Modified Rodnan Skin Score Research Articles

The relationship between left ventricular deformation and heart rate variability in patients with systemic sclerosis: Two- and three-dimensional strain analysis

ObjectiveWe sought to investigate left ventricular (LV) function and deformation, as well as heart rate variability (HRV), and their relationship, in patients with systemic sclerosis (SSc). MethodsThe study included 49 SSc patients and 38 age-matched healthy subjects. All patients underwent clinical examination, serological tests, 24-h Holter monitoring, and comprehensive two- and three-dimensional echocardiography (2DE and 3DE). Results2DE and 3DE LV global longitudinal and circumferential strain, as well as 3DE area strains are significantly reduced in SSc patients comparing with controls. 2DE and 3DE LV radial strains are similar between the observed groups. 2DE LV layer-specific longitudinal and circumferential strains are also significantly affected by SSc. Parameters of cardiac autonomic nervous system, assessed by HRV indices, SDNN, SDANN, rMMSD, p50NN, 24-h HF, LF and TP are significantly lower in SSc group. HRV indices (24-h HF and LF) are associated with 2DE LV global, 2DE LV layer-specific and 3DE LV mechanics independently of main demographic, clinical and echocardiographic parameters of the study population. Additionally, Modified Rodnan Skin Score, clinical parameter of skin involvement in SSc, is significantly associated with HRV (24-h HF and LF), 2DE and 3DE LV deformation. ConclusionSSc significantly impacts LV deformation, all myocardial layers, and cardiac autonomic nervous function. A significant association between cardiac autonomic nervous system function, skin involvement and LV mechanics is revealed in SSc patients. These findings should encourage detailed cardiac assessment and further cardiac follow-up of the SSc patients with higher skin involvement, even when traditional echocardiographic parameters are within normal range.

Assessment of extent of skin involvement in scleroderma using shear wave elastography

Introduction: Scleroderma (systemic sclerosis [SSc]) is a rare autoimmune disease which manifests as fibrosis in the skin and other internal organs. Conventionally, the modified Rodnan skin score (MRSS) has been used to quantify the extent of skin fibrosis (resulting in skin tightness) in SSc. This technique, although widely validated, is limited by the requirement of a trained, experienced assessor. Recent literature suggests that utilization of the objective ultrasound-based assessment of skin fibrosis utilizing shear wave elastography (SWE) may be a more robust technique to detect early skin tightness in SSc. Methods: We evaluated the use of SWE (assessed by an experienced radiologist) in 24 patients with SSc compared with 16 healthy controls. Results: Our patients were predominantly females, with median disease duration of 1.5 years and median MRSS of 17. There was minimal intraobserver variation in the assessment of SWE. Patients with SSc had higher SWE values (mean elasticity [Emean]) compared to healthy controls at most assessed sites for the MRSS. The Emeancorrelated significantly at all sites with the MRSS scores. At the sites where MRSS was scored as 0 (normal), the Emeanin patients with SSc was higher when compared with similarly clinical normal skin in patients with SSc, suggesting potential early involvement of these areas of the skin with fibrosis. Conclusion: SWE is a promising tool to objectively assess skin fibrosis in SSc and may be useful in detecting early, subclinical skin involvement in this disease.

Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis.

The modified Rodnan skin score (mRSS) is a measure of skin thickness and is used as a primary or secondary outcome measure in clinical trials of systemic sclerosis (scleroderma). This state-of-art review provides a historical perspective of the development of the mRSS, summarizes the performance of mRSS as an outcome measure, provides guidance on assessing mRSS, and makes recommendations for incorporation of the mRSS into clinical trials.

