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Concept: Systemic scleroderma


We assessed the cutaneous microcirculatory reactivity of a clinically unaffected skin region in patients with systemic sclerosis (SSc) compared to healthy controls by measuring transcutaneous oxygen saturation (TcPO2) and Laser Doppler flowmetry (LDF). Twelve consecutive patients with SSc and twelve healthy controls were subjected to TcPO2 monitoring and LDF during cuff-induced ischemia and reactive hyperemia in order to measure the skin oxygen tension and the microcirculatory blood flow. Mean minimal and maximal values of oxygen tension and blood flow, time to peak (TTP), and declining slopes after peaking (slope) were compared between patients with SSc and controls. Compared to the controls, TcPO2 values in SSc were similar during ischemia and diminished during reactive hyperemia, with shorter TTP, and a slower return to baseline (-60% vs. -58%, p = 1.000, +76% vs. +210%, p = 0.047, 137 s vs. 108 s, p = 0.028, -0.009%/s vs. -0.019%/s, p = 0.021, respectively). LDF values, however, did not differ significantly between patients with SSc and controls. Unaffected skin regions of SSc patients showed a significantly diminished postischemic vasodilatory reactivity when assessed by TcPO2 monitoring, but not by LDF, indicating that vasculopathy may represent an early mechanism in the onset of skin sclerosis. TcPO2 measurement may help to detect changes in the microcirculation in SSc with no skin affection.

Concepts: Oxygen, Measurement, Rheumatology, Skin, Hypoxia, Scleroderma, Systemic scleroderma, Laser Doppler velocimetry


Context:There is no effective treatment for systemic sclerosis and related fibrosing diseases. Recently the action of CYP11A1 on vitamin D(3) was shown to produce biologically active 20S-hydroxyvitamin D [20(OH)D(3)] and 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), and 17,20,23(OH)(3)D(3).Objectives:Because 20(OH)D(3) is noncalcemic (nontoxic) in vivo at very high doses, we evaluated its antifibrogenic activities both in vitro and in vivo. Because it is further metabolized by CYP11A1, we also tested preclinical utilities of its hydroxyderivatives, especially 20,23(OH)(2)D(3).Design:Human dermal fibroblasts from scleroderma and normal donors were used to test the efficiency of hydroxyvitamin D derivatives in inhibiting TGF-β1-induced collagen and hyaluronan synthesis and inhibiting cell proliferation. The in vivo activity of 20(OH)D(3) was tested using bleomycin-induced sclerosis in C57BL/6 mice.Results:20(OH)D(3) and 20,23(OH)(2)D(3) inhibited TGF-β1-induced collagen and hyaluronan synthesis similarly to 1,25(OH)(2)D(3) in cultured human fibroblasts. Also, 20(OH)D(3), 20,23(OH)(2)D(3), and 1,25(OH)(2)D(3) suppressed TGF-β1-induced expression of COL1A2, COL3A1, and hyaluronan synthase-2 mRNA, indicating that they regulate these matrix components at the transcriptional level. 20(OH)D(3), 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), and 17,20,23(OH)(3)D(3) inhibited proliferation of dermal fibroblasts with comparable potency with 1,25(OH)(2)D(3), with 20(OH)D(2) being less active and 1α(OH)D(3) being almost inactive. 20,23(OH)(2)D(3) at 3 μ g/kg had no effect on serum Ca(++) or fibroblast growth factor-23 levels and did not cause any noticeable signs of morbidity. 20(OH)D(3) markedly suppressed fibrogenesis in mice given sc bleomycin as demonstrated by total collagen content and hematoxylin and eosin staining of skin biopsies.Conclusions:20(OH)D(3) is an excellent candidate for preclinical studies on scleroderma, with other CYP11A1-derived products of its metabolism deserving further testing for antibrogenic activity.

Concepts: Protein, Vitamin D, Wound healing, Collagen, Fibroblast, In vivo, In vitro, Systemic scleroderma


To assess the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for Systemic Sclerosis (SSc) on defined subgroups of SSc and in mixed connective tissue disease (MCTD) as an SSc-related disease.

Concepts: Blood, Rheumatology, Scleroderma, Systemic scleroderma


To translate and adapt the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GIT 2.0) into Dutch and validate it among Dutch systemic sclerosis (SSc) patients.

Concepts: Rheumatology, California, Scleroderma, Systemic scleroderma, Mucinoses, University of California, University of California, Los Angeles, Pacific-10 Conference


Raynaud’s phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760-0.932), lower values of FMD (AUC 0.754, 95%CI 0.643-0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649-0.866), ADMA (AUC 0.634, 95%CI 0.511-0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579-0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14-0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41-10.26) and late NVC pattern (HR 2.29, 95%CI 0.97-5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06-77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up.

Concepts: Angiogenesis, Vascular endothelial growth factor, Rheumatology, Endothelium, Scleroderma, Systemic scleroderma, Raynaud's phenomenon, CREST syndrome


Interstitial lung disease (ILD) complicates the course of systemic sclerosis (SSc), representing the main cause of death in these patients. The identification of parameters that can predict the early onset and progression of ILD in SSc represents an unmet need in clinical practice. The study was designed to explore whether the surfactant proteins (SP) A and D may be used as noninvasive tools for the early identification of ILD in SSc. Alveolar exhaled nitric oxide (NO) was investigated as a surrogate marker of distal inflammation.

Concepts: Epidemiology, Medical terms, Nitrogen, Nitric oxide, C-reactive protein, Exhaled nitric oxide, Systemic scleroderma, Surfactant protein D


Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc.

Concepts: Immune system, White blood cell, Innate immune system, Macrophage, Systemic scleroderma


Impaired hand function greatly contributes to disability and reduced quality of life in SSc patients. Autologous adipose-derived stromal vascular fraction (ADSVF) is recognized as an easily accessible source of regenerative cells. We reported positive 6-month safety and efficacy results from an open-label clinical trial assessing s.c. injection of autologous ADSVF into the fingers in SSc patients. The objective of this report is to describe the effects at 12 months.

Concepts: Effectiveness, Rheumatology, Disability, Scleroderma, Systemic scleroderma, Accessibility, Disability rights movement, Americans with Disabilities Act of 1990


Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case-fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.

Concepts: Epidemiology, Epithelium, Rheumatology, Autoimmune disease, Autoimmune diseases, Connective tissue diseases, Scleroderma, Systemic scleroderma


A 46-year-old woman with a 7-year history of systemic sclerosis treated with methotrexate presented with abdominal pain, persistent nausea, and vomiting of undigested food that had begun 3 months earlier. A barium-swallow examination revealed duodenal distention.

Concepts: Hepatitis, Rheumatoid arthritis, Abdominal pain, Gastroenteritis, Nausea, Scleroderma, Systemic scleroderma