Macular choroidal thickness, volume, and vascularity index in patients with systemic sclerosis.

PURPOSE: The aim of this study was to investigate choroidal parameters in patients with systemic sclerosis (SSc) using enhanced depth imaging spectral-domain optical coherence tomography (EDI-SD-OCT) and to determine their relationships with clinical variables and ocular features. METHODS: Thirty-three patients with SSc and 40 controls were enrolled. The groups did not differ with regard to age, sex, and axial length. The mean choroidal thickness and volume were obtained in each conventional Early Treatment of Diabetic Retinopathy Study grid subfield. The choroidal vascularity index (CVI), which provides a quantitative analysis of vasculature by calculating the proportion of the luminal area (LA) to the total choroidal area (TCA), was determined. RESULTS: Lower choroidal thickness and volume were observed in the SSc group. The CVI was significantly higher in SSc patients, whereas the TCA, LA, and stromal area were significantly lower in the SSc group; however, the significant difference of the stromal component was more pronounced than that of the luminal component. Regression analyses did not identify any clinical factors associated with the CVI (except Ca-blocker use), central macular thickness, or volume. No significant differences in choroidal parameters were found within the SSc subtypes (diffuse cutaneous systemic sclerosis (dcSSc) vs. limited cutaneous systemic sclerosis (lcSSc)), or between eyes stratified according to SSc pattern (early, active, or late) using nailfold capillaroscopy (p > 0.05 for all). CONCLUSION: Our results, with notably higher CVI values, may shed new light on choroidal impairment in patients with SSc. Stromal involvement appeared to dominate the vascular component.

Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model.

OBJECTIVE: To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. METHODS: We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. RESULTS: Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. CONCLUSION: The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Development and validation of a patient-reported outcome measure for systemic sclerosis: the EULAR Systemic Sclerosis Impact of Disease (ScleroID) questionnaire.

OBJECTIVES: Patient-reported outcome measures (PROMs) are important for clinical practice and research. Given the high unmet need, our aim was to develop a comprehensive PROM for systemic sclerosis (SSc), jointly with patient experts. METHODS: This European Alliance of Associations for Rheumatology (EULAR)-endorsed project involved 11 European SSc centres. Relevant health dimensions were chosen and prioritised by patients. The resulting Systemic Sclerosis Impact of Disease (ScleroID) questionnaire was subsequently weighted and validated by Outcome Measures in Rheumatology criteria in an observational cohort study, cross-sectionally and longitudinally. As comparators, SSc-Health Assessment Questionnaire (HAQ), EuroQol Five Dimensional (EQ-5D), Short Form-36 (SF-36) were included. RESULTS: Initially, 17 health dimensions were selected and prioritised. The top 10 health dimensions were selected for the ScleroID questionnaire. Importantly, Raynaud's phenomenon, impaired hand function, pain and fatigue had the highest patient-reported disease impact. The validation cohort study included 472 patients with a baseline visit, from which 109 had a test-retest reliability visit and 113 had a follow-up visit (85% female, 38% diffuse SSc, mean age 58 years, mean disease duration 9 years). The total ScleroID score showed strong Pearson correlation coefficients with comparators (SSc-HAQ, 0.73; Patient's global assessment, Visual Analogue Scale 0.77; HAQ-Disability Index, 0.62; SF-36 physical score, -0.62; each p<0.001). The internal consistency was strong: Cronbach's alpha was 0.87, similar to SSc-HAQ (0.88) and higher than EQ-5D (0.77). The ScleroID had excellent reliability and good sensitivity to change, superior to all comparators (intraclass correlation coefficient 0.84; standardised response mean 0.57). CONCLUSIONS: We have developed and validated the EULAR ScleroID, which is a novel, brief, disease-specific, patient-derived, disease impact PROM, suitable for research and clinical use in SSc.

Could IL-1ß, IL-6, IFN-γ, and sP-selectin serum levels be considered as objective and quantifiable markers of rheumatoid arthritis severity and activity?

