Modified Rodnan Skin Score Research Articles

Analysis of serum interleukin(IL)-1α, IL-1β and IL-18 in patients with systemic sclerosis.

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis, vascular dysfunction and immune dysregulation. The pathogenesis of SSc remains poorly understood, although studies have indicated a role for the innate immune response.MethodsHere, we measured serum interleukin (IL)‐1α, IL‐1β and IL‐18 levels in 105 SSc patients and 47 healthy controls (HC) and analysed them with respect to multiple clinical parameters.ResultsSerum IL‐18 concentrations were significantly higher in SSc patients than in HC, while no significant differences in concentrations of IL‐1α and IL‐1β were observed between SSc and HC. In both SSc and HC serum, IL‐1α and IL‐1β were positively correlated, while in SSc, both cytokines negatively correlated with IL‐18. Serum IL‐18 was significantly negatively correlated with both carbon monoxide transfer coefficient (KCO) and diffusing capacity of the lungs for carbon monoxide (DLCO). Serum IL‐1β was positively correlated with the modified Rodnan skin score (mRSS), particularly in patients with limited subtype. DLCO, KCO and tricuspid regurgitation (TR) velocity were significantly higher in patients with high serum IL‐1β. Serum IL‐1α was significantly lower in SSc patients with low KCO and positively correlated with KCO. SSc patients with high serum IL‐1α concentrations were more likely to have digital ulcers.ConclusionsOur data suggest that these IL‐1 family cytokines may have different roles in the pathogenesis of SSc fibrotic complications.

Ophthalmic Findings in Systemic Sclerosis and Its Association with Dermal Fibrosis

Objective: To determine frequency and type of ophthalmologic findings in Systemic Sclerosis (SSc) and to establish their association with the extent and severity of cutaneous fibrosis. Methods: Descriptive-transversal study of 34 patients, (January-December 2017). It included patients with limited cutaneous Systemic Sclerosis (lcSS) and diffuse cutaneous Systemic Sclerosis (dcSS). The severity of cutaneous fibrosis was measured using the modified Rodnan skin score (mRSS). The ophthalmologic examination consisted of the evaluation of the palpebral fibrosis and the ocular surface by Schirmer’s test, tear rupture time (BUT), OSDI (Ocular Disease Surface Index) and SANDE (Symptom Assessment in Dry Eye) questionnaires, eye fundus and retinography. We use simple logistic regression (OR) to establish the association with p

Systemic Sclerosis and Serum Content of Transforming Growth Factor.

Systemic sclerosis is a connective tissue disease characterized by tissue fibrosis leading to interstitial lung disease. Transforming growth factor-β (TGF-β) has been of interest as a potential diagnostic marker and also as a drug target in systemic sclerosis. The aim of this study was to assess the serum content of TGF-β1 in patients with systemic sclerosis and to assess its potential role in tissue fibrosis. The study included 30 patients, 5 men and 25 women, of the mean age of 46.9±12.8years, diagnosed with systemic sclerosis. The control group consisted of 19 women of the mean age of 28.4±7.8years, diagnosed with primary Raynaud's disease. TGF-β1 serum levels were measured, chest imaging examinations were performed, and fibrotic tissue changes were assessed using the modified Rodnan Skin Score. We found that the mean serum TGF-β1 content in patients with systemic sclerosis was 598.7±242.6pg/mL, whereas it was 568.4±322.2pg/mL in the control group (p=0.378). We also failed to substantiate any significant relationship between TGF-β1 serum levels and the severity of pulmonary and skin fibrosis in systemic sclerosis. In conclusion, systemic sclerosis does not seem a disease that would be accompanied by a specific enhancement of serum TGF-β1. Thus, this cytokine is rather unlikely to play an essential role in the development and course of the disease, nor can it be considered diagnostic or prognostic marker.

Fibroblast Growth Factor 23 to Alpha-Klotho Index Correlates with Systemic Sclerosis Activity: A Proposal for Novel Disease Activity Marker.

