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Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS). Our aim was to evaluate serum anti-vinculin antibodies in patients with SSc. Patients were recruited from two SSc centers: group I (GI-enriched group), University of Leeds, UK, and Group II (vascular predominant), University of California, Los Angeles. Serum samples of patients recruited from two SSc centres, Group I ( GI enriched group), University of Leeds, UK and Group II (Vascular predominant), University of California, Los Angeles) were collected. Samples from age- and sex-matched healthy volunteers (N = 88) were used as controls. Group I (GI-enriched group, N = 83) patients were 58 [50–67] years old; 83% were females with a median body mass index (BMI) of 20.3 (21.2 ± 4.5) [18–23]. Group II (vascular-enriched group, N = 72) patients were 58 [50–67] years old; 80% were female, and BMI was 23.9 (21.3–26.9). More subjects in group I had prominent GI involvement (N = 55, 66%) than group II (12, 16%), p ˂ 0.0001. Anti-vinculin antibody levels in SSc group I (1.3 [0.9]) were significantly higher than in HC (0.7 [0.8]; p = 0.002). When pooled, circulating anti-vinculin levels in both SSc groups remained significantly higher than in the HC group (p = 0.02). Higher anti-vinculin levels were associated with higher GI-visual analogue scale (GI-VAS) scores and specifically with GI-VAS scores of ≥ 4 (p < 0.0001). This study demonstrates that elevated anti-vinculin antibody levels are common in SSc and suggests a potential link between increased anti-vinculin levels and GI tract symptoms.

ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Objective: Coronavirus disease 2019 (COVID-19) is a disease with a high rate of progression to critical illness. However, the stratification of patients at risk of mortality is not well defined. In this study, we aimed to define a mortality risk index to allocate patients to the appropriate intensity of care.Methods: This is a 12 months observational longitudinal study designed to develop and validate a pragmatic mortality risk score to stratify COVID-19 patients aged ≥18 years and admitted to hospital between March 2020 and March 2021. Main outcome was in-hospital mortality.Results: 244 patients were included in the study (mortality rate 29.9%). The Covid-19 Assessment for Survival at Admission (CASA) index included seven variables readily available at admission: respiratory rate, troponin, albumin, CKD-EPI, white blood cell count, D-dimer, Pa02/Fi02. The CASA index showed high discrimination for mortality with an AUC of 0.91 (sensitivity 98.6%; specificity 69%) and a better performance compared to SOFA (AUC = 0.76), age (AUC = 0.76) and 4C mortality (AUC = 0.82). The cut-off identified (11.994) for CASA index showed a negative predictive value of 99.16% and a positive predictive value of 57.58%.Conclusions: A quick and readily available index has been identified to help clinicians stratify COVID-19 patients according to the appropriate intensity of care and minimize hospital admission to patients at high risk of mortality.

Objective: Malnutrition is a severe complication in Systemic Sclerosis (SSc) and it is associated with significant mortality. Notwithstanding, there is no defined screening or clinical pathway for patients, which is hampering effective management and limiting the opportunity for early intervention. Here we aim to identify a combined index predictive of malnutrition at 12 months using clinical data and specific serum adipokines.Methods: This was an international, multicentre observational study involving 159 SSc patients in two independent discovery (n = 98) and validation (n = 61) cohorts. Besides routine clinical and serum data at baseline and 12 months, Malnutrition Universal Screening Tool (MUST) score and serum concentration of leptin and adiponectin were measured for each participant at baseline. The endpoint of malnutrition was defined according to European Society of Clinical Nutrition and Metabolism (ESPEN) recommendation. Significant parameters from univariate analysis were tested in logistic regression analysis to identify the predictive index of malnutrition in the derivation cohort.Results: The onset of malnutrition at 12 months correlated with adiponectin, leptin and their ratio (A/L), MUST, clinical subset, disease duration, Scl70 and Forced Vital Capaciy (FVC). Logistic regression analysis defined the formula: −2.13 + (A/L*0.45) + (Scl70*0.28) as the best PREdictor of MAlnutrition in SSc (PREMASS) (AUC = 0.96; 95% CI 0.93, 0.99). PREMASS < −1.46 had a positive predictive value (PPV) > 62% and negative predictive value (NPV) > 97% for malnutrition at 12 months.Conclusion: PREMASS is a feasible index which has shown very good performance in two independent cohorts for predicting malnutrition at 12 months in SSc. The implementation of PREMASS could aid both in clinical management and clinical trial stratification/enrichment to target malnutrition in SSc.

