to better ascertain the relationships of the RANKL/RANK/OPG system with the progression of macro- and microvascular damage.

BackgroundProkinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed.MethodsForty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods.ResultsThere were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035).ConclusionsThe safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating.Trial registrationEU Clinical Trial Registry, EudraCT2012-005348-92. Registered on 19 February 2013.