Systemic sclerosis, a connective tissue disease, is characterized by thickening of the skin, massive fibrosis of internal organs, vasculopathy, and immune system functioning aberration. Recently, vitamin D (VD) deficit, seen almost universally in patients with systemic sclerosis (SSc), has gained much attention. VD metabolism is precisely orchestrated at the level of the kidney by regulators: parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) and their receptors with a FGF23 co-receptor—α-Klotho. The aim of this study was to assess the levels of VD, α-Klotho, FGF23 in SSc patients and to find the relationship between those parameters and disease activity. We enrolled 48 SSc patients with a diffuse variant of SSc and 23 sex- and age-matched healthy volunteers that served as the control group (CG). Patients were characterized by lower level of VD in comparison to CG (19.8 (12.6–28.9) vs. 24.5 (21.3–31.5) ng/mL; p < 0.01), significantly reduced levels of iFGF23 (19.3 (12.1–30.5) vs. 73.9 (59.7–110.2) pg/mL p < 0.001), and similar α-Klotho concentrations (1415 ± 557 vs. 1526 ± 397 pg/mL), respective. None of these parameters correlated with the extent of skin involvement (modified Rodnan Skin Score) and disease activity according to Eustar 2017 guidelines. The FGF23/α-Klotho index was significantly reduced in SSc patients (0.013 (0.0081–0.025) vs. 0.055 (0.038–0.095); p < 0.001), and its log10 correlated (r = 0.35; p < 0.001) with disease activity score (Eular2017). Our data showed that the FGF23/α-Klotho index may be considered as a novel, potential marker of systemic sclerosis activity.

Correlation Between Serum C-Reactive Protein (CRP) and Soluble Cd40 Ligand (sCD40L) with Disease Activity by Modified Rodnan Skin Score (mRSS) in Systemic Sclerosis Patients in Indonesia

Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease which presents immunological, endothelial dysfunction, skin and organs fibrosis. The inflammatory process is an important pathophysiology of systemic sclerosis. Disease activity assessment using clinical parameters of Modified Rodnan Skin Score (mRSS) changes and inflammatory laboratory parameters of C-Reactive Protein (CRP), Erytrocyte Sedimentation Rate (ESR) and soluble CD40 ligand. The European Scleroderma Study Group (EscSG) Activity Index uses CRP. CRP is higher sensitivity and specificity than ESR (80% and 91.2%). The study aims to evaluate the correlation between CRP and sCD40L with disease activity by mRSS.Methods: This research was a cross-sectional study, and data of mRSS and sCD40L were obtained from the study, "Blind Clinical Trials Extract Ciplukan Herbs on Clinical Improvement of Skin Disorders, Inflammatory Process, Immunology and Fibrosis in Scleroderma Patients”. CRP examination was done by using the rest samples of the study, conducted in December 2017. Data analysis with Rank-Spearman and Pearson Correlation..Result: There were fifty-eight subjects with mean age 38 ± 11 years old. Most of subjects were female (94.8%) and with a late disease duration &gt; 2 years (74.1 %). Subjects consisted of 35 (60.3%) diffuse SSc and 23 (39.7 %) limited SSc. CRP was measured by Turbidimetric Immunoassay. Median (range) CRP serum was 2.89 (0.16–17.29) mg/L, while the median of sCD40L was 6457 (1018–17976) pg/mL, and the median of mRSS was 17 (4–36). There was no correlation between CRP and sCD40L with mRSS (r = -0.134, p = 0.167; and r = 0.023, p = 0.433).Conclusion: There was no correlation between CRP and sCD40L serum with mRSS in systemic sclerosis patients.

Improving Treatment Related Mortality over Time - Data from the Non-Observational Trial on Autologous Stem Cell Transplantation in Systemic Sclerosis By the EBMT Autoimmune Diseases Working Party (ADWP)

