Dual αvß3 and αvß5 blockade attenuates fibrotic and vascular alterations in a murine model of systemic sclerosis.

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 αvß3 and αvß5 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-ß1 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-ß1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of aνß3 and aνß5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins aνß3 and aνß5 could prove useful as a therapeutic target in SSc.

Clinical, autoimmune, and psychiatric parameters correlate with sleep disturbance in patients with systemic sclerosis and rheumatoid arthritis.

OBJECTIVES: Sleep disturbance is an important contributor to poor quality of life in rheumatic disorders. This study aims to test whether clinical, autoimmune and psychological factors are associated with sleep disturbance in systemic sclerosis (SSc) compared to rheumatoid arthritis (RA) patients and controls. METHODS: 101 female subjects (SSc=33, RA=34, healthy controls=34) participated in this observational, cross-sectional, parallel group study. Sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). Other assessments included the visual analogue scale (VAS) for pain, 36-item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). Clinical parameters, therapeutic regimen, and serologic status were recorded. RESULTS: In SSc patients, PSQI scores were higher than in RA patients and controls. Linear regression analysis showed that in SSc patients PSQI scores was associated with BDI, disease duration, modified Rodnan skin score and VAS, while DAS28 and BDI were associated with PSQI scores in RA patients. Anti-Scl70 and ANA positive SSc patients showed higher PSQI scores compared to those ANA positive only, while no differences were observed in RA patients classified according to rheumatoid factor positivity. SSc patients treated with immunosuppressants had lower PSQI scores compared to those not on therapy, whereas only corticosteroid treatment was significantly associated with higher PSQI scores in RA patients. RA patients with disease activity higher than moderate (DAS28≥3.2) had higher PSQI scores than those with lower than moderate (DAS28<3.2). CONCLUSIONS: Longitudinal studies are needed to identify disease-specific patterns associated with sleep disturbances and the influence on sleep function induced by immunosuppressive therapy among rheumatic patients.

Mastocytosis and systemic sclerosis: a clinical association.

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.

Toll-like receptor 3 and interleukin 1ß expression in CD34+ cells from patients with rheumatoid arthritis: association with inflammation and vascular involvement.

OBJECTIVES: Circulating proangiogenic haematopoietic cells (PHCs), including CD34+ cells, play an important role in endothelial homeostasis. Among PHCs, CD34+ cells are the largest cell population, thus, much of the regenerative/reparative potential of PHCs may be attributed to CD34+ cells. Our aim was to determine the association between inflammation and CD34+ cell number, intracellular levels of reactive oxygen species (ROS) and expression of Toll-like receptor 3 (TLR3) and interleukin 1ß (IL-1ß), arterial stiffness (AS) indices, and carotid intima-media thickness (cIMT) in patients affected by rheumatoid arthritis (RA). METHODS: CD34+ cells were isolated from 24 RA patients and 26 matched controls. ROS levels, TLR3 and IL-1ß expression were measured. C-reactive protein (CRP), fibrinogen, AS, and cIMT were also evaluated. RESULTS: CD34+ count was lower in RA patients as compared to controls. In CD34+ cells from RA patients, ROS, TLR3 and IL-1ß expressions were increased compared to controls. In RA patients, we found higher CRP and fibrinogen levels, and higher values of Pulse Wave Velocity (PWV) and Augmentation Index (AIx), both AS indices, and of cIMT. CD34+ cell numbers were inversely correlated with CRP, TLR3, IL-1ß, ROS, and AS indices. TLR3 levels were related to CRP, IL-1ß, fibrinogen and ROS. IL-1ß levels were correlated with expression of CRP, ROS, and PWV. CONCLUSIONS: Inflammatory status in RA is associated with an increased expression of TLR3 and of IL-1ß in CD34+ cells, which appear to affect cell number. These new findings suggest a perspective on accelerated atherosclerosis and vascular damage in RA.

Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis.

OBJECTIVE: The antifibrotic effect of simvastatin has been demonstrated in human lung fibroblasts. This study aimed to measure the effects of simvastatin in the development of pulmonary and cutaneous fibrosis in a murine model of SSc and to explore the mechanisms of these effects. METHODS: Chronic oxidant stress SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: treatment with HOCl, HOCl plus simvastatin or vehicle alone. Statin treatment was initiated 30 min after HOCl s.c. injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histological methods. Immunohistochemical staining for α-smooth muscle actin in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of VEGF, extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homologue gene family (Rho) and TGF-ß were analysed by western blot. RESULTS: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. Simvastatin treatment prevented both skin thickness and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by simvastatin in the skin and in the lung. Increased cutaneous and pulmonary expression of VEGF, ERK, Ras and Rho in mice treated with HOCl was significantly lower in mice treated with HOCl plus simvastatin. CONCLUSION: Simvastatin reduces the development of pulmonary fibrosis, potentially modulating adverse lung remodelling, as shown by the reduced deposition of collagen in alveolar septae. Simvastatin also reduces skin thickness in this model.