Objectives: Rheumatoid arthritis (RA) is a multisystem, chronic, T-cell-mediated disease in which immunological abnormalities result in symmetrical small joint inflammation, articular destruction due to synovitis, and extra-articular organ involvement. An important role in the pathogenesis of RA is attributed to a combination of genetic factors and environmental triggers. Literature data on the utility of circulating IL-1ß, IL-6, IFN-γ, and sP-selectin concentration evaluation depending on the activity and advancement of RA seems to be inconclusive. The aim was a case-control study evaluating IL-1ß, IL-6, IFN-γ, and sP-selectin concentrations in 77 RA patients dependent on the Steinbrocker classification as well as the disease activity score with examination of 28 joints (DAS28), and compared to 30 control subjects. Material and methods: Serum IL-1ß, IL-6, IFN-γ, and sP-selectin concentrations were measured using ELISA kits. Results: The concentrations of all molecules tested, except for IL-1ß, were significantly different from the control group. Univariate logistic regression analysis indicated that their levels significantly influenced the likelihood of RA diagnosis. Differences between IL-1ß, IL-6, IFN-γ, and sP-selectin concentrations dependent on the disease activity assessed on the basis of the DAS28 score, as well as the severity of the disease assessed based on the Steinbrocker classification, were not observed. IL-6 positively correlated with the DAS28 score. Conclusions: Among the tested molecules, only IL-6 positively correlated with the DAS28 score. Thus, we postulate that next to C-reactive protein and the erythrocyte sedimentation rate, also IL-6 could be clinically relevant and possibly reflects RA activity. Because recently the IL-6 concentration can be determined in applied in vitro diagnostic tests, it presents us with the possibility to test this protein as a marker of RA activity in routine laboratory practice.

Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database.

OBJECTIVES: To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up. METHODS: Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models. RESULTS: 826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms. CONCLUSION: SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage.

Transferrin isoforms analysis by capillary electrophoresis in systemic lupus erythematosus and systemic sclerosis.

The systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are a diseases in which disturbances in plasma proteins glycosylation exist. The aim of the study was to compare the serum profile of transferrin isoforms between SLE and SSc. The study was carried out in 38 patients with SLE and 43 patients with SSc. Transferrin isoforms were analyzed by capillary electrophoresis method. Among the transferrin isoforms only the level of pentasialotransferrin in SLE patients was significantly higher than in SSc patients (p = .014). The median concentrations of trisialotransferrin and pentasialotransferrin were significantly lower in SLE patients (p < .001, p = .042; respectively) and SSc (p = .001, p < .001; respectively) than in the healthy subjects. In contrast, the level of tetrasialotransferrin manifested significant increase in comparison to the controls (p < .001 for all comparisons). The serum profile of transferrin isoforms alters in SLE and SSc but only level of pentasialotransferrin differs between SLE and SSc patients. We confirm that the serum profile of transferrin isoforms in SLE and SSc is unique to these diseases.

Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual.

BACKGROUND: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). OBJECTIVE: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. METHODS: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. RESULTS: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. CONCLUSION: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.

Increased expression of the TNF superfamily member LIGHT/TNFSF14 and its receptors (HVEM and LTßR) in patients with systemic sclerosis.

OBJECTIVES: This study aimed to assess the potential role of the TNF superfamily member lymphocyte T-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) in SSc through evaluation of: skin expression of LIGHT and its receptors, herpesvirus entry mediator and lymphotoxin ß-related receptor, and serum concentration of LIGHT in SSc patients. METHODS: Expression of LIGHT and its receptors was investigated by immunohistochemistry and evaluated semi-quantitatively in skin biopsies from 19 SSc patients and 9 healthy controls. Serum levels of LIGHT were measured using ELISA in 329 patients with SSc and 50 control subjects. RESULTS: Expression of LIGHT and both receptors was higher in SSc patients compared with controls (P < 0.05 for all comparisons). Patients with early SSc (⩽ 3 years from the first non-Raynaud's phenomenon symptom) showed higher expression of LIGHT and herpesvirus entry mediator compared with patients with longer disease duration (P < 0.05 for both comparisons). The mean serum concentration of LIGHT was significantly higher in SSc patients compared with the controls (P < 0.05). High serum concentration of LIGHT was associated with male sex, presence of digital ulcers, muscle involvement (defined by elevated serum creatine kinase levels), steroid treatment and lack of ACA. However, in multivariate regression analysis only presence of digital ulcers and creatine kinase elevation were independently associated with serum concentration of LIGHT. CONCLUSION: These data provide the first evidence of overexpression of LIGHT and its receptors in SSc and suggest that the LIGHT axis might contribute to the pathogenesis of SSc. Increased serum concentrations of LIGHT seem to reflect vascular injury in SSc.

The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a preliminarily revised EUSTAR activity index.

BACKGROUND: Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. METHODS: Three investigators assigned an activity score on a 0-10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate-multivariate linear regression analyses were used to define variables predicting the 'gold standard', their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0-10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). RESULTS: A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). CONCLUSIONS: A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.

Update of EULAR recommendations for the treatment of systemic sclerosis.