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease with ongoing high disease related mortality. Three randomized controlled trials proofed efficacy of autologous stem cell transplantation (aHSCT) in patients with severe SSc and superiority over the standard cyclophosphamide pulse therapy. Treatment related mortality is a major point of criticism and different treatment regimen are used in different centers.Methods: This prospective, open, multi-center, non-interventional study of the European Group for Blood and Marrow Transplantation (EBMT) analyzed data for consecutive aHSCT performed in SSc. Every center followed its own local protocol which usually refers to the recent update of the EBMT Guidelines. In order to be eligible for inclusion, patients had to be transplanted for the diagnosis of progressive SSc and aged between 18 and 65 years. Major exclusion criteria were an ejection fraction <40% by cardiac echo, pulmonary arterial hypertension with systolic pulmonary arterial pressure (sPAP) >50mmHg, creatinine clearance <30ml/min, reduced lung function with either FVC <50% or DLCO <30% of predicted values. Concurrent neoplasms, myelodysplasia, severe psychiatric illnesses as well as previously damaged bone marrow had to be ruled out.Progression free survival (PFS) was chosen as primary endpoint. Response to treatment, defined as the number of patients who achieve >25% improvement of the skin thickness, measured by the modified Rodnan Skin score (mRSS; range 0-51) and/or ≥10% improvement in forced vital capacity (FVC) or hemoglobin-adjusted diffusion lung capacity for carbon monoxide (DLCO) and relapse rate as well as safety considerations were secondary endpoints.Results: Between 2013 and 2015, 80 patients from 12 centers were followed for a median of 24.1 (5.97 - 59.8) months. Patients had a median age of 43 years at aHSCT and 70% were female. All patients were mobilized with cyclophosphamide (CYC) with a median of 2g/m2 and granulocyte-colony stimulating factor (GCSF) in 98%. In 45% of transplants stem cells were purified using CD34-positive selection. For conditioning, centers used CYC at 200 mg/kg (50 - 240) in 76 patients (95%) or CYC at 100 mg/kg and thiotepa 10 mg/kg in 4 patients. All patients received additional anti-thymocyte globulin (ATG; different brands were used) over 4-5 days.Progression free survival at 1 year was reached by 83.6% of our patients. Response to treatment at 1 year was achieved by 75% (63.7 - 83.2) and 10.1% relapsed or had further progression despite aHSCT. Figure 1 demonstrates the improvement of skin fibrosis over time. Median mRSS decreased from 24 (2 - 49) at baseline to 13 (0 - 40) at month 12, and 10.5 (0 - 32) at month 24. On multivariate analysis, creatine kinase (CK) levels < 250 U/ml, mRSS <24 and lung crepitation at baseline were significantly associated with response to treatment, but especially CD34-positive selection is a strong positive predictor for response to treatment with a hazard ratio of 2.19 as compared to patients treated with non-selected stem-cell.The 100-day treatment-related mortality for this population was 6.2% (n=5) (CI 2.3 - 13). Three of these 5 patients had a cardiac or cyclophosphamide related event that led to death. During the 24 months of follow up another 3 patients died due to progressive disease, which leads to an overall survival of 91.2% (CI: 85.1 - 97.4) at 2 years.Discussion: Although aHSCT has been proven effective in SSc, we still do not know which regimen is the best. With data from this non-interventional trial we could demonstrate the effectiveness of aHCST in a daily practice setting. Treatment seems to become safer over time with reduction of TRM from 10% in the European phase III Autologous stem cell transplantation international scleroderma trial (ASTIS; JAMA. 2014; 311(24): 2490-8) to 6.2% in our actual study; mainly due to increasing experience of the centers and exclusion of patients with advanced organ damage. Nevertheless indication for aHSCT should also be driven by negative predictive parameters for disease related mortality and it is fairly unlikely to further reduce TRM in these sick patients.We also found a potential value of CD34-selection in these patients. As a retrospective approach demonstrated no benefit to the outcome of SSc patient treated with AHSCT (Bone Marrow Transplant.2016; 51(4): 501-5), these findings have to be confirmed by prospective randomized trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Median neuropathy at the wrist in patients with systemic sclerosis: two-year follow-up study.

