Impairment of microcirculation in juvenile idiopathic arthritis - studies by nailfold videocapillaroscopy and correlation with serum levels of sICAM and VEGF.

Impairment of vascular endothelium plays a key role in the pathogenesis of inflammatory diseases including juvenile idiopathic arthritis (JIA) and atherosclerosis. We hypothesized that structural abnormalities of the smallest blood vessels (capillaries) might exist and reflect endothelial dysfunction in children with JIA. Microcirculation was studied, by means of nailfold videocapillaroscopy with computer-associated image analysis, in 43 patients with JIA and compared with 20 healthy children. Moreover, capillaroscopic findings were correlated with the activity of the disease and the levels of serum biomarkers of endothelial injury, namely soluble intercellular adhesion molecule (sICAM) and vascular endothelial growth factor (VEGF). We found that in JIA patients capillaries were significantly wider and longer than in healthy controls. Moreover, irregular capillaries and dilated subpapillary venous plexus were found significantly more frequently in JIA in comparison with the control group. Serum levels of sICAM and VEGF were significantly higher in JIA patients with capillary abnormalities than in JIA patients with normal capillaroscopy. Our study indicates that there are structural changes in the microcirculation of patients with JIA and that these changes might reflect endothelial injury. Whether capillaroscopy might have a role in early identification of JIA patients being at higher risk of atherosclerosis requires further studies

Comparison of hyaluronic acid in patients with rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus

The aim of the present study was to determine and compare the concentration of hyaluronic acid (HA) in rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE), and its correlation with parameters of disease activity and duration. The hypothesis was that HA should be increased in rheumatic diseases. We also expected that HA could be a marker of disease activity and inflammation in some of these diseases. The study group comprised 149 patients with RA, SSc and SLE hospitalized in the Department of Rheumatology and Internal Diseases, Medical University of Bialystok (Bialystok, Poland) and 30 healthy controls. The concentrations of HA, C-reactive protein (CRP) and rheumatoid factor (RF) were measured using Architect ci8200; haemoglobin, platelets on Sysmex XS-800i; and erythrocyte sedimentation rate (ESR) on Sediplus S 2000 analysers. Statistical analysis was performed using Statistica 13.3 PL. Hyaluronic acid was increased in RA, SLE and SSc when compared to controls (P < 0.001, P = 0.011, and P = 0.015, respectively). There were no differences in HA between rheumatic diseases (P = 0.840). Hyaluronic acid positively correlated with SLE activity (P = 0.025). In RA, HA positively correlated with ESR (P = 0.028) and CRP (P = 0.009). However, HA was not found to correlate with the duration of rheumatic diseases. Hyaluronic acid concentration undergoes changes in rheumatic diseases with no difference between RA, SLE and SSc. In RA, HA concentration can be a marker of inflammation, while in SLE patients an indicator of disease activity

Diminished production of TWEAK by the peripheral blood mononuclear cells is associated with vascular involvement in patients with systemic sclerosis.

Widespread vasculopathy and profound fibrosis are key features of the pathogenesis of systemic sclerosis (SSc). We hypothesized that the TNF-like weak inducer of apoptosis (TWEAK), a recently recognized multifunctional cytokine which regulates angiogenesis and tissue remodeling, may play a role in the development of SSc. The production of TWEAK by the peripheral blood mononuclear cells (PBMC) was investigated, by means of ELISA, in 24 SSc patients and 14 healthy subjects. Moreover, production of TWEAK was correlated with clinical features of SSc. PBMC were isolated using density gradient centrifugation on Histopaque and were cultured in FCS supplemented RPMI medium at 37 degrees C under 5% CO2. Production of TWEAK by PBMC was significantly diminished in patients with more severe microvascular damage, as indicated by the presence of "active" capillaroscopic pattern, compared with SSc patients with less pronounced microangiopathy ("slow" pattern), and healthy subjects. Moreover production of TWEAK correlated inversely with duration of Raynaud's phenomenon. PBMC from patients with scleroderma-related interstitial lung disease tended to produce lower amounts of TWEAK compared with SSc patients without lung involvement but the difference was not significant. The results of our study suggest that diminished production of TWEAK might play a role in the pathogenesis of vascular injury in SSc patients. Whether TWEAK may represent a new therapeutic target in SSc requires further studies

Systemic sclerosis-associated pulmonary hypertension: why disease-specific composite endpoints are needed

Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc). In clinical trials PAH-SSc has been grouped with other forms, including idiopathic PAH. The primary endpoint for most pivotal studies was improvement in exercise capacity. However, composite clinical endpoints that better reflect long-term outcome may be more meaningful. We discuss potential endpoints and consider why the same measures may not be appropriate for both idiopathic PAH and PAH-SSc due to inherent differences in clinical outcome and management strategies of these two forms of PAH. Failure to take this into account may compromise progress in managing PAH in SSc

An expert opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation and the Polish Society for Rheumatology on the diagnosis and treatment of pulmonary hypertension in patients with connective tissue disease

Systemic connective tissue diseases (CTDs) comprise a large group of diseases that are auto-immune in nature and characterized by the involvement of multiple systems and organs. Pul-monary hypertension (PH) of various etiologies may develop in the course of CTD, including pulmonary arterial hypertension (PAH), PH secondary to the lung disease, postcapillary PH in the course of left heart disease, and chronic thromboembolic pulmonary hypertension (CTEPH). In addition, the different forms of PH may coexist with each other. Among patients with CTD, PAH occurs most commonly in those with systemic sclerosis, where it affects ap-proximately 8%–12% of patients. The prognosis in patients with untreated PAH is very poor. It is particularly important to identify the high-risk CTD-PAH population and to perform effi-cient and accurate diagnostics so that targeted therapy of the pulmonary arteries can be intro-duced. Echocardiography is used to screen for PH, but clinical and echocardiographic suspicion of PH always requires confirmation by right heart catheterization. Confirmation of PAH ena-bles the initiation of life-prolonging pharmacological treatment in this group of patients, which should be administered in referral centers. Drugs available for pharmacological management include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins

Health Assessment Questionnaire-Disability Index (HAQ-DI) use in modelling disease progression in diffuse cutaneous systemic sclerosis: an analysis from the EUSTAR database

BACKGROUND: Patients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression. METHODS: This was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient's lifetime. RESULTS: The analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p &lt; &nbsp;0.001) and multiple advanced major organ involvement multiplied the risk of death by 2.8 (p &lt; &nbsp;0.05). Multivariable analysis showed that baseline modified Rodnan Skin Score (mRSS) and baseline HAQ-DI score were associated with HAQ-DI score progression at 1 year (p &lt; &nbsp;0.05), but there was no association between baseline organ involvement and HAQ-DI score progression at 1 year. HAQ-DI score, major advanced organ involvement, and death were successfully used to model long-term disease progression in dcSSc. CONCLUSIONS: HAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc

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