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

The arachidonate 5-lipoxygenase activating protein gene polymorphism is associated with the risk of scleroderma-related interstitial lung disease: a multicentre European Scleroderma Trials and Research group (EUSTAR) study.

Objectives: The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates synthesis of leukotrienes (LTs), which are important mediators of inflammation and connective tissue remodelling. The aim of this study was to evaluate if single nucleotide polymorphisms (SNPs) of ALOX5AP confer risk of SSc and/or SSc-related organ involvement. Methods: Seven SNPs of ALOX5AP (rs17222814, rs17216473, rs10507391, rs4769874, rs9551963, rs9315050 and rs7222842) were genotyped in a cohort of 977 patients with SSc and 558 healthy controls from centres collaborating within the European Scleroderma Trials and Research group. In 22 SSc patients, concentrations of cysteinyl LTs and LT B4 (LTB4) were measured in the supernatants of ionophore-stimulated peripheral blood mononuclear cells (PBMCs) by means of commercially available enzyme immunoassay kits. Results: Significant association was found between rs10507391 polymorphism (T/A) of ALOX5AP and the risk of SSc [odds ratio (OR) 1.27 (95% CI 1.07, 1.50), P < 0.05 vs controls], the presence of SSc-related interstitial lung disease on high-resolution CT of the lungs [OR 1.45 (95% CI 1.17, 1.79), P < 0.05 vs patients without SSc-related interstitial lung disease] as well as with restrictive ventilatory defect [forced vital capacity <70% of predicted; OR 1.51 (95% CI 1.16, 1.97), P < 0.05 vs SSc patients without pulmonary restriction]. PBMCs from SSc carriers of rs10507391 allele A synthesized greater amounts of cysteinyl LTs as compared with SSc patients with rs10507391 TT genotype ( P < 0.05). Synthesis of LTB4 did not differ significantly between the two groups. Conclusion: The results of our study indicate that the genetic variants of ALOX5AP might play a role in the development of SSc-related pulmonary fibrosis.

Plasma endothelial microparticles reflect the extent of capillaroscopic alterations and correlate with the severity of skin involvement in systemic sclerosis.

INTRODUCTION AND AIM: Endothelial microparticles (EMPs) are membrane-coated vesicles shed from endothelial cells and are considered markers of the endothelial state. It has been shown that total numbers of circulating EMPs are increased in patients with systemic sclerosis (SSc), but their clinical correlations have not yet been investigated in detail. We aimed to assess possible relationships between circulating EMPs and clinical as well as laboratory features among SSc patients with special attention to possible association with alteration in microvascular morphology objectified on nailfold videocapillaroscopy and clinical signs of microvascular complications. MATERIALS AND METHODS: The study included 47 SSc patients and 27 age- and sex-matched healthy controls. EMPs were identified with flow cytometry after staining platelet-poor plasma with combinations of fluorescent cell-specific monoclonal antibodies (anti-CD31, -51, -42b, -62E and Annexin V). The following types of EMPs were evaluated: total EMPs (CD31+/CD42b-), activated EMPs (CD62E+/AnnV-,) and apoptotic EMPs (CD62E+/AnnV+ or CD51+). Clinical evaluation of patients was obtained, including nailfold videocapillaroscopy. RESULTS: All types of EMPs were significantly elevated in SSc patients as compared with healthy controls. We found significant inverse correlation between severity of skin involvement and values of total EMPs (r=-0.32; p=0.02) and their levels tended to be lower in SSc patients with digital ulcers when compared to those without ischaemic skin lesions (p=0.09). Total EMPs and activated EMPs showed correlations with the number of ramified capillaries (r=-0.40 and r=0.37, respectively, p<0.05 for both). Moreover, total EMPs inversely correlated with the severity of capillary loss (r=-0.35, p<0.05) and their levels were significantly lower in patients with late NVC pattern with respect to those with early microangiopathy (p<0.05). On the other hand, active NVC pattern was characterized by strongly elevated levels of activated EMPs when compared to an early vascular alteration (p<0.05). CONCLUSIONS: Our results suggest that quantity and phenotype of circulating EMPs might indicate on molecular vascular damage with endothelial dysfunction and to reflect progressive loss of capillaries consequencing in microvascular insufficiency in SSc patients.

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis.

OBJECTIVES: Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc. METHODS: We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied. RESULTS: From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors. CONCLUSIONS: Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials.

RATIONALE: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. METHODS: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). RESULTS: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. CONCLUSION: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Serum levels of CD163 and TWEAK in patients with pulmonary arterial hypertension.