ObjectivesTo determine the incidence and factors associated with median neuropathy at the wrist (MNW) in systemic sclerosis (SSc) patients using an electrodiagnostic (EDX) study.Material and methodsSSc patients who attended the scleroderma clinic, Srinagarind Hospital, were prospectively evaluated by questionnaire, physical examination, and EDX study. The questionnaire consisted of the baseline characteristics, type of scleroderma, clinical signs and symptoms associated with scleroderma, and the Boston questionnaire. The physical examinations were the Modified Rodnan Skin Score, motor power grading of bilateral abductor pollicis brevis muscle, and pinprick sensation of median nerve distribution of both hands. Moreover, the EDX study, which was composed of median and ulnar sensory and motor nerve conduction studies of both hands and electromyography of the abductor pollicis brevis muscles, was evaluated at baseline and following two years.ResultsOut of 75 systemic sclerosis patients, 50 individuals participated in the study. Diffuse cutaneous type of SSc is the most common type (72%). The common SSc associated symptoms were Raynaud phenomenon, skin tightness and hand deformity. Incidence of MNW was 90 cases per 1000 person-years. Following a two-year interval, the percentages of mild, moderate and severe MNW were 28%, 22% and 6% respectively. Most of those with MNW were still particularly asymptomatic in a mild degree. Moreover, 12 out of 50 patients (24%) had a worse EDX result. There was no statistically significant association between MNW occurrence and studied factors.ConclusionsMNW commonly has high incidence in SSc patients. Therefore, SSc patients should be followed up in both clinical and EDX studies for MNW screening. SSc patients with asymptomatic MNW might need clinical follow-up for early diagnosis.

Association of low socioeconomic status and physician assessment of disease severity with oral health-related quality of life in patients with systemic sclerosis: a pilot study from Croatia, a country in transition.

ObjectiveThis study was performed to identify a possible association of the clinical parameters of systemic sclerosis (SSc) and the socioeconomic status (SES) with oral health-related quality of life (OHrQoL) as measured by the Oral Health Impact Profile 49 (OHIP 49), taking into account the effect of educational level (as a proxy of SES) on oral health.MethodsSubjects were recruited from the Croatian SSc Center of Excellence cohort. Detailed dental and clinical examinations were performed according to standardized protocols. The associations of OHrQoL with disease characteristics and socioeconomic status were examined.ResultsThirty-one consecutive patients with SSc were enrolled (29 women; mean age, 56.45 ± 13.60 years). OHIP 49 scores were significantly correlated with disease activity and severity. Furthermore, OHrQoL was positively correlated with skin involvement as evaluated by the modified Rodnan skin score. Impaired OHrQoL was positively correlated with the severity of general, skin, gastrointestinal, and joint/tendon involvement. The OHIP 49 score differed between patients who were positive and negative for anti-topoisomerase I antibody. Higher OHIP 49 scores were detected in patients with lower SES (primary school educational level).ConclusionCollaboration between rheumatologists and dental professionals is required to improve dental care and oral health outcomes of SSc.

High-frequency ultrasound of the skin in systemic sclerosis: an exploratory study to examine correlation with disease activity and to define the minimally detectable difference

BackgroundThickened skin is a major clinical feature in patients with systemic sclerosis (SSc). We investigated changes of skin thickness in patients with SSc using both high frequency ultrasound (HFU) and the modified Rodnan skin score (mRSS) to evaluate the feasibility of application of HFU in skin involvement and the relationship between HFU and clinical profiles.MethodsWe recruited 31 consecutive patients with SSc and 31 age-matched and sex-matched healthy controls in this prospective, cross-sectional study. Skin thickness was measured by an 18-MHz ultrasonic probe at five different skin sites. Total skin thickness (TST) and skin thickness using categorical mRSS scores were recorded and compared to HFU. The European Scleroderma Trial and Research (EUSTAR) group Disease Activity Index (EUSTAR-DAI) and other clinical manifestations were assessed and analyzed.ResultsTST in patients with SSc was thicker than in healthy controls (P < 0.001), and correlated positively with total mRSS and the EUSTAR-DAI and correlated negatively with disease duration (P < 0.05). Patients with higher TST had higher EUSTAR-DAI, mRSS, C-reactive protein (CRP) and lower diffusing capacity of the lung for carbon monoxide (DLCO) (P < 0.05). Even in patients who on clinical assessment were assigned an mRSS that suggested the skin thickness was normal. This was also true to mRSS locally of 1 and 2 (P < 0.01). The area under the receiver operator characteristic (ROC) curve was 0.831 and yielded sensitivity of 77.4% and specificity of 87.1% at the predicted probability of 7.4 mm as the optimal cutoff point to access skin thickness.ConclusionsIn the study, HFU was able to measure skin thickness, it correlated quantitatively with a valid measure of SSc activity, and a minimal detectable difference was identified.

