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Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

Only a few studies have addressed sexual health in patients with systemic sclerosis (SSc). This study aimed to compare female sexual function and pelvic floor muscle function in SSc patients with healthy controls (HC) matched by age, and to identify the potential implications of clinical features on sexual function. Our cohort included 90 women with SSc and 90 HC aged 18–70 years that completed six well-established and validated questionnaires assessing sexual function (Brief Index of Sexual Function for Women, Female Sexual Function Index, Sexual Quality of Life Questionnaire–Female, Sexual Function Questionnaire) and pelvic floor function (Pelvic Floor Impact Questionnaire–Short Form 7 and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire Short Form). Results from women with SSc and HC were contrasted and correlated with relevant clinical features. The prevalence of female sexual dysfunction was 73% in SSc patients (vs. 31% in HC). Women with SSc reported significantly worse pelvic floor function and sexual function than HC. Impaired sexual function was correlated with higher disease activity, the presence of dyspnea and interstitial lung disease, increased systemic inflammation, reduced physical activity, functional disability, more severe depression, more pronounced fatigue, and impaired quality of life. We demonstrate that sexual dysfunction is highly prevalent among women with SSc. This aspect of the disease deserves more attention both in clinical care and at the level of international research collaboration.

In the original publication [...]

ObjectivesRiociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression.MethodsIn this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10–22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52.ResultsAt week 52, change from baseline in mRSS units was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo (difference of least squares means –2.34 (95% CI –4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud’s condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths.ConclusionsRiociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

Background Interleukin 40 (IL-40) is a cytokine implicated in malignancies and rheumatic disorders. Its association with fibrotic mediators has been previously described. Since inflammation and fibrosis are hallmarks of systemic sclerosis (SSc), we aimed to analyze the role of IL-40 in SSc. Methods IL-40 levels were analyzed in the serum of 90 SSc patients and 75 healthy controls (HCs). IL-40 expression in dermal biopsies from 5 SSc patients and 5 HCs was assessed via immunohistochemistry. IL-40 was analyzed in 39 SSc patients with interstitial lung disease treated with cyclophosphamide (CPA) and in 24 SSc patients with active progressive disease treated with rituximab (RTX). SSc activity was assessed by the European Scleroderma Study Group (ESSG) index. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from 10 SSc patients was determined in vitro. IL-40 was analyzed in 24 individuals at risk of developing SSc (VEDOSS), who were categorized as progressors ( n  = 11) and nonprogressors ( n  = 13). Results IL-40 expression was elevated in the skin of SSc patients compared to HCs, particularly in fibroblasts and immune infiltrates. Serum IL-40 was increased in SSc compared to HCs ( p  < 0.0001) and was associated with ESSG ( r  = 0.372, p  = 0.0005) and gastrointestinal involvement ( p  < 0.05). IL-40 correlated with serum IL-8 ( r  = 0.270, p  = 0.019) and TGF-β1 ( r  = 0.301, p  = 0.024) levels. In the CPA and RTX cohort, no significant changes in the serum IL-40 were observed upon treatment. Baseline and changes in IL-40 levels were associated with changes in several clinical parameters. IL-40 was elevated in patients at risk of SSc compared to HCs ( p  = 0.0003). No significant changes were observed in progressors vs. nonprogressors; however, IL-40 was associated with capillaroscopy findings ( p  < 0.05). IL-40 induced the upregulation of IL-6 ( p  = 0.002), MCP-1 ( p  = 0.002) and IL-10 ( p  = 0.002) in PBMCs from SSc patients in vitro. Conclusions IL-40 was upregulated in the skin and serum of SSc patients and was associated with disease activity, gastrointestinal involvement and fibrotic mediators. Our in vitro findings indicate that IL-40 might be involved in the immune response and fibrotic processes in SSc.

Introduction Systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM) are very rare rheumatic diseases burdened by a high prevalence of sexual dysfunctions. However, no specific treatment has been proposed to date. To our knowledge, this is the first (pilot) study aiming to investigate the effect of an 8-week tailored physiotherapy program on the sexual health of women with SSc and IIM. Methods In total, 12 women with SSc and 4 women with IIM were enrolled in the study. Based on the patients’ capability to participate in the program, they were divided into an intervention group (IG) (mean ± SD age 46.8 ± 8.6 years) and a control group (CG) (mean ± SD age 46.3 ± 8.5 years). IG underwent the 8-week program (1 h of supervised physiotherapy twice weekly), whereas CG received no physiotherapy. At weeks 0 and 8, all patients filled in questionnaires assessing sexual function (Female Sexual Function Index [FSFI], Brief Index of Sexual Functioning for Women [BISF-W]), sexual quality of life (Sexual Quality of Life-Female [SQoL-F]), functional ability (Health Assessment Questionnaire [HAQ]), quality of life (Medical Outcomes Short Form-36 [SF-36]), and depression (Beck’s Depression Inventory-II [BDI-II]). The changes were analyzed with two-way ANOVA and Friedmann’s test. Results Compared to the statistically significant deterioration in CG over weeks 0–8, we found statistically significant improvements in the total scores of FSFI and BISF-W, and some of their domains, functional status, and the physical component of quality of life. Conclusion Our 8-week physiotherapy program not only prevented the natural course of progressive deterioration of functional ability but also led to a significant improvement in sexual function and quality of life in women with SSc and IIM. However, due to the lack of randomization and a relatively small sample size resulting from the strict inclusion criteria, further validation of our results is needed. Trial registration number : ISRCTN91200867 (prospectively registered).

Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.