Anemia occurs in 25 to 40% of SSc and predicts both mortality and PAH. There are numerous forms of anemia found in systemic sclerosis (SSc) including iron deficiency anemia (16 to 18%) often with gastric arteriovenous ectasia(GAVE), vitamin B12 and folate deficiency anemia and autoimmune anemia with hemolysis and reticulocytosis.

Malnutrition is a medical condition characterized by an unbalance between energy expenditure and nutritional intake. Intuitively, weight loss is the clinical manifestation that best represents malnutrition despite weight loss per se is not a synonym of malnutrition. The common definition of malnutrition is based on a body mass index (BMI, kg/m2) ≤18.5. Recently, the European Society of Clinical Nutrition and Metabolism (ESPEN) extended this definition to include the possibility to track changes in BMI based on weight loss in a specific amount of time resulting in the following combination: Weight loss (unintentional) > 10% indefinite of time, or >5% over the last 3 months combined with either BMI 70 years of age or fat free mass index (FFMI)

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell–integrin interaction are sufficient to initiate profibrotic processes. SSc fibroblasts express both αvβ3 and αvβ5 integrins and their activation induces myofibroblasts differentiation. The aim of the present study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: HOCl alone (n=8), HOCl + Cilengitide (n=8), or Vehicle alone (n=8). Treatment with cilengitide 20 (mg/kg/i.p./day) was started 4 weeks after the first administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung, skin, and heart fibrosis were evaluated by histology while kidney morphology by PAS staining. Collagen type I, focal adhesion kinase (FAK), and a-SMA were evaluated by immunostaining and p-FAK and TGF-β1 by Western blot and gene expression. Both cutaneous and pulmonary fibrosis induced by HOCl were attenuated by cilengitide treatment. Cilengitide administration reduced a-SMA, TGF-β1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of aνβ3 and aνβ5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins aνβ3 and aνβ5 could prove useful as a therapeutic target in SSc.

Objectives: The aim of the present study was to assess the prevalence of temporomandibular joint (TMJ)symptoms, clinical and magnetic resonance imaging (MRI) findings in a cohort of Southern Italian patientswith SSc.Methods: Twenty-seven patients with SSc (12 diffuse, 15 limited, mean age 53.9, SD ± 1.2) and 28 healthysubjects (mean age 54.8, SD ± 4.2) were enrolled in this observational cohort study. In all patients, clinicalexamination for assessing the presence of TMJ sounds, pain in the TMJ area, tenderness of masticatorymuscles, limited mouth opening, pain assessment, MRI scan and Anamnestic and Dysfunctional Indexwere performed.Results: The test groups reported more clinical and MRI findings of TMJ symptoms and dysfunction thancontrol group. The frequency distributions of symptoms were significantly different (P < 0.05), in thetest groups for TMJ sounds, pain during mandibular movement and difficulty in the maximum mouthopening. There was also a significant decrease (P < 0.001), in the test groups, in the mean of leftward,rightward laterotrusion and protrusion. Correlation analysis allowed to affirm that maximum openingleftward laterotrusion, protrusion and click were significantly correlated to Modified Rodnan Skin Score.The mean duration of disease was significantly correlated, ever in total SSc group, only for the maximummouth opening value.Conclusion: This study demonstrates that TMJ involvement is common in SSc patients and is correlatedwith a length and involvement of disease and supports the notion that TMJ examination should be encour-aged in the rheumatology setting and clinicians should provide a right pain management and patientsupport. Objectives: The aim of the present study was to assess the prevalence of temporomandibular joint (TMJ)symptoms, clinical and magnetic resonance imaging (MRI) findings in a cohort of Southern Italian patientswith SSc.Methods: Twenty-seven patients with SSc (12 diffuse, 15 limited, mean age 53.9, SD ± 1.2) and 28 healthysubjects (mean age 54.8, SD ± 4.2) were enrolled in this observational cohort study. In all patients, clinicalexamination for assessing the presence of TMJ sounds, pain in the TMJ area, tenderness of masticatorymuscles, limited mouth opening, pain assessment, MRI scan and Anamnestic and Dysfunctional Indexwere performed.Results: The test groups reported more clinical and MRI findings of TMJ symptoms and dysfunction thancontrol group. The frequency distributions of symptoms were significantly different (P < 0.05), in thetest groups for TMJ sounds, pain during mandibular movement and difficulty in the maximum mouthopening. There was also a significant decrease (P < 0.001), in the test groups, in the mean of leftward,rightward laterotrusion and protrusion. Correlation analysis allowed to affirm that maximum openingleftward laterotrusion, protrusion and click were significantly correlated to Modified Rodnan Skin Score.The mean duration of disease was significantly correlated, ever in total SSc group, only for the maximummouth opening value.Conclusion: This study demonstrates that TMJ involvement is common in SSc patients and is correlatedwith a length and involvement of disease and supports the notion that TMJ examination should be encour-aged in the rheumatology setting and clinicians should provide a right pain management and patientsupport.