Association between Clinical Manifestations of Systemic Sclerosis and Esophageal Dysmotility Assessed by High-Resolution Manometry

Purpose To characterize esophageal involvement according to high-resolution manometry (HRM) findings using the 3rd version of the Chicago Classification, in a French population of patients fulfilling the ACR/EULAR 2013 classification criteria for systemic sclerosis (SSc). Methods Thirty-six patients were consecutively included in this cross-sectional non-interventional study and had HRM performed in Rennes University hospital. Demographic and clinical characteristics, SSc history and interstitial lung disease (ILD) on CT-scan were assessed, and compared with esophageal motility. Results Sixty-one percent of SSc patients had ineffective peristalsis (55.6% failed peristalsis and 5.6% weak peristalsis), 33.3% had hypotensive esophagogastric junction pressure, 75% did not have a physiologic contraction following multiple rapid swallow (MRS), and 44.4% had an abnormal peristaltic reserve. One patient had type 1 achalasia and another one had Jackhammer esophagus. Failed peristalsis was associated with pyrosis (odds ratio [OR] 7.28, 95% confidence interval [CI] 1.51-35.21, p = 0.009), a higher modified Rodnan skin score (MRSS) (without failed peristalsis: 4.68 ± 2.95 vs. with failed peristalsis: 10.68 ± 9.23; p<0.05), the presence of telangiectasia (OR 7, 95% CI 1.59-30.8, p = 0.007), and low diffusing capacity of the lung for carbon monoxide (DLCO) (p = 0.013). Food in the esophagus and esophageal dilation on CT-scan were associated with failed contractions on HRM (respectively, OR 6.85, 95% CI 1.12-40.82, p = 0.05, and OR 14.67, CI 2.4-88.5, p = 0.002). Conclusions This study confirms that failed peristalsis is frequent in SSc and associated with other organ involvement. We found a concordance between HRM results and CT-scan findings regarding esophageal involvement.

Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity.

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.

Analysis of anti-topoisomerase I antibodies in patients with systemic sclerosis before and after autologous stem cell transplantation.

To evaluate the effect of autologous stem cell transplantation (aSCTrans) on antibody (Ab) reactivity towards topo I in patients with SSc, and to see whether it may correlate with clinical outcome after aSCTrans. Eighteen anti-topo/Scl70-positive patients with SSc in whom non-myeloablative aSCTrans had been performed were analysed. Seven patients showed good response without relapse for several years (group 1), eight primarily responded but later relapsed and three did not respond (group 2). A total of 74 sera were analysed at different time points and tested by ELISA against full length ( fl ) topo I, truncated ( tr ) topo I and a previously identified immunodominant epitope covering amino acid 489-573. Eighty-three percent had IgG Abs to topo fl and topo tr . Ab reactivity significantly decreased after aSCTrans, but remained positive in 10 of the 11 patients followed for up to 24 months. The decrease did not correlate with the clinical outcome after aSCTrans. Fifty-six percent of the patients reacted with topo489-573, and reactivity was nearly confined to group 2. There was no correlation between Ab reactivity towards topo fl or topo489-573 and the modified Rodnan Skin Score before aSCTrans or its decrease after aSCTrans. Although aSCTrans is a good treatment option in patients with progressive SSc, it does not abrogate Ab reactivity towards topo I. The presence of anti-topo489-573 Abs before aSCTrans may indicate a less favourable course after aSCTrans.

Serum Soluble CD163 and its association with various disease parameters in patients with systemic sclerosis

Cluster of differentiation 163 (CD163) is a receptor that binds haptoglobin-hemoglobin complexes and is mainly expressed on macrophages and monocytes. As a result of shedding, the extracellular portion of CD163 circulates in the blood as a soluble CD163 (sCD163). This study aimed to measure serum sCD163 levels in patients with systemic sclerosis (SSc) and to assess its association with the clinical, laboratory, and radiological features of the disease. We measured serum sCD163 levels in 24 patients with SSc and in 30 healthy controls. Complete history of the patients was recorded and thorough clinical, rheumatological, and dermatological examinations were performed. For SSc, the skin thickness score was scored according to the modified Rodnan skin score method and pulmonary involvement was assessed in all patients using high-resolution computed tomography and by performing pulmonary function tests. The mean serum sCD163 levels in patients with diffuse and limited SSc (61.64±19.57 and 60.8±21.43 ng/mL, respectively) demonstrated a highly statistically significant increase compared with the mean serum levels in healthy controls (36.97±16.37 ng/mL) (p<0.001). Patients with SSc having elevated serum sCD163 levels had significantly higher pulmonary artery systolic pressure (PASP) than those with normal serum sCD163 levels (p<0.05). Furthermore, the serum sCD163 levels were significantly correlated with PASP (r=0.53, p<0.05) in patients with SSc. The mean serum sCD163 level in patients with SSc having digital ulceration (DU) (70.82±18.3 ng/mL) demonstrated a statistically significant increase (p<0.05) compared with that in SSC patients without DU (53.23±18.09 ng/mL). The elevated serum sCD163 levels in patients with SSc and its association with pulmonary hypertension suggest a possible role of macrophages in the pathogenesis and vascular involvement of SSc.