Remission in early, aggressive rheumatoid arthritis: a multicentre prospective observational Italian study ARPA (Artrite Reumatoide Precoce Aggressiva).

OBJECTIVES: To provide a survey of disease activity in patients treated with standard care in Italian clinical practice. METHODS: This was an observational prospective cohort study in patients with early, aggressive rheumatoid arthritis (RA; duration ≤2 years but ≥6 weeks; DAS28 >3.2) naïve to anti-tumour necrosis factor (TNF) therapy who were treated with disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics according to standard practice at 15 Italian ARPA (Artrite Reumatoide Precoce Aggressiva) centres. Patients were evaluated at baseline and after 6, 12 and 24 months. The primary endpoint was the proportion of patients achieving remission, as defined by disease activity score in 28 joints (DAS28) <2.6, after 1 year. RESULTS: Among the 152 patients enrolled, 92 were evaluable after 1 year and 77 after 2 years for DAS28. At baseline, patients had a mean DAS28 of 6.1±1.0. At 12 months, 62.6% of patients were treated with DMARDs (in monotherapy or in combination), and 37.4% with anti-TNFs (in monotherapy or in association with DMARDs). At 24 months, 35.1% were receiving anti-TNF therapy. The rate of DAS28 remission rates at 12 months and 24 months were 28.3% (95% confidence interval [CI] 19.1-37.5) and 41.6% (95% confidence interval [CI] 30.6-52.6), respectively. CONCLUSIONS: The remission rate was lower at 12 months compared with previous large randomised clinical trials for early, aggressive RA, but significantly improved at 24 months. These results suggest that patients in real-world clinical settings in Italy may experience a delay in receiving the best possible care.

Role of 2D strain in the early identification of left ventricular dysfunction and in the risk stratification of systemic sclerosis patients.

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.

Polydeoxyribonucleotide reduces cytokine production and the severity of collagen-induced arthritis by stimulation of adenosine A(2A) receptor.

OBJECTIVE: Broad antiinflammatory effects following adenosine A(2A) receptor stimulation have been demonstrated in acute inflammatory diseases, including arthritis. Polydeoxyribonucleotide (PDRN) activates the adenosine A(2A) receptor. This study was undertaken to investigate the effects of PDRN in collagen-induced arthritis (CIA) in mice. METHODS: Arthritis was induced in DBA/1 mice by an intradermal injection of 100 µl of bovine type II collagen in Freund's complete adjuvant. Mice were immunized a second time 21 days later. Control animals received 100 µl of a saline solution. Animals with CIA were randomized to receive one of the following: vehicle (1 ml/kg); PDRN (8 mg/kg intraperitoneally daily); 3,7-dimethyl-propargylxanthine (DMPX), a specific adenosine A(2A) receptor antagonist (0.1 mg/kg intraperitoneally daily); or PDRN plus DMPX. The treatment was initiated immediately after the second immunization and continued to day 45. Clinical evaluation of arthritis was performed throughout the study. On day 45, the animals were killed and the severity of arthritis was evaluated histologically. Cartilage expression and circulating levels of high mobility group box chromosomal protein 1 (HMGB-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-10 were investigated. Inflammatory cytokine production was also evaluated in stimulated human chondrocytes treated with PDRN. RESULTS: PDRN treatment significantly ameliorated clinical signs of arthritis, improved histologic damage, reduced the cartilage expression and circulating levels of HMGB-1, TNFα, and IL-6, and enhanced IL-10 expression. The concomitant administration of DMPX and PDRN ablated the PDRN-induced protective effect in experimental arthritis. PDRN also reduced cytokine production from stimulated human chondrocytes. CONCLUSION: Our findings indicate that PDRN may represent a new alternative for the treatment of arthritis.

Patient-reported impact of spondyloarthritis on work disability and working life: the ATLANTIS survey.