Background Macrovascular involvement in Systemic Sclerosis (SSc) is caused by proliferation of vascular smooth muscle cells within the intima of arteries (neointimal proliferation). The resulting decrease in arterial volume is responsible for the severity of Raynaud’s and for the onset of severe clinical manifestations such as Renal Crisis and Pulmonary Artery Hypertension. Several RCTs have demonstrated the efficacy of Endothelin Receptor Antagonists (ERAs) in targeting neointimal proliferation, which makes them to date, the only disease modifying agent available in SSc. Nevertheless, the lack of validated early diagnostics means the intention to treat with ERAs remains limited to the diagnosis of end stage clinical manifestations of neointimal proliferation, such as presence of Digital Ulcer (DU) and PAH. Objectives Here we aimed to determine the proof of concept validity of automated Digital Artery Volume Index (DAVIX) measured by non-contrast Time of Flight (TOF) MRI as an objective diagnostic tool to be used as surrogate outcome measure of neointimal proliferation in SSc. Methods 10 Healthy Volunteers (HV) and 8 SSc patients were enrolled. Six patients underwent longitudinal assessments at least 12 months apart. MRI scans were performed on a 3T Magnetom Verio (Siemens) and consisted of a VIBE 3D T1 scan and a 2D TOF sequence of 8 min. DAVIX was calculated as the percentage of the ratio of digital artery and the respective finger volumes. The vessels and fingers were manually outlined by an expert radiologist and used as a ‘gold standard’ (DAVIX-1) and compared to a 2nd independent radiologist assessment (DAVIX-2). An automated segmentation algorithm was developed using threshold based segmentation and region growing (DAVIX-A) and validated against gold standard. Intraclass correlation coefficient (ICC) and absolute agreement were calculated to estimate reliability. Bland-Altman bias and 95% limits of agreement (LoA) were calculated as well. Results SSc patients and HV had comparable age (44±8 vs 45±8) and gender (F:M=5:2 vs 4:2). 4 fingers were affected by DUs at baseline and two fingers were affected by new DU at follow up. Mean(±SD) DAVIX in HV was 1.21 (±0.39) with no significant difference among individual fingers. Mean DAVIX in SSc patients was 0.37 (±0.18) and 0.32 (±0.39) at baseline and follow-up, respectively (p Conclusions This proof of concept study demonstrated validity and sensitivity to change of DAVIX for the automated volumetric assessment of digital arteries, which reflected clinical worsening in patients with new DU. Larger, longitudinal studies are planned to assess DAVIX’ predictive value for the onset of DU and its potential use as early diagnostic of neointimal proliferation in SSc. Disclosure of Interest None declared