Imaging of connective tissue diseases: Beyond visceral organ imaging?

Connective tissues diseases (CTDs) can also be diagnosed early by "external" and safe imaging methods beyond the visceral organ analysis. This study aims to explore various imaging techniques used in diagnosing CTDs. Skin impairment in systemic sclerosis (SSc) may be recognized and studied by the modified Rodnan skin score (mRSS), which has some drawbacks, whereas high-frequency ultrasound (US) seems advantageous for the early identification of skin involvement. Salivary gland involvement in Sjögren syndrome (SS) can be assessed using standard tests such as unstimulated salivary flow test, salivary gland scintigraphy or contrast sialography. However, US of the major salivary glands, as an alternative, seems a reliable method with good sensitivity and specificity for the diagnosis of SS. Both the qualitative and quantitative nailfold capillaroscopic (NVC) assessments in SSc patients affected by the Raynaud's phenomenon (RP) may assist in making a differential diagnosis between primary and secondary RP. Microcirculatory imaging by NVC, along with the laser Doppler analysis, seems useful in the prediction of complications and prognosis in CTDs (i.e. SSc) and in monitoring therapeutic trials.

Correlation of delta high-resolution computed tomography (HRCT) score with delta clinical variables in early systemic sclerosis (SSc) patients

The correlation of changes (delta: Δ) of high-resolution computed tomography (HRCT) score with the Δ of other clinical variables has not been well studied. The purpose of this study was to determine the correlation of Δ HRCT score with Δ percent predicted forced vital capacity (%pFVC), Δ modified Rodnan Skin Score (mRSS), Δ erythrocyte sedimentation rate (ESR), and Δ percent of oxygen saturation at room air (%SpO2) in patients with early systemic sclerosis (SSc). We used an inception cohort of early-SSc patients seen at the Rheumatology Clinic, Chiang Mai University, Thailand, between January 2010 and June 2014. All patients underwent HRCT at study entry and every 12 months thereafter. Thirty-one SSc patients who underwent pulmonary function test (PFT) within 12 weeks of their corresponding HRCT at baseline and last visit were identified. The extent of ground glass (GG), lung fibrosis (Fib), bronchiectasis (B), and honeycombing (HC) was scored, and then aggregated to produce a total (t) HRCT score. Mean ± SD age and disease duration from non-Raynaud's phenomenon (NRP) to undergo HRCT at baseline were 52.2±8.8 years and 11.7±7.1 months, respectively. Seventeen (54.8%) patients were female and 20 (64.5%) were classified as dcSSc. The mean ± SD interval between the two HRCT tests was 16.0±7.2 months. The Δ HRCT scores [total fibrosis scores (t-Fib), total bronchiectasis scores (t-B), and total HRCT score (t-HRCT) scores] and Δ mRSS, but not Δ %pFVC, showed significant change over the observation period. We found significant correlation of Δ total honeycombing scores (t-HC) with Δ ESR (r=-0.44, P<0.05), and Δ t-Fib with Δ %SpO2 (r=-0.38, P<0.05). However, no significant correlation of any Δ HRCT scores with Δ %pFVC and Δ mRSS were observed. In this study, the changes in the HRCT scores were greater than %pFVC; this, along with their correlations with the changes in ESR and %SpO2, suggest that HRCT scores are a useful and sensitive method for monitoring disease progression in early SSc-related ILD (SSc-ILD).

Prevalence and predictors of hand involvement in Thai patients with systemic sclerosis.