BACKGROUND: The aim was to establish how patients experience the impact of spondyloarthritis (SpA) on work disability and working life. METHODS: The survey was performed in 17/20 regions in Italy (1 January to 31 March 2013). A multiple-choice questionnaire was published on the official website of the sponsor - the National Association of Rheumatic Patients (ANMAR) - and hard-copies were distributed at outpatient clinics for rheumatic patients. RESULTS: Respondents (n = 770) were of both sexes (56 % men), educated (62 % at high school or more), of working age (75 % aged ≤60 years), and affected by SpA. The most common types diagnosed were ankylosing spondylitis (AS) (39 %) and psoriatic arthritis (PsA) (36 %). Respondents were working full-time (45 %), part-time (8 %) or had retired (22 %); 15 % were unemployed (for reasons linked to the disease or for other reasons, students or housewives). Patients reported disability (39 %), were receiving disability benefits (34 %), were experiencing important limitations that were hindering their professional development/career (36 %) and some had to change/leave their job or lost it because of SpA (21 %). Employed respondents (n = 383) had worked on average 32.2 h in the last 7 days. More hours of work were lost over the last 7 days due to SpA (2.39 h vs 1.67 h). The indirect costs of the disease amounted to €106/week for patients reporting well-being/good physical conditions/improvement and €216/week for those reporting permanent impairment. CONCLUSIONS: Most patients were in the midst of their productive years and were experiencing considerable difficulties in carrying out their job because of the disease: half of them reported disability and one third were experiencing important limitations in their career perspective.

Propylthiouracil modulates aortic vasculopathy in the oxidative stress model of systemic sclerosis.

BACKGROUND: In systemic sclerosis (SSc) vasculopathy affects small arteries and capillaries, but recent evidences show also macrovascular alterations. Experimental data suggest that propylthiouracil (PTU) abrogates the development of cutaneous and pulmonary fibrosis during SSc. The aim of this study was to evaluate the effect of propylthiouracil on aortic lipid peroxidation, intima-media thickness and myofibroblasts differentiation in experimental SSc. METHODS: SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6weeks. Mice (n=25) were randomized to receive daily: HOCl (n=10), HOCl+PTU (n=10), or vehicle (n=5). Thoracic aorta was evaluated by histological methods to measure intima-media thickness and by immunostaining for α-smooth muscle actin (α-SMA) to assess myofibroblast differentiation. Aortic and plasma levels of malondialdehyde (MDA) were also measured. RESULTS: HOCl induced a significant increase in aortic intima-media thickness compared to controls (p<0.001), while PTU administration prevented intima-media thickening (p<0.01). Myofibroblast differentiation was also less evident in HOCl+PTU-treated animals (p<0.05) compared to mice treated with HOCl alone. The increase in aortic and plasma MDA levels induced by HOCl, was significantly prevented by PTU administration (p<0.05). CONCLUSION: PTU, by reducing lipid peroxidation, prevents aortic thickening and myofibroblast differentiation induced by HOCl, reducing macrovascular alterations in experimental SSc.

Pain threshold and intensity in rheumatic patients: correlations with the Hamilton Depression Rating scale.

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.

Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis C virus infection: a multicenter randomized clinical trial.

OBJECTIVE: To evaluate the safety and efficacy of therapy with etanercept and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and mild hepatitis C virus (HCV) infection. METHODS: In this prospective open study, 29 patients with active RA were randomly assigned to receive therapy with MTX alone, etanercept alone, or a combination of MTX and etanercept, and monitored up to 54 weeks. The primary endpoint was safety; secondary aims were efficacy as defined by the 44-joint Disease Activity Score (DAS44) and health assessment questionnaire (HAQ). Serum liver enzymes and HCV viral load were serially measured. RESULTS: In the whole cohort, aspartate aminotransferase (AST) serum levels were (mean ± SD) 35 ± 3 at entry, 39 ± 5, 41 ± 7, and 38 ± 4 at 14, 30, and 54 weeks, respectively; alanine aminotransferase (ALT) serum levels were 43 ± 5 at entry, 47 ± 5, 53 ± 9, and 50 ± 6 at 14, 30, and 54 weeks, respectively. HCV viral load was 5.6 ± 0.5 at entry, 5.9 ± 0.6, 5.7 ± 0.3, and 5.6 ± 0.6 at 14, 30, and 54 weeks, respectively. AST and ALT did not significantly change in all 3 arms of treatment, nor did HCV viral load. A significant reduction of DAS44 (p < 0.01) and HAQ (p < 0.04) was detected at 54 weeks compared to baseline. No patient discontinued the therapy because of worsening of liver disease. CONCLUSION: This study showed that patients with RA and chronic HCV and mild hepatitis may be successfully treated with etanercept and MTX without increasing the risk of hepatotoxicity and HCV replication. ClinicalTrials.gov Identifier NCT01543594.

Bone mineral density, quantitative ultrasound parameters and bone metabolism in postmenopausal women with depression.

