25-hydroxyvitamin D3 Levels and Their Clinical Associations in a Polish Cohort of Systemic Sclerosis Patients: A Cross-Sectional Study

Vitamin D exhibits immunomodulatory effects in autoimmune diseases. We aimed to evaluate the associations of vitamin D levels with clinical and laboratory features of systemic sclerosis (SSc) in a Polish cohort. The study was prospective in design. SSc patients who met ACR-EULAR 2013 criteria underwent comprehensive clinical and laboratory investigations using the European Scleroderma Trials and Research group (EUSTAR) methodology. We assessed patients’ sera for 25(OH)D3 using a radioimmunoassay, and the cutoff value for vitamin D deficiency was set at 20 ng/mL. Statistical analyses were performed using the Mann–Whitney U test, the Fisher’s exact, and the Spearman’s rho, where appropriate, with a significance threshold set at 0.05. We recruited 68 SSc patients (85% female). The mean 25(OH)D3 level was 21.6 ± 10 ng/mL, and 50% of subjects (n = 34) presented vitamin D deficiency (mean 13.7 ± 3.9 ng/mL). Vitamin D-deficient SSc patients exhibited higher prevalence of arterial hypertension (p = 0.002), proteinuria (p = 0.002), and lung fibrosis (p = 0.032), as well as higher CRP (p = 0.035). The modified Rodnan skin score correlated negatively with 25(OH)D3 in diffuse cutaneous SSc (dcSSc). We found no correlation with the disease duration, age, joints, and the heart. Vitamin D deficiency was common in the studied population of Polish SSc patients and was associated with arterial hypertension, proteinuria, lung involvement, and increased CRP.

Hands and feet radiologic involvements in systemic sclerosis

Aim Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by vascular and fibrosing involvement of the skin and internal organs. In this study we determined the prevalence and characteristics of radiological hands and feet involvements in Iranian SSc patients identified disease–phenotype associations. Methods 43 SSc patients (41 women and 2 men), with a median age of 44.79 years (ranges 26 to 70 years) and a mean disease duration of 11.78 years (ranges 2 to 28 years) were studied in this cross-sectional study. Results 42 patients had radiological changes both in hands and feet. Only one patient had changes just in hand. The most frequent changes that we found in hand was Juxta-articular Osteoporosis (93%), Acro-osteolysis (58.2%), Joint Space Narrowing (55.8%). The prevalence of joint space narrowing or acro-osteolysis were higher in subjects with active skin involvement (modified Rodnan skin score (mRSS)>14) (16/21 v 4/16 for patients with inactive skin involvement (mRSS<14); p = 0.002). The most frequent changes that we found in foot were Juxta-articular Osteoporosis (93%), Acro-osteolysis (46.5%), Joint Space Narrowing (58.1%), subluxation (44.2%). The presence of anti-ccp antibody was detected in 4 (9.3%), while positive rheumatoid factor was found in 13 (30.2%) of SSc patients. Conclusion This study corroborates that an arthropathy is common in SSc patients. The introduction of the specific radiological involvements of SSc needs to be confirmed by further studies. in order to define the appropriate prognosis and treatment of patients.

Serum lysyl oxidase concentration increases in long-standing systemic sclerosis: Can lysyl oxidase change over time?

Objectives: This study aims to investigate the association of serum lysyl oxidase (LOX) levels with systemic sclerosis (SSc), to examine the relationship between LOX and disease onset, and to evaluate the probable effects of hyperlipidemia on the circulating levels of LOX among patients with SSc. Patients and methods: Between May 2017 and November 2018, a total of 39 patients with SSc (2 males, 37 females; mean age: 46.6±12.3 years; range, 18 to 65 years) and 35 healthy controls (4 males, 31 females; mean age: 43.1±14.1 years; range, 18 to 65 years) were included. Serum LOX concentration was measured using the enzyme-linked immunoassay in triplicate. Results: We found higher levels of serum LOX in patients with SSc compared to healthy controls. There was a significant relationship between serum LOX levels and disease onset. Patients with long-standing disease demonstrated increased levels of LOX in the blood compared to the recent-onset group. Hyperlipidemia did not have a significant effect on circulating levels of LOX. There was a significant negative correlation between LOX levels and modified Rodnan Skin Score in the subgroup of patients with skin involvement only and in patients without gastrointestinal involvement. Conclusion: Our study findings show an increased level of LOX protein level in the blood of patients diagnosed with SSc. Hyperlipidemia seems not to affect the concentrations of LOX in the peripheral blood of patients with SSc.