BACKGROUND: Inflammation may play a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH). We evaluated the concentrations of serum sTWEAK, its scavenger receptor sCD163 and sTWEAK/sCD163 ratio in patients with PAH. DESIGN: The study enrolled 26 stable patients with PAH confirmed by right heart catheterization and 24 healthy volunteers matched for age, sex and body weight. All patients underwent transthoracic echocardiography, cardiopulmonary exercise test, 6-min walk test, measurement of lung diffusing capacity for the carbon monoxide (DLCO) and venous blood tests. Concentrations of sTWEAK and sCD163 were determined using ELISA kits. RESULTS: The PAH patients were characterized by significantly higher median serum sCD163 levels (1072 vs 890ng/ml, p=0.04) together with lower serum sTWEAK concentrations (200 vs 278.1pg/ml, p=0.003) comparing to control subjects. sTWEAK/sCD163 ratio was therefore significantly lower in PAH group (0.18 vs 0.33, p=0.0005). No correlation was found between sTWEAK and sCD163 concentrations in both groups. We observed statistically significant inverse correlation between peak VO2 consumption and sCD163 concentrations (r=-0.52, p<0.05) and positive with sTWEAK/sCD163 ratio (r=0.45, p<0.05) in PAH group. Moreover, sTWEAK/sCD163 ratio positively correlated with % of predicted values of DLCO (r=0.42, p<0.05). CONCLUSIONS: Patients with PAH present altered serum sTWEAK and sCD163 levels. The sTWEAK/sCD163 ratio appears to be a better indicator of the severity of PAH as compared to sTWEAK or sCD163 alone. The exact role of sCD163 or interaction between CD163 and sTWEAK in the initiation or progression of PAH as well as their potential prognostic significance remains to be established.

2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.

Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI [0.60-0.79]; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 [1.18-1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSIONS: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Subclinical cardiovascular system changes in obese patients with juvenile idiopathic arthritis.

OBJECTIVE: We aimed to determine the prevalence of excess body mass in juvenile idiopathic arthritis (JIA) children and to investigate the influence of obesity into the early, subclinical changes in cardiovascular system in these patients. METHODS: Fifty-eight JIA patients, aged median 13 years, were compared to 36 healthy controls. Traditional cardiovascular risk factors and inflammatory markers (hsCRP, IL-6, TNF α, adiponectin) were studied together with IMT (intima-media thickness), FMD (flow mediated dilation), and LVMi (left ventricle mass index) as surrogate markers of subclinical atherosclerosis. RESULTS: Thirteen JIA children (22%) were obese and had increased systolic blood pressure, cholesterol, triglycerides, insulin, HOMA, hsCRP, and IL-6 compared to nonobese JIA and controls. FMD was decreased compared to nonobese JIA and controls, whereas IMT and LVMi were increased. In multivariate regression analysis, TNF α, SDS-BMI, and systolic blood pressure were independent predictors of early CV changes in JIA. CONCLUSIONS: Coincident obesity is common in JIA children and is associated with insulin resistance, dyslipidemia, and increased levels of inflammatory markers leading to early changes in cardiovascular system. Thus, medical care of children with JIA should include strategies preventing cardiovascular disease by maintenance of adequate body weight.

Purtscher-like Retinopathy in a Patient with Systemic Sclerosis: A Case Report and Narrative Review.

Purtscher-like retinopathy (PLR) is an uncommon occlusive microangiopathy associated with various systemic conditions. We report a case of PLR related to severe progressive systemic sclerosis (SSc), an autoimmune disease characterized by widespread angiopathy and fibrosis, in a 44-year-old Caucasian male diagnosed with early diffuse cutaneous systemic sclerosis (dSSc). Upon ophthalmological examination, pathognomonic fundoscopy abnormalities were found. Spectral domain optical coherence tomography (SD-OCT), angio-OCT, and visual field results are documented at initial diagnosis and follow-up visits. The detailed ophthalmological assessment is juxtaposed with rheumatological evaluation and treatment. Current literature on probable pathophysiological mechanisms is reviewed in accordance with the described case. The PLR seems to be connected to severe SSc-related angiopathy initiated by capillary endothelial damage, with ultimate arteriolar precapillary occlusion in the inner retinal layer. Although this is not routinely recommended, we suggest that ophthalmological examinations may be advantageous in patients with SSc, as serious eye pathology may be present despite the lack of symptoms reported by the patient. Patients with PLR require a differential diagnosis and regular follow-up. Proper treatment of the underlying disease may have beneficial effects on the natural course of PLR.