Are diffuse and limited juvenile systemic sclerosis different in clinical presentation? Clinical characteristics of a juvenile systemic sclerosis cohort.

Juvenile systemic sclerosis is an orphan disease. Currently, the majority of juvenile systemic sclerosis cohort studies are retrospective in design without standardized assessment. This study was conducted prospectively to investigate the difference in manifestations of limited cutaneous juvenile systemic sclerosis and diffuse cutaneous juvenile systemic sclerosis subtypes. An additional aim was to compare these data to other juvenile systemic sclerosis cohorts and a large adult systemic sclerosis cohort. Patients fulfilling the Paediatric Rheumatology European Society juvenile systemic sclerosis classification criteria were included. Clinical characteristics and patient-related outcomes were assessed. In all, 88 patients with a mean disease duration of 3.5 years were enrolled, 72.5% with diffuse cutaneous juvenile systemic sclerosis with a mean modified Rodnan Skin score of 18 and 27.5% with limited cutaneous juvenile systemic sclerosis with mean modified Rodnan Skin score of 9. The mean age at the onset of Raynaud's and first non-Raynaud's symptoms was similar in both groups, approximately 9 and 10.5 years. Active digital tip ulcerations were present in 29% diffuse cutaneous juvenile systemic sclerosis and none in the limited cutaneous juvenile systemic sclerosis subjects (p = 0.005). Of those with cardiopulmonary testing, 3% of diffuse cutaneous juvenile systemic sclerosis and 23% of limited cutaneous juvenile systemic sclerosis group had cardiac involvement (p = 0.015), and 41% diffuse cutaneous juvenile systemic sclerosis and 22% of the limited cutaneous juvenile systemic sclerosis group had pulmonary involvement (p = 0.009). Physician global disease damage assessment was higher in the diffuse cutaneous juvenile systemic sclerosis group compared to the limited cutaneous juvenile systemic sclerosis group: 35 and 15 (p = 0.021). The majority of this international juvenile systemic sclerosis cohort had diffuse cutaneous juvenile systemic sclerosis (72.5%) with more frequent vascular and pulmonary involvement compared to the limited cutaneous group, who had increased cardiac involvement. Our cohort reflects prior findings of published juvenile systemic sclerosis cohorts and emphasizes a difference in the presentation compared to adult-onset systemic sclerosis.

Computed tomography trachea volumetry in patients with scleroderma: Association with clinical and functional findings.

BackgroundIn scleroderma, excessive collagen production can alter tracheal geometry, and computed tomography (CT) volumetry of this structure may aid in detecting possible abnormalities. The objectives of this study were to quantify the morphological abnormalities in the tracheas of ​​patients with scleroderma and to correlate these findings with data on clinical and pulmonary function.MethodsThis was a cross-sectional study in which 28 adults with scleroderma and 27 controls matched by age, gender and body mass index underwent chest CT with posterior segmentation and skeletonization of the images. In addition, all participants underwent pulmonary function tests and clinical evaluation, including the modified Rodnan skin score (mRSS).ResultsMost patients (71.4%) had interstitial lung disease on CT. Compared to controls, patients with scleroderma showed higher values ​​in the parameters measured by CT trachea volumetry, including area, eccentricity, major diameter, minor diameter, and tortuosity. The tracheal area and equivalent diameter were negatively correlated with the ratio between forced expiratory flow and forced inspiratory flow at 50% of forced vital capacity (FEF50%/FIF50%) (r = -0.44, p = 0.03 and r = -0.46, p = 0.02, respectively). The tracheal tortuosity was negatively correlated with peak expiratory flow (r = -0.51, p = 0.008). The mRSS showed a positive correlation with eccentricity (r = 0.62, p < 0.001) and tracheal tortuosity (r = 0.51, p = 0.007), while the presence of anti-topoisomerase I antibody (ATA) showed a positive correlation with tracheal tortuosity (r = 0.45, p = 0.03).ConclusionsIn a sample composed predominantly of scleroderma patients with associated interstitial lung disease, there were abnormalities in tracheal geometry, including greater eccentricity, diameter and tortuosity. In these patients, abnormalities in the geometry of the trachea were associated with functional markers of obstruction. In addition, tracheal tortuosity was correlated with cutaneous involvement and the presence of ATA.

Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis

BackgroundA pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis.MethodsAn NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation.ResultsSSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-γ signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-β signaling (R = − 0.796, p < 0.0001) and the modified Rodnan skin score (R = − 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-γ.ConclusionsOur results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-γ pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-γ signaling may represent a novel strategy to control skin fibrosis in SSc.

Nutritional Decline in Scleroderma Patients Data from a single Romanian center

Malnutrition has been known to provide poor survival outcomes in systemic sclerosis (SSc). We recruited a series of 40 consecutive SSc patients, 22 (55%) with limited cutaneous involvement and 18 (45%) with the diffuse form of disease. The study group was evaluated using the modified Rodnan skin score (mRSS), anthropometric measurements, the EPIC-Norfolk Food Frequency Questionnaire, the Malnutrition Universal Screening Tool (MUST) as well as circulating albumin and vitamin D. MUST scores were correlated with mRSS and serum albumin (R=0.40, p=0.010, and R=-0.46, p=0.003, respectively). Serum vitamin D values were inversely related to mRSS (R=-0.35, p=0.026). We recorded a greater number of daily gastrointestinal symptoms associated with diets rich in sodium, fat, sugars and snacks, carotene, and �-tocopherol equivalents (vitamin E) in our study population. Scleroderma patients might benefit from nutritional counseling in order to follow a diet tailored to their specific needs.

Higher levels of serum interleukin-35 are associated with the severity of pulmonary fibrosis and Th2 responses in patients with systemic sclerosis.

The aim of the study is to investigate the levels of serum interleukin-35 (IL-35) before and after treatment and its relationship with clinical parameters as well as the frequency of different subsets of CD4+ T cells in patients with systemic sclerosis (SSc) to explore the role of IL-35 in the pathogenesis of SSc. The levels of serum IL-35, interferon-γ (IFN-γ), IL-4, IL-17A, and IL-10 in 49 patients with SSc and 50 age- and gender-matched healthy subjects were measured by enzyme-linked immunosorbent assay (ELISA). The percentages of peripheral blood Th1, Th2, Th17 cells and Tregs in 49 SSc patients and 20 healthy controls were characterized by flow cytometry. The relationship between the levels of serum IL-35 and the percentages of different subsets of CD4+ T cells, disease duration, the values of forced vital capacity (FVC), modified Rodnan skin scores (MRSS) or high-resolution computed tomography (HRCT) scores was analyzed in patients with SSc. The levels of serum IL-35 in SSc patients were significantly higher than that of healthy controls (P < 0.001), but significantly reduced after treatment for 3months (P = 0.001). The levels of serum IL-35 were positively correlated with the HRCT scores in SSc patients (P = 0.014) and with disease duration in patients with diffuse cutaneous SSc (P = 0.03), but negatively correlated with the FVC values in SSc patients (P = 0.034). In comparison with that in the healthy controls, significantly decreased percentages of Th1, but increased Th2 and Th17 cells were detected in patients, leading to reduced ratios of Th1/Th2 and increased ratios of Th17/Tregs (P < 0.001). The levels of serum IL-35 were positively correlated with IL-4 (P = 0.036) and tended to be positively associated with the frequency of Tregs in SSc patients (P = 0.054). Higher levels of serum IL-35 may be associated with the development of SSc and severity of pulmonary fibrosis in SSc patients.

A prospective, open-label, non-comparative study of ambrisentan with anti-fibrotic agent combination therapy in the treatment of diffuse systemic sclerosis

BackgroundSystemic Sclerosis is a multifactorial autoimmune rheumatic disease characterized by inflammation, fibrosis, immune dysregulation and vascular dysfunction.MethodsAn open label, prospective, non-comparative study evaluating ambrisentan with an antifibrotic agent in diffuse cutaneous systemic sclerosis (dcSSc). Recruited 15 consecutive patients with dcSSc who were already on a stable dose of an antifibrotic agent and if they met inclusion criteria they were initiated on ambrisentan 5 mg/day for 12 months. Primary outcome measure was the modified Rodnan skin score (mRSS) while secondary measures were the short form 36 (SF-36) questionnaire, the Medsger severity score and pulmonary function studies.ResultsFifteen patients were recruited and ten patients completed all 12 months of the study. An intention to treat was used to analyze the data. There was statistical improvement of the mean mRSS and the perceived change in health component of the SF-36. The Medsger severity score and pulmonary function studies remained unchanged over the course of the study.ConclusionPatients who tolerated the combination of an antifibrotic with ambrisentan had an improvement of their mRSS over the course of the study as well as an improvement of their perceived health.Trial registrationClinicaltrials.gov, NCT01093885; March 2010.

Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis.

To evaluate the utility of cardiac magnetic resonance (CMR) T1 mapping in early systemic sclerosis (SSc) and its association with skin score. Twenty-four consecutive patients with early SSc referred for cardiovascular evaluation and 12 controls without SSc were evaluated. All patients underwent cine, T1 mapping, and late gadolinium enhanced (LGE) CMR imaging. T1 mapping indices were compared between SSc patients and controls (extracellular volume fraction [ECV], gadolinium partition coefficient [λ], pre-contrast T1, and post-contrast T1). The association between T1 mapping parameters and the modified Rodnan skin score (mRSS) was determined. There were no significant differences in cardiac structure/function between SSc patients and controls on cine imaging, and 8/24 (33%) SSc patients had evidence of LGE (i.e., focal myocardial fibrosis). Of the T1 mapping parameters (indices indicative of diffuse myocardial fibrosis), ECV differentiated SSc patients from controls the best, followed by λ, even when the eight SSc patients with LGE were excluded. ECV had a sensitivity and specificity of 75% and 75% for diffuse myocardial fibrosis (optimal abnormal cut-off value of >27% [area under ROC curve=0.85]). In the 16 patients without evidence of LGE, each of the 4 CMR T1 mapping parameters (ECV, λ, Pre-T1 and Post-T1) correlated with mRSS (R=0.51-0.65, P=0.007-0.043), indicating a correlation between SSc cardiac and skin fibrosis. The four T1 mapping indices are significantly correlated with mRSS in patients with early SSc. Quantification of diffuse myocardial fibrosis using ECV should be considered as a marker for cardiac involvement in SSc clinical studies.

Personalized Gene Expression Profile Information Predicts Severity of Systemic Sclerosis Despite Heterogeneity of Disease

BackgroundSystemic sclerosis (scleroderma, SSc) is an autoimmune disease that shows considerable heterogeneity in progression rate and clinical presentation amongst patients. Along with vascular damage and aberrant autoantibody production, SSc causes fibrosis of skin and internal organs. SSc is classified into two clinical subgroups: diffuse and limited, based on amount of skin involvement. Fibrosis of vital organs, mainly lung and heart, causes morbidity and mortality as a result of SSc. The modified Rodnan skin score (mRSS) is currently used to measure severity and disease progression, but is limited by variable sensitivity across disease progression. Thus, the objective of our study was to improve understanding of SSc by developing a method to predict SSc severity based on unbiased, personalized information (gene expression profiles) and evaluate heterogeneity of fibroblast activity between patients.MethodsWe used gene expression data from skin biopsies from 93 donors (mRSS 0–43) to train and test performance of several candidate prediction models. We used the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to identify pathways associated with the genes that defined low and high severity SSc patient groups. We performed qRT‐PCR on fibroblasts derived from multiple SSc patients to examine heterogeneity between donors.ResultsWe developed the first classification model to accurately predict SSc severity based on gene signature and the clinical measurement of mRSS. DAVID analysis identified several pathways that were enriched with genes from the high and low severity profiles and relevance of several of these pathways were supported by the current literature. Overall, patients with more severe SSc expressed higher levels of genes associated with JAK/STAT signaling and innate immunity. We are currently investigating these and other pathways for their role in disease. qRT‐PCR analysis of fibroblasts demonstrated a heterogeneous response to fibrotic and anti‐fibrotic factors, underscoring the need for a personalized medicine approach to this disease. Treatment with TGF‐beta elicited variable levels of expression of pro‐fibrotic genes including Fibronectin, Tenascin C, and Collagen I. Likewise, pro‐fibrotic chemokines had variable effects across fibroblast samples.ConclusionsOur study represents the first time that an independently validated classification model has been used to predict SSc severity based on personalized, patient‐specific information. This model yields gene signatures of high and low severity groups and may inform treatment of this highly variable disease. Our methodology can be applied to other datasets to build prognostic models for SSc and other fibrotic diseases.Support or Funding InformationThis work was supported by grants from NIAMS (AR68317 CCY) and the University of Pittsburgh School of Nursing.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Progressive systemic sclerosis in Egyptian patients: Clinical characteristics and nail fold capillaroscopy