Data regarding the clinical and radiographic hand involvement in Asian patients with systemic sclerosis (SSc) are limited. Thus, we determined the prevalence of clinical and radiographic hand involvement in Thai SSc patients, comparing diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). We also determined the factors associated with arthritis, contracture of fingers and digital ulcers. SSc patients seen at the Rheumatology Clinic, Chiang Mai University, Thailand, from December 2012 to June 2013 were consecutively invited to enroll in the study. After study entry, demographic data, clinical features and hand radiographs were evaluated. We studied 110 SSc patients (73 dcSSc) with mean±SD age of 53.2±9.2years and disease duration from non-Raynaud's phenomenon of 4.9±4.8years. The prevalence of arthritis, finger contractures and digital ulcers were 10 (9.1%), 47 (42.7%), and 14 (12.7%), respectively. DcSSc patients had significantly more of the following hand complications than lcSSc patients: digital pitting scar (53.4% vs. 27.0%, P=0.008), digital ulcer (17.8% vs. 2.7%, P=0.032), traumatic ulcer (27.4% vs. 0%, P<0.001), acrolysis (45.2% vs. 18.9%, P=0.007) and flexion contracture (60.3% vs. 8.1%, P<0.001). Radiographic finger contractures were more prevalent in the dcSSc subset. In multivariate logistic regression analysis, a positive rheumatoid factor was associated with arthritis; dcSSc, arthritis and modified Rodnan skin score (MRSS) >18 were associated with contracture of fingers. Furthermore, hand MRSS >4 was associated with digital ulcers. Our results confirm that dcSSc patients had more severe clinical hand complications than lcSSc. However, radiographic findings were similar among subgroups, except that more finger contractures were seen in dcSSc. Finally, the presence of rheumatoid factor is associated with arthritis, and high MRSS is associated with finger contractures and digital ulcers.

Musculoskeletal Involvement in SSc Is Associated with Worse Scores on Short Form-36 and Scleroderma Health Assessment Questionnaire and Lower Tumor Necrosis Factor-α Gene Expression in Peripheral Blood Mononuclear Cells.

Systemic sclerosis (SSc) is characterized by a wide variety of symptoms and disease manifestations including joint pain, gastrointestinal dysfunction, interstitial lung disease, and cardiomyopathy. Using the Scleroderma Health Assessment Questionnaire (SHAQ) and Short Form-36 (SF-36) we explored how patient-reported physical health, mental health, and functional status related to these clinical characteristics and to cytokine levels utilizing the Hospital for Special Surgery Scleroderma Registry. In a cross-sectional study of 185 patients meeting the 2013 ACR/EULAR criteria for SSc, we compared disease features and patient-reported outcomes (PROs). Interleukin-6 (IL-6), interleukin-1β (IL1β), and tumor necrosis factor-α (TNFα) levels were assessed by luminex and ELISA assays in a subset of 32 patients. The Pearson correlation coefficient, Spearman correlation coefficient, two-sample t test or Wilcoxon rank sum test, ANOVA or Kuskal-Wallis test, and Pearson chi-squared or Fisher's exact test were performed as applicable to detect the association between disease manifestations, PROs, and blood biomarkers. The modified Rodnan skin score (MRSS) was positively correlated with SHAQ scores. Patients who had musculoskeletal involvement scored worse on both the SHAQ and SF-36. Lower levels of TNFα expression in PBMCs were also correlated with musculoskeletal involvement. No other significant correlations were found between clinical factors, PROs, and cytokine data. Musculoskeletal outcomes are a major determinant of quality of life and function in patients with SSc. These results emphasize the importance of musculoskeletal outcomes in clinical studies of SSc.

Induced Sputum Analysis in Subjects With Systemic Sclerosis.