Background Malnutrition and severe gastrointestinal dysfunction are the cause of mortality in 4%–15% of systemic sclerosis (SSc) patients whereas overall gastrointestinal involvement is observed in 75%–90% of cases.1 Hence, a reliable tool for stratification of risk for malnutrition would be of great value in the clinical management of SSc. Objectives Here we set out to identify a combined index predictive of significant weight loss at 12 months employing Malnutrition Universal Screening Tool (MUST) and serum adiponectin to leptin ratio (A/L) already used in other conditions. Methods This was an international, multicentre, longitudinal study employing 180 SSc patients in two independent cohorts: a study cohort (110 consecutive SSc patients) enrolled from University of Messina (60) and University of Padova,50 and a validation cohort (70) at the University of Leeds. Serum A/L ratio was measured by ELISA. MUST score, which includes BMI and weight loss reported by the patient in the last 3–6 months, was calculated as described: 0=no, 1=mild,>2= moderate/severe risk of malnutrition. End point of the study was weight loss >10% of baseline weight at 12 months. Results The two cohorts showed no significant differences in demographic and clinical features. Overall, median BMI decreased over time in both study and validation cohorts (23.5 vs 22.35 and 23.44 vs 22.49, respectively; p 10% wt despite having “no” or “mild” MUST scores. Logistic regression analysis identified the combination of BMI and A/L as the best PREdictor of MAlnutrition in Systemic Sclerosis (PREMASS). The formula 12.18-(0.63*BMI)+(1.51*A/L) predicted the end point with AUC=0.91 (95% CI:0.77–0.84). A PREMASS score >0.23 showed 91.3% sensitivity (95% CI:79.79–100) and 80.46% specificity (95% CI:72.13–88.79) for >10% wt loss with an overall 55.26% positive predictive value (PPV) (95% CI:39.45–71.07) and 97.22% negative predictive value (NPV) (95% CI:93.43–100) and a relative risk (RR) of 19.90 (95% CI:4.93–80.37). In the validation cohort, PREMASS showed 76.47% sensitivity (95% CI:56.31–96.63) and 75.47% specificity (95% CI:63.89–87.06) with an overall 50% PPV (95% CI:30.78–69.22) and 90.91% NPV (95% CI:82.41–99.4) and a RR of 5.5 (95% CI: 2–15.10). Conclusions PREMASS is the first validated index for weight loss risk stratification in the following 12 months in SSc. Prediction of future weight loss in SSc could aid both in clinical management and stratification/enrichment in clinical trials. Disclosure of Interest None declared

The aim of the study was to evaluate whether a reduced pain threshold is associated with increased temporomandibular dysfunction in systemic sclerosis (SSc) compared to psoriatic arthritis (PsA) and healthy controls. Ninety subjects participated in the study (30 SSc, 30 PsA, and 30 healthy controls). The Helkimo index was used to evaluate temporomandibular dysfunction. Digital palpation was performed at the temporomandibular joint (TMJ) surface and at the superficial masseter muscle (SMM) and pain intensity was recorded on a visual analog scale (VAS), while pain pressure threshold (PPT) was measured at the same sites through a pressure algometer. PPT scores were lower in SSc patients compared to PsA patients and controls. In addition, the average Helkimo index score, measuring the degree of TMJ dysfunction, was higher in SSc compared to PsA and controls. A significant inverse correlation was observed between every PPT score, and both Helkimo index and VAS palpation in SSc and PsA. Both the range of motion and all the other pain-related subdomains of the Helkimo index score (pain on movement, pain palpation TMJ and pain palpation muscle) were significantly worse in SSc compared to PsA, while no significant differences were observed in the TMJ function subdomain. In SSc patients, the skin score was directly associated with the range of motion subdomain of the Helkimo index. Our results confirm that TMJ function is impaired in SSc; further longitudinal studies are needed to assess the role of pain threshold in the assessment of limitations in TMJ function and to identify an objective marker of therapeutic response.

The authors present a case of a 51-year-old woman with clinical diagnosis of mixed connective tissue disease and overlap systemic lupus erythematosus features, with a 6-month history of progressive painless abdominal distension. On examination, evident signs of ascites were present. Both the abdominal-pelvic ultrasound and CT scan confirmed a large amount of ascites. A diagnostic paracentesis was performed, which revealed typical features of chylous ascites (CA). An extensive diagnostic work-up led by a multidisciplinary team was performed, excluding malignancy, cirrhosis, infectious, as well as cardiac and primary lymphatic causes. The patient was kept under surveillance, with dietary therapy and periodic ascitic drainages. The hypothesis of an autoimmune cause for CA was considered by exclusion. Rituximab therapy was initiated and an excellent response was achieved, with reduction of the rate of accumulation of CA and an increase in quality of life of the patient.