Aim of the workTo present the clinical and laboratory disease characteristics in Egyptian patients with progressive systemic sclerosis (SSc) and their nail fold capillaroscopy findings. Patients and methods50 SSc patients were included. For all patients detailed history taking and clinical and rheumatological examination were performed. The modified Rodnan skin score (mRSS) and nail fold capillaroscopy were assessed. ResultsThe mean age was 41.4 ± 12.7 years (range 16–67 years) and median disease duration was 5 years (range 1–40 years). Eight patients (16%) were males and 42 (84%) females (M:F 1:5.25). Skin tightness was present in all patients; mean mRSS was 17.5 ± 10.4 (ranges 4–45). 44 (88%) patients had abnormal pulmonary function tests; 42 (84%) restrictive and 2 (4%) obstructive; 25 (50%) presented with interstitial lung disease. Pulmonary artery hypertension was recorded in 9 (18%) patients. Renal manifestations were the least common recorded system involvement (20%). Antinuclear antibodies were positive in 98%, rheumatoid factor in 4%, antitopoisomerase I in 36% and anticentromere in 8% of patients. 96% of patient had abnormal nail fold capillaroscopy. There was a significant negative correlation between mRSS with forced expiratory volume (r = −0.46, p = 0.001), forced volume capacity (r = −0.47, p = 0.001) and positively with the FEV1/FVC (r = 0.3, p = 0.035). ConclusionAlmost all patients have ANA seropositivity, abnormal PFTs and abnormal nailfold capillaroscopy. Antitopoisomerase I antibody seropositivity, ILD, abnormal PFT, worsening skin score, late pattern of nailfold capillaroscopy are more common in dcSSc. Extensive clinical examination and investigations should be considered for early diagnosis and follow up of Egyptian SSc patients.

Correlation Between Serum Procollagen Type 1 N-Terminal Propeptide Level With Modified Rodnan Skin Score In Systemic Sclerosis Patients.

Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease, characterized by vasculopathy, specific autoimmune, and fibrosis. Assesment of skin fibrosis by modified Rodnan Skin Score (mRSS) can not detect the minimal changes of skin fibrosis within lessthan 3 months. A biomarker is needed to assess the minimal changes of skin fibrosis progressivity with a more objective, quantitative, and rapid way. Procollagen type-1 N-Terminal Propeptide (P1NP), a degradation product of collagen type-1, may become a potential biomarker for skin fibrosis. This study aims to evaluate the correlation between skin fibrosis by mRSS with P1NP serum in systemic sclerosis.Methods: This was a cross-sectional study performed among systemic sclerosis patients at Rheumatology outpatient clinic, Dr.Hasan Sadikin Hospital Bandung, from May 2016 to July 2016. Skin fibrosis was measured by mRSS. P1NP level was determined by ELISA. Data were analyzed using Rank-Spearman Correlation.Result: There were thirty-seven subjects, with mean age 37 (SD ±7) years old. Most of subjects were female (91.9%). Subjects consisted of 23 (62.2%) limited SSc and 14 (37.8%) diffuse SSc. Six subjects (16.2%) were DMARD naïve. We found median (range) P1NP serum was 43.85 (9.81-127.90) ng/dL, while the median of MRSS was 14 (3-36). There is a moderate correlation between MRSS and P1NP serum (r=0.443, p=0.003)Conclusion: There was a significant correlation between mRSS and P1NP serum in systemic sclerosis patient at Dr. Hasan Sadikin Hospital Bandung.Keywords: systemic sclerosis, P1NP, modified rodnan skin score

Factors influencing early referral, early diagnosis and management in patients with diffuse cutaneous systemic sclerosis.

ObjectiveTo gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA. MethodsSemi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes.ResultsThe interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries.ConclusionPatients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.