Induced sputum is a noninvasive tool, aimed at collecting cellular and soluble materials from lung airways. Induced sputum sampling analysis has been validated in chronic obstructive lung diseases as well as in various diffuse interstitial lung disorders. Our objective was to evaluate the utility of induced sputum speciments of cellular and soluble materials noninvasively sampled from the lung airways of subjects with systemic sclerosis compared with healthy controls and determine possible correlation with disease manifestations. The study population included 20 consecutive subjects with systemic sclerosis and 16 healthy volunteers (controls). All of the participants underwent pulmonary function testing (PFT), single-breath diffusion capacity of carbon monoxide, and induced sputum cytology analysis. The systemic sclerosis subjects' induced sputum samples contained a higher neutrophil count (P = .09) and lower lymphocyte count (P = .045) compared with the controls. Within the systemic sclerosis population, several clinical, PFT, and induced sputum findings were positively correlated: the modified Rodnan skin score score and CD3 (P = .044), modified Rodnan skin score and CD4 (P = .04), modified Rodnan skin score and percentage neutrophils (P = .059), and total lung capacity (TLC) and percentage lymphocytes (P = .02). Induced sputum neutrophil counts were inversely associated with TLC (P = .02) and FVC (P = .02). Induced sputum samples from the subgroup of systemic sclerosis subjects with PFT restrictive pattern contained a significantly lower percentage of lymphocytes (P = .004) and lower CD4/CD8 ratio (P = .03) compared with controls. In this subgroup, TLC also was negatively correlated with the neutrophil count (P = .043), and positive correlations were found between TLC and CD3 (P = .053), disease duration and CD4/CD8 ratio (P = .033), TLC and FVC and percentage macrophages (P = .033 and P = .052, respectively), diffusion per unit of alveolar volume, and percentage macrophages (P = .032), and C-reactive protein and percentage lymphocytes, percentage macrophages, and neutrophil count (P = .02, P = .008, and P = .006, respectively). Induced sputum analysis of subjects with systemic sclerosis, including those with restrictive lung disease, shows changes in cellular pattern and correlation with several highly relevant clinical and PFT parameters.

Serum vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1) and sVEGFR-2 in systemic sclerosis patients: Relation to clinical manifestations and capillaroscopy findings

IntroductionThe role of angiogenesis in the pathogenesis of systemic sclerosis (SSc) is well known. The imbalance between vascular endothelial growth factor (VEGF) and their anti-angiogenic soluble receptors (sVEGFR-1 and VEGFR-2) has been proposed as a possible cause of microangiopathy. Aim of the workTo determine the levels of VEGF, sVEGFR-1 and sVEGFR-2 and the VEGF/sVEGFR1 and VEGF/sVEGFR2 ratios in SSc patients and to study their relation with clinical manifestations and capillaroscopy findings. Patients and methodsThe study included 44 SSc patients and 44 controls. The sclerosis severity was assessed by the modified Rodnan skin score (mRss) and capillaroscopy performed in patients. Serum VEGF, sVEGFR-1 and sVEGFR-2 were measured in patients and control. ResultsSSc patients had a mean age of 40.7±12.8years, M:F (1:9) and disease duration was 56.2±60.6months. 27 patients (61.4%) had diffuse-SSc and 17 (38.6%) limited. The mean VEGF was significantly higher (363.4±133.9pg/ml) and sVEGFR-2 lower (2039.6±109pg/ml) in patients compared to control (93.9±25.2pg/ml and 2366±116.5pg/ml; p=0.05 and p=0.04, respectively). Serum levels of sVEGFR-2 in patients with early, active and nonspecific scleroderma pattern of capillaroscopy was higher in comparison to patients with late scleroderma pattern (p=0.05). There were no significant differences in the studied parameters between those patients with and without digital ulcerations and interstitial pulmonary fibrosis. A significant correlation was found between mRss and VEGF (p=0.04). ConclusionAn overproduction of VEGF, a potent angiogenic molecule or down regulated production of its natural inhibitors (sVEGFR-2) might be involved in the development of vasculopathy in SSc patients.

The Modified Hand Mobility in Scleroderma Test and Skin Involvement - A Followup Study.

To study the change in the modified Hand Mobility in Scleroderma (mHAMIS) test from early to advanced stages of systemic sclerosis (SSc), and the relationship between mHAMIS and skin involvement during followup. This retrospective study includes 65 patients with baseline disease duration of ≤ 3 years who were assessed with the mHAMIS test at baseline and at 1 or 2 predefined followup points (3.1-5 yrs and 5.1-9 yrs after disease onset). Studied measures were the modified Rodnan skin score (mRSS), mRSS of the hand, serum cartilage oligomeric matrix protein, and digital vascular lesions. The mHAMIS and the mRSS hand changed synchronously during the first 5 years after disease onset (rs = 0.44, p = 0.001). In the group with high mHAMIS at baseline, both mHAMIS and mRSS hand improved significantly at the first followup (p < 0.05), and the improvement sustained during the followup in the mRSS hand. Patients with antitopoisomerase I and anti-RNA polymerase III antibodies had significantly higher mHAMIS at baseline (p = 0.003) and at the second followup (p = 0.030) compared to patients with anticentromere antibodies. Patients with digital vascular lesions at baseline had significantly higher mHAMIS during the followup (p < 0.05) compared to patients without. The mHAMIS improved significantly during the followup in patients with immunosuppressive treatment in early disease (p < 0.05), but not in patients without this treatment. The mHAMIS reflects disease activity in fibrosis in early stages of SSc. In later stages it can be regarded as a measure of damage arising from fibrotic and vascular involvement, making it suitable as an endpoint in followup examinations.