Several lines of evidence support the relevance of reactive oxygen species (ROS) in vitiligo, but the exact role of glycation and oxidation of macromolecules needs to be better addressed. To investigate the involvement of advanced oxidation protein products (AOPPs) and advanced glycation end-products (AGEs), we performed a case-control association study by spectrofluorimetry and spectrophotometry, in 47 patients with non-segmental generalized vitiligo and 47 age- and sex-matched controls. Significantly higher levels of both AOPPs (p

Lung fibrosis can be observed in systemic sclerosis and in idiopathic pulmonary fibrosis, two disorders where lung involvement carries a poor prognosis. Although much has been learned about the pathogenesis of these conditions, interventions capable of reversing or, at the very least, halting disease progression are not available. Recent studies point to the potential role of micro messenger RNAs (microRNAs) in cancer and tissue fibrogenesis. MicroRNAs are short non-coding RNA sequences (20–23 nucleotides) that are endogenous, evolutionarily conserved and encoded in the genome. By acting on several genes, microRNAs control protein expression. Considering the above, we engaged in a systematic review of the literature in search of overlapping observations implicating microRNAs in the pathogenesis of both idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). Our objective was to uncover top microRNA candidates for further investigation based on their mechanisms of action and their potential for serving as targets for intervention against lung fibrosis. Our review points to microRNAs of the -29 family, -21-5p and -92a-3p, -26a-5p and let-7d-5p as having distinct and counter-balancing actions related to lung fibrosis. Based on this, we speculate that readjusting the disrupted balance between these microRNAs in lung fibrosis related to SSc and IPF may have therapeutic potential.

Pain perception and threshold show complex interactions with the inflammatory, psychiatric and neuroendocrine stimuli. This study aims to test whether lower serum cortisol levels are associated with lower pain thresholds and higher degree of depression in systemic sclerosis (SSc) and major depression with atypical features (MD-AF) patients compared to controls. 180 female subjects (SSc = 60, MD-AF = 60, healthy controls = 60) participated in this observational, cross-sectional, parallel group study. Pressure pain threshold (PPT) was assessed in three anatomical sites: nail bed (NB), metacarpophalangeal joint (MCP) and quadriceps muscle (QDR). Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) scale and morning serum cortisol levels were collected. In SSc patients, quality of life was measured through the Health Assessment Questionnaire (HAQ-DI) and the scleroderma-specific visual analogue scales (scleroderma-VAS). Lower PPT scores (NB 4.42 ± 1.6; MCP 4.66 ± 1.4; QDR 4.79 ± 1.5) were observed in SSc patients compared to both MD-AF (NB 7.33 ± 2.2; MCP 6.01 ± 1.9; QDR 6.31 ± 1.6; p

Background Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular alterations and autoimmune activation leading to widespread organ fibrosis. At the early stage of disease when organ involvement and extent of disease are emerging, mast cells may have some role, as implied by both symptoms and histologic evidence. Case presentation A female patient diagnosed with cutaneous mastocytosis experienced the onset of systemic sclerosis after 15 years followed by the switch of mastocytosis to the systemic phenotype. A literature review on the evidences related to mast-cells activation in systemic sclerosis is presented below. Conclusions For clinicians, more attention must be paid to the potential association between systemic sclerosis and cancer. This case suggests that a proliferative disease in the mast cell compartment—though representing a rare association—may not be completely unexpected in SSc and perhaps excess mast cell activity can serve a pathogenic role in promoting fibrotic disease.

Objectives. This trial aimed to test the effectiveness of a wearable pulsed electromagnetic fields (PEMF) device in the management of pain in knee OA patients. Methods. In this randomized [with equal randomization (1:1)], double-blind, placebo-controlled clinical trial, patients with radiographic evidence of knee OA and persistent pain higher than 40 mm on the visual analog scale (VAS) were recruited. The trial consisted of 12 h daily treatment for 1 month in 60 knee OA patients. The primary outcome measure was the reduction in pain intensity, assessed through VAS and WOMAC scores. Secondary outcomes included quality of life assessment through the 36-item Medical Outcomes Study Short-Form version 2 (SF-36 v2), pressure pain threshold (PPT) and changes in intake of NSAIDs/analgesics. Results. Sixty-six patients were included, and 60 completed the study. After 1 month, PEMF induced a significant reduction in VAS pain and WOMAC scores compared with placebo. Additionally, pain tolerance, as expressed by PPT changes, and physical health improved in PEMF-treated patients. A mean treatment effect of −0.73 (95% CI − 1.24 to − 0.19) was seen in VAS score, while the effect size was −0.34 (95% CI − 0.85 to 0.17) for WOMAC score. Twenty-six per cent of patients in the PEMF group stopped NSAID/analgesic therapy. No adverse events were detected. Conclusion. These results suggest that PEMF therapy is effective for pain management in knee OA patients and also affects pain threshold and physical functioning. Future larger studies, including head-to-head studies comparing PEMF therapy with standard pharmacological approaches in OA, are warranted. Trial registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01877278","term_id":"NCT01877278"}}NCT01877278

Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of α(v)β(3) integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined.