The Relationship Between Modified Rodnan Skin Score (mRSS) With Pulmonal Hypertension and Lung Fibrosis in Systemic Sclerosis Patients

Background: Systemic sclerosis (SSc) is a connective tissue disease, which affects the skin, blood vessels, heart, lungs, kidneys, gastrointestinal tract and musculoskeletal system. The manifestations in blood vessels include pulmonary hypertension which can be seen from echocardiography, while the manifestations to the lungs in the form of pulmonary fibrosis are examined by high-resolution computed tomography (HRCT). Modified Rodnan Skin Score (mRSS) a method for measuring skin thickness in SSc patients. Objective: This study aims to determine the relationship between mRSS and pulmonary hypertension and pulmonary fibrosis in SSc patients. Methods and Materials: Research with a cross sectional approach at Dr Kariadi Hospital. There were 23 study subjects with SSc patients having their mRSS measured by a rheumatologist and an HRCT examination by a radiologist to see the percent of lung damage and echocardiographic examination by a cardiologist to measure the Tricuspid Regurgitation Velocity Maximum (TRV Max) as a marker of pulmonary hypertension. Normality test using Saphiro-Wilk. The Spearman rank correlation test was used to analyze the relationship between the mRSS score, pulmonary hypertension and pulmonary fibrosis. Results: The proportion of study subjects with a mean age of 40.39 years, women, and 4.43 years of illness. The mean mRSS score was 17.43. Examination of pulmonary hypertension from echocardiography found most of the light category 95.6%, heavy category 4.4%, while the HRCT examination found pulmonary fibrosis of 86.9%, normal 13.1%. There are significant relationship between mRSS and pulmonary fibrosis (r = 0.485, p = 0.019), and significant relationship between pulmonary hypertension (r = 0.63, p = 0.001) Conclusion: There is a significant relationship between mRSS, pulmonary fibrosis and pulmonary hypertension.

Circulating Gremlin-1 is elevated in systemic sclerosis patients

Introduction: Systemic sclerosis is an autoimmune connective tissue disease in which there is activation of the immune system, vascular disease and fibrosis. Activation of quiescent fibroblasts to myofibroblasts is key to disease pathogenesis. Gremlin-1 is a bone morphogenetic protein antagonist which is important in development and we recently reported in skin fibrosis. The aim of this study was to determine the serum circulating levels of Gremlin-1 in early diffuse systemic sclerosis. Methods: Twenty-one early diffuse systemic sclerosis patients (less than 2 years from first non-Raynaud’s symptom) were included and age and sex-matched healthy controls. Serum was isolated from blood and measured with a specific enzyme-linked immunoassay for Gremlin-1. Clinical variables were also measured. Results: Significantly elevated Gremlin-1 was found in sera of early diffuse systemic sclerosis patients ( p < 0.001). In patients with interstitial lung disease, this compared to systemic sclerosis without evidence of interstitial lung disease, Gremlin-1 was significantly elevated ( p < 0.0007). A correlation was found between circulating Gremlin-1 and modified Rodnan Skin Score, albeit weak. Discussion: In early diffuse systemic sclerosis patients, elevated Gremlin-1 is found in serum. This is particularly prominent in systemic sclerosis–associated interstitial lung disease. This suggests that Gremlin-1 may be a biomarker for systemic sclerosis interstitial lung disease.

An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod

Objectives To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). Methods In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. Results Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. Conclusions Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. Trial registration ClinicalTrials.gov, NCT01487551. Registered on 7 September 2011

Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by fibrosis of the skin and internal organs, autoimmunity-driven damage and vasculopathy. The current approved disease-modifying treatments have limited efficacy, and treatment is guided toward alleviating organ complications. Thus, there is an unmet need for discovering new effective treatment options. There is recent evidence that the JAK/STAT signaling pathway is markedly activated in SSc patients. To assess the efficacy and safety of tofacitinib (TOF) on skin and musculoskeletal involvement as compared to methotrexate (MTX) in systemic sclerosis (SSc). In this 52-week pilot study, 66 patients with SSc were enrolled: 33 patients received 5 mg of oral TOF twice a day; 33 received 10 mg of MTX weekly. The proportion of dcSSc and lcSSc patients was similar (dcSSc: 42% TOF group and 36% MTX group; lcSSc: 58% TOF group and 64% MTX group). The primary outcome was the change in the modified Rodnan skin score (mRSS). Secondary outcomes included ultrasound (US) skin thickness and musculoskeletal involvement (US10SSc score). Digital ulcers (DUs) and adverse events (AEs) were documented through the treatment. Both groups had similar characteristics and medians on the outcome measures at baseline. At week 52, the TOF median mRSS was significantly lower than the MTX (p < 0.001) with a mean reduction of 13 points versus MTX 2.57. The mean percent improvement in the TOF group was 44% higher than in the MTX group. TOF median US skin thickness was significantly lower than MTX (p < 0.001), with a mean reduction of 0.31 mm versus 0.075 mm in the MTX group. The US10SSc median score was significantly lower in the TOF group (p = 0.002); mean reduction of 10.21 versus 5.27 in the MTX group. Healing of DUs with no new occurrences was observed in the TOF group. There was no significant difference between the groups in the number of AEs from baseline to week 52. TOF showed greater efficacy than MTX in reducing mRSS, skin thickness and musculoskeletal involvement in SSc and a satisfactory safety profile.

Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells. The number of myofibroblasts in SSc skin correlates with the modified Rodnan skin score, the most widely used clinical measure of skin disease severity. Murine fibrosis models indicate that myofibroblasts can arise from a variety of different cell types, but their origin in SSc skin has remained uncertain. Utilizing single cell RNA-sequencing, we define different dermal fibroblast populations and transcriptome changes, comparing SSc to healthy dermal fibroblasts. Here, we show that SSc dermal myofibroblasts arise in two steps from an SFRP2hi/DPP4-expressing progenitor fibroblast population. In the first step, SSc fibroblasts show globally upregulated expression of transcriptome markers, such as PRSS23 and THBS1. A subset of these cells shows markers indicating that they are proliferating. Only a fraction of SFRP2hi SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. Bioinformatics analysis of the SSc fibroblast transcriptomes implicated upstream transcription factors, including FOSL2, RUNX1, STAT1, FOXP1, IRF7 and CREB3L1, as well as SMAD3, driving SSc myofibroblast differentiation.

Validation of the Raynaud’s Condition Score in Argentina

Objective: the aim of our study was to adapt and validate the Raynaud’s Condition Score (RCS) in patients with Systemic Sclerosis (SSc) who attend a public hospital in Argentina. Materials and Methods: for adaptation, rheumatologists translated to Spanish the original version in English. To assess the construct validity we used: Health Assesment Questionnaire (HAQ), Duruöz´s Hand Index (DHI), spanish validation for Argentina, Raynaud Visual Analogue Scale (VAS) by an expert and Modified Rodnan skin score (mRSS).To assess reproducibility, a subgroup of patients was randomly evaluated with no changes in treatment or clinical condition ten days after the baseline evaluation. Results: A total of 35 patients with SSc were included. The correlation between RCS and Raynaud VAS by an expert was 0.89; RCS and HAQ 0.58; RCS and mRSS 0.61; RCS and DHI 0.57 indicating a very good correlation mainly between the studied Score and the Raynaud VAS and being all statistically significant. The reproducibility was 0.998. Conclusion: The results show that the RCS is a reliable and valid tool for this argentinian population with SSc.

POS0873 IMPROVEMENT IN MODIFIED RODNAN SKIN SCORE (MRSS) IN SYSTEMIC SCLEROSIS PATIENTS TREATED WITH RITUXIMAB: A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE SCIENTIFIC LITERATURE

Background:Systemic sclerosis (SSc) is a chronic autoimmune disease of the connective tissue characterized by vascular disease and fibrosis in different organs and systems such as lung and skin (1). Recently, several case reports and small series of patients reported on the efficacy of rituximab in SSc, showing a possible improvement in skin and lung affectations (2). However, registered clinical trials are lacking to determine factors associated with response, maintenance regimen, and long-term efficacy of rituximab in SSc.Objectives:To analyze the efficacy of Rituximab in the treatment of skin fibrosis using the changes of the modified Rodnan Skin Score (mRSS) of patients diagnosed with systemic sclerosis from the data published in Registered Clinical Trials (RCTs) in the scientific literature.Methods:We perform a systematic review and a meta-analysis using the main electronic databases to locate all the articles available so far: Medline, Embase, Cochrane Library and Web of science and ACR and EULAR abstracts congress were extracted to assess efficacy outcomes. That efficacy was measured based on the variation of mRSS at 12, 24 and 48 weeks for patients treated with Rituximab versus patients treated with another drug or placebo.Results:3 RCTs contained data regarding mRSS at week 12 of treatment with Rituximab. The estimated SMD was -1.071 (95% CI -1.608, -0.535 [p <0.001]) with a non-significant P value in the Egger Test (P = 0.703) and non-significant heterogeneity through I2 (I2 = 0.00%).9 studies contained data regarding mRSS at week 24 of treatment with Rituximab. The estimated SMD was -1.743 (CI95% -2.622, -0.864 [p <0.001], see image below) with a non-significant P value in the Egger Test (P = 0.072) and significant heterogeneity through I2 (I2 = 86.6%). Meta-regression analysis could not be performed to assess such heterogeneity, due to the lack of comparable data.8 RCTs contained data regarding mRSS at week 48 of Rituximab treatment. The estimated SMD was -1.327 (CI95% -2.018, -0.636 [p <0.001]) with a significant P value in the Egger Test (P = 0.018), estimating that there may be publication bias in the studies analyzed and significant heterogeneity by I2 (I2 = 85.2%). Meta-regression analysis could not be performed to assess such heterogeneity, due to the lack of comparable data.Conclusion:Our meta-analysis shows that Rituximab treatment in patients affected with systemic sclerosis shows efficacy in the treatment of cutaneous fibrosis measured by the mRSS, turning this molecule into a potential drug to add to the therapeutic armamentarium of systemic sclerosis. However, more studies are necessary to try to elucidate whether this change is powerful enough to become the new gold standard for the treatment of systemic sclerosis skin involvement.References:[1]Stern EP, Denton CP. The pathogenesis of systemic sclerosis. Rheum Dis Clin North Am 2015;41:367–82. https://doi.org/10.1016/j.rdc.2015.04.002.[2]Thiebaut M, Launay D, Rivière S, et al. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582-587. https://doi:10.1016/j.autrev.2017.12.010.Disclosure of Interests:None declared