Validity and responsiveness of the Michigan Hand Questionnaire in patients with systemic sclerosis.

The aim was to assess the validity and responsiveness of the Michigan Hand Questionnaire (MHQ) in patients with SSc. Data were gathered in connection with a randomized, controlled trial comparing the effectiveness of a 12-week multidisciplinary team care programme, including a hand function treatment module, with regular care. Hand function was evaluated by the MHQ (37 items, six domains: Function, Daily activities, Pain, Work, Aesthetics and Satisfaction) and other measurements, including the HAQ, Hand Mobility in Scleroderma, Sequential Occupational Dexterity Assessment (SODA), grip strength, pinch grip and modified Rodnan Skin Score. Fifty-three patients (28 intervention group and 25 control group) completed evaluation at baseline and after 12 weeks. Validity was determined by computing Spearman correlation coefficients between the baseline MHQ total score and subscales and other measures of (hand) disability. Responsiveness in the intervention group was evaluated by the standardized response mean and effect size (ES). In addition, the pooled ES for the difference between the two groups was computed. Significant correlations were seen between the MHQ total score and the HAQ (r = -0.62), Hand Mobility in Scleroderma (r = -0.54), SODA (r = 0.47), SODA Pain (r = 0.32) and modified Rodnan Skin Score (r = 0.46). The ES of the MHQ total score within the intervention group was 0.49, which was larger than that of all other outcome measures. Similar results were obtained for the standardized response mean. The pooled ES of the difference between intervention and control groups for the MHQ total score was 0.86. The MHQ demonstrated adequate validity and responsiveness in patients with SSc.

Rapid, noninvasive quantitation of skin disease in systemic sclerosis using optical coherence elastography.

Systemic sclerosis (SSc) is a connective tissue disease that results in excessive accumulation of collagen in the skin and internal organs. Overall, SSc has a rare morbidity (276 cases per million adults in the United States), but has a 10-year survival rate of 55%. Currently, the modified Rodnan skin score (mRSS) is assessed by palpation on 17 sites on the body. However, the mRSS assessed score is subjective and may be influenced by the experience of the rheumatologists. In addition, the inherent elasticity of skin may bias the mRSS assessment in the early stage of SSc, such as oedematous. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess mechanical contrast in tissues with micrometer spatial resolution. In this work, the OCE technique is applied to assess the mechanical properties of skin in both control and bleomycin (BLM) induced SSc-like disease noninvasively. Young’s modulus of the BLM-SSc skin was found be significantly higher than that of normal skin, in both the in vivo and in vitro studies (p<0.05 p<0.05 ). Thus, OCE is able to differentiate healthy and fibrotic skin using mechanical contrast. It is a promising new technology for quantifying skin involvement in SSc in a rapid, unbiased, and noninvasive manner.

Effect of endothelin-1 receptor antagonists on skin fibrosis in scleroderma patients from the EUSTAR database