Vascular involvement in systemic sclerosis (SSc) plays a key role in the pathogenesis of fibrosis. We assessed arterial stiffness using a new echo-tracking technique in patients with SSc asymptomatic for cardiovascular diseases. We enrolled 22 patients (21 female, 63 ± 14 years) and 20 controls (12 female, 62 ± 3 years). Carotid intima-media thickness (IMT) was comparable between the 2 groups (1.1 ± 0.3 vs 1.0 ± 0.4 mm, P = ns), whereas the stiffness parameters were significantly increased in patients (β: 9.5 ± 4.2 vs 5.8 ± 1.1, P = .001; pulse wave velocity [PWV]: 6.5 ± 1.5 vs 5.2 ± 0.6 m/sec, P = .003). A correlation between stiffness parameters, anti-Scl-70 antibodies (β: r = .46, P = .03; PWV: r = .50, P = .02), and anticentromere antibodies (β: r = -.54, P = .020; PWV: r = -.53, P = .023) was found. Echo-tracking technique may be valuable in early identification of vascular involvement in patients with SSc.

Background and aims Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA. Methods and results CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen. Conclusions RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA.

Interstitial lung disease (ILD) encompasses a large and diverse group of pathological conditions that share similar clinical, radiological and pathological manifestations, despite potentially having quite different aetiologies and comorbidities. Idiopathic pulmonary fibrosis (IPF) represents probably the most aggressive form of ILD and systemic sclerosis is a multiorgan fibrotic disease frequently associated with ILD. Although the aetiology of these disorders remains unknown, in this review we analyse the pathogenic mechanisms by cell of interest (fibroblast, fibrocyte, myofibroblast, endothelial and alveolar epithelial cells and immune competent cells). New insights into the complex cellular contributions and interactions will be provided, comparing the role of cell subsets in the pathogenesis of IPF and systemic sclerosis.

Individuals suffering from chronic pain are frequently affected by depression, which in turn increases the risk of developing chronic pain over time. This study aims to investigate the relationship between depression and pain intensity and threshold in a group of rheumatic patients compared to healthy subjects. One hundred twenty-four individuals of whom 50 were affected by rheumatoid arthritis (RA), 23 by psoriatic arthritis (PsA), 23 by ankylosing spondylitis (AS), and 28 age-matched controls without chronic pain underwent quantitative sensory testing to assess pressure pain threshold with pressure algometry. Pain intensity was evaluated through the visual analogue scale (VAS) and depression through the Hamilton Depression Rating scale (HAMD). A significant inverse correlation between HAMD values and pressure pain thresholds was found in the entire group of patients (p < 0.0001), in controls (p = 0.02), and also in RA (p = 0.002), PsA (p < 0.0002), and AS (p = 0.02) patients when analyzed separately, while no significant correlation was found between HAMD and VAS values or pressure pain thresholds and VAS. We found lower pain thresholds in RA and PsA patients while no difference has been evidenced in AS patients compared to healthy controls. HAMD scores were also significantly higher in rheumatic patients than in controls. The use of pressure algometry in the evaluation of chronic pain in patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis that display comorbid depression could represent an additional and integrative method to improve pain/depression overlap management or research.

Recent advances suggest that the cellular redox state may play a significantrole in the progression of fibrosis in systemic sclerosis (SSc). Another,and as yet poorly accounted for, feature of SSc is its overlap with thyroidabnormalities. Previous reports demonstrate that hypothyroidism reducesoxidant stress. The aim of this study was therefore to evaluate the effectof propylthiouracil (PTU), and of the hypothyroidism induced by it, on thedevelopment of cutaneous and pulmonary fibrosis in the oxidant stress murinemodel of SSc. Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneousinjections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25)were randomized into three arms: HOCl (n = 10), HOCl plus PTU(n = 10) or vehicle alone (n = 5). PTU administrationwas initiated 30 minutes after HOCl subcutaneous injection and continueddaily for 6 weeks. Skin and lung fibrosis were evaluated by histologicmethods. Immunohistochemical staining for alpha-smooth muscle actin(α-SMA) in cutaneous and pulmonary tissues was performed to evaluatemyofibroblast differentiation. Lung and skin concentrations of vascularendothelial growth factor (VEGF), extracellular signal-related kinase (ERK),rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforminggrowth factor (TGF) β were analyzed by Western blot. Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTUtreatment prevented both dermal and pulmonary fibrosis. Myofibroblastdifferentiation was also inhibited by PTU in the skin and lung. The increasein cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in micetreated with HOCl was significantly prevented in mice co-administered////with PTU. PTU, probably through its direct effect on reactive oxygen species orindirectly through thyroid function inhibition, prevents the development ofcutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERKpathway in the oxidant-stress animal model of SSc.

OBJECTIVE: The aim of our study was to elucidate the pathophysiology of systemic sclerosis-related osteoporosis and the prevalence of vertebral fragility fracture in postmenopausal women with systemic sclerosis (SSc). METHODOLOGY: Fifty-four postmenopausal women with scleroderma and 54 postmenopausal controls matched for age, BMI, and smoking habits were studied. BMD was measured by dual energy-x-ray absorptiometry at spine and femur, and by ultrasonography at calcaneus The markers of bone turnover included serum osteocalcin and urinary deoxypyridinoline. All subjects had a spine X-ray to ascertain the presence of vertebral fractures. RESULTS: bone mineral density at lumbar spine (BMD 0.78±0.08 vs 0.88±0.07; p

Background Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by diffuse fibrosis involving several organs, including heart. Aim of our study was to analyze left ventricular (LV) myocardial deformation, by use of 2D strain, in asymptomatic SSc patients with normal LV ejection fraction. Methods We enrolled 29 SSc patients (28 female, 65±4 years) and 30 controls (23 female, 64±2 years). Echocardiographic study with tissue Doppler imaging (TDI) and 2D strain analysis was performed; moreover, patients were submitted to a two-year follow-up for the occurrence of cardiovascular events. Results Standard echocardiographic parameters and TDI velocities were comparable between groups. LV longitudinal (LS) and circumferential (CS) strains were lower in patients than in controls (−13.1±4.8 vs −22.6±4.1, p < 0.001; -15.3±6.2 vs −20.4±5.6, p = 0.001), whereas radial strain (RS) was comparable between groups; moreover, a significant correlation of LS and CS with serum levels of Scl-70 antibodies was found (r = 0.74, p = 0.001; r = 0.53, p = 0.025). In addition, patients with cardiovascular events during follow-up showed a greater impairment of LS and CS (−10.3±2.5 vs −14.4±4.1, p = 0.015; -14.2±3.1 vs −20.1±1.6, p = 0.048) and higher values of Scl-70 antibodies serum levels (p = 0.047). Conclusion The impairment of LV function, often subclinical, worsens prognosis of SSc patients, leading to increased risk of cardiovascular complications. 2D strain, allowing the early detection of LV abnormalities and the identification of patients at greater cardiovascular risk, may be a useful tool in order to provide a more accurate management of SSc patients.

Objective. Therapeutic approach of osteoarthritis (OA) still represents a challenge in clinical practice. The aim of the study is to assess the efficacy of far infrared (FIR) emitting plaster in the treatment of knee OA. Design. This is a randomized, single-blind, placebo-controlled, parallel group with equal randomization (1:1), clinical trial. Patients affected by knee OA were randomly allocated to 1 of 2 treatment groups, either placebo plaster or far infrared emitting plaster. Primary endpoint was to assess pain improvement from baseline to 1 months posttreatment in the visual analogue score (VAS). Secondary end point was to evaluate pain score after 1 week of treatment and to compare ultrasonographic findings after 1 month of treatment. Results. Each group comprised 30 (in the FIR group) and 30 (in the placebo group) completers. VAS scores of the placebo and the FIR group were significantly lower at 1 week post-treatment (95% confidence interval CI = -1.14 to 0.31; PConclusions. Far infrared emitting plaster could be considered an effective non-pharmacological choice for the therapeutic management of knee OA.