Introduction The aim of the study was to evaluate the effect of endothelin-1 receptor antagonists (ETRAs) on skin fibrosis in systemic sclerosis (SSc) patients from the (EULAR Scleroderma Trials and Research) EUSTAR cohort. Methods SSc patients from the EUSTAR cohort with at least three visits (pre-study visit without ETRA treatment, baseline and follow-up visit with ETRA treatment) were included. The control group consisted of SSc patients with the same inclusion criteria, but without ETRA treatment. The primary endpoint was the comparison of the delta change of the modified Rodnan skin score (mRSS) between baseline and follow-up in the ETRA versus the control group. Results Data on 75 ETRA treated (68 bosentan, 1 sitaxentan, 6 ambrisentan) and 969 control patients were included. The delta change of mRSS was not significantly different between the ETRA group and the control group (n = 969; 0 (-2-1) vs. n = 75; 0 (-2-1); p = 0.4). Similarly, subgroup analysis on patients with diffuse, extended SSc disease (mRSS ≥16) did not show differences in the delta change of mRSS between the ETRA group and the control group (n = 125; −1 [-7-0] vs. n = 23; −1 [-7-2], p = 0.8). Likewise, diffuse SSc patients with mRSS 7-21 at baseline, reflecting recently identified enrichment criteria for clinical trials, did not show any difference between the ETRA and the control group (n = 219; −1 [-3-1] vs. n = 27; −1 [-3-2]; p = 0.5). Conclusions This controlled, observational, real-life cohort study with a large sample size did not show effects of ETRAs on skin fibrosis in patients with SSc.

The association between systemic sclerosis disease manifestations and esophageal high-resolution manometry parameters.

We aimed to evaluate the associations between systemic sclerosis (SSc)-related systemic manifestations and esophageal function using high-resolution manometry (HRM). Patients with SSc that had undergone HRM between 1/2004 and 9/2014 were identified and HRMs were analyzed according to the Chicago Classification. Clinical characteristics were identified via retrospective chart review and compared among motility diagnoses while adjusting for age, gender, race, and SSc-disease duration. Seventy-nine patients (85% female, ages 25-77) were included. Clinical characteristics were compared between patients with absent contractility (AC, n = 40), ineffective esophageal motility (IEM; n = 15), and normal motility (n = 19); the five remaining patients met criteria for other motility diagnoses. Groups differed in severity of skin involvement measured by the modified Rodnan skin score (0-51): AC (adjusted mean 12.6), IEM (4.4), normal (4.3), p = 0.043. Pulmonary function tests [percent predicted FVC and DLCO) were lower in AC (adjusted mean, FVC: 70.3, DLCO 51.1), than IEM (FVC: 92.0; DLCO: 76.9) and normal motility (FVC: 80.0; DLCO: 67.2), p values 0.057 (FVC) and 0.007 (DLCO). Groups did not differ by SSc-disease duration, autoantibodies, or reported symptoms of dysphagia or reflux. In patients with SSc, absent esophageal contractility on HRM was associated with increased skin disease severity and worse lung function. Obtaining HRM to identify SSc patients with more severe esophageal dysfunction could be considered to enable implementation of management strategies in patients potentially at risk for increased morbidity and mortality.

The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis.

To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease.

Interleukin-33 in systemic sclerosis: correlation with clinical manifestations and disease subset

Background Systemic sclerosis (SSc) is a generalized connective tissue disorder characterized by sclerotic changes in the skin and internal organs. Interleukin-33 (IL-33) is a newly reported cytokine of the IL-1 family. Aim of the work The aim of this study was to determine serum levels of IL-33 in SSc patients and evaluate its association with clinical manifestations and disease subset. Patients and methods The patients in this study were divided into group A and group B. Group A included 30 adult patients with SSc, which was subdivided into diffuse systemic sclerosis (dSSc) and limited systemic sclerosis (lSSc). All cases were diagnosed according to the American College of Rheumatology criteria for SSc. Group B included 15 healthy adults (age and sex matched) who served as controls. Serum IL-33 levels were examined by means of enzyme-linked immunosorbent assay in 30 patients with SSc and in 15 healthy individuals. Skin assessment was done using the modified Rodnan skin score. Results IL-33 was increased in all SSc patients compared with controls. The levels of IL-33 were significantly higher in the dSSc subset compared with the lSSc subset. IL-33 is highly correlated to the presence of pulmonary fibrosis, Raynaud’s phenomenon, pitting scars and ulcers, pulmonary hypertension, joint contracture, and modified Rodnan skin score. Thus, IL-33 levels were increased in SSc patients and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. Therefore, IL-33 possibly plays a role in cutaneous and pulmonary fibrosis in SSc patients. Conclusion IL-33 may have a significant role in the pathogenesis of SSc. IL-33 serum levels paralleled the severity of the disease subset. Understanding of IL-33 functions is important for the development of new therapeutic approaches including IL-33 inhibitors and IL-33 receptor blockers as a therapeutic target.