Low bone mineral density, which increases the risk of stress fragility fractures, is a frequent, often persistent finding in patients with major depressive disorder (MDD). The clinical association between major depressive disorder and osteopenia is still unclear, although several factors are associated with a loss of bone mass. The aim of our study, therefore, was to evaluate bone mineral density and bone metabolism in patients with MDD. Bone mineral density was evaluated in fifty postmenopausal women with MDD, and in 50 matched postmenopausal control women by dual-energy X-ray absorptiometry of the lumbar spine and femur, and by ultrasonography of the calcaneus and phalanges. Serum levels of 25-hydroxivitamin D, parathyroid hormone, Osteoprotegerin/Receptor Activator for Nuclear Factor κB Ligand ratio, bone turnover markers, serum and urinary cortisol were examined. Bone mineral density of the lumbar spine (BMD: 0.72 ± 0.06 vs. 0.82 ± 0.09 g/cm(2), p < 0.001), femoral neck (BMD: 0.58 ± 0.04 vs. 0.71 ± 0.07 g/cm(2), p < 0.001) and total femur (BMD 0.66 ± 0.09 vs. 0.54 ± 0.06 g/cm(2), p < 0.001); and ultrasound parameters at calcaneus (SI: 81.30 ± 6.10 vs. 93.80 ± 7.10, p < 0.001) and phalanges (AD-SOS: 1915.00 ± 37.70 vs. 2020.88 ± 39.46, p < 0.001; BTT : 1.30 ± 0.8 vs. 1.45 ± 0.9, p < 0.001) are significantly lower in patients with MDD compared with controls. Moreover bone turnover markers, parathyroid hormone levels and Receptor Activator for Nuclear Factor κB Ligand are significantly higher in MDD patients compared with controls, while serum levels of 25-hydroxivitamin D and osteoprotegerin are significantly lower. There are no differences in urinary excretion and serum cortisol between groups. Postmenopausal women with depressive disorder have an elevated risk for osteoporosis. Our data suggest that a high level of parathyroid hormone may play a role in the pathogenetic process underlying osteopenia in these patients.

Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: a case control study.

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<0,001), femoral neck (BMD: 0.56±0.04 vs 0.72±0.07; p<0,001) and total femur (BMD: 0.57±0.04 vs 0.71±0.06; p<0,001) and ultrasound parameter at calcaneus (SI: 80.10±5.10 vs 94.80±6.10 p<0,001) were significantly lower in scleroderma compared with controls; bone turnover markers and parathyroid hormone level were significantly higher in scleroderma compared with controls, while serum of 25(OH)D3 was significantly lower. In scleroderma group the serum levels of 25(OH)D3 significantly correlated with PTH levels, BMD, stiffness index and bone turnover markers. One or more moderate or severe vertebral fractures were found in 13 patients with scleroderma, wherease in control group only one patient had a mild vertebral fracture. CONCLUSION: Our data shows, for the first time, that vertebral fractures are frequent in subjects with scleroderma, and suggest that lower levels of 25(OH)D3 may play a role in the risk of osteoporosis and vertebral fractures.

Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis.

INTRODUCTION: Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc. METHODS: Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections 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 administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) ß were analyzed by Western blot. RESULTS: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered with PTU. CONCLUSIONS: PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.

Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis.

OBJECTIVE: To investigate the relationship among focal bone erosions and bone mineral density (BMD), 25(OH) vitamin D (25OHD), and parathyroid hormone (PTH) values in patients with rheumatoid arthritis (RA). METHODS: The study included 1191 RA patients (1014 women, 177 men, mean age 58.9 ± 11.1 yrs) participating in a multicenter, cross-sectional study. RESULTS: Radiographic evidence of typical bony erosions on hands or forefeet was found in 64.1% of patients. In those with bone erosions as compared to those without, mean BMD Z score values were significantly lower at both the spine (-0.74 ± 1.19 vs -0.46 ± 1.31; p = 0.05) and the hip (-0.72 ± 1.07 vs -0.15 ± 1.23; p < 0.001). In the subgroup of patients not taking vitamin D supplements, PTH levels were significantly higher in those with erosive arthritis (25.9 ± 14.0 vs 23.1 ± 11.6 pg/ml; p = 0.01); whereas the 25OHD concentrations were very similar in the 2 groups. The mean differences for BMD and PTH among the erosive and nonerosive RA remained statistically significant when values were simultaneously adjusted for all disease and mineral metabolism factors (i.e., age, sex, menopause, disease duration, Disease Activity Score 28-joint count, Health Assessment Questionnaire, activities of daily living, Steinbrocker functional state, glucocorticoid therapy, body weight, and bisphosphonate treatment). CONCLUSION: Our results suggest that the presence of bone erosions in RA correlates with low BMD levels and high PTH levels, and that these associations are independent of the degree of functional impairment and other common determinants of bone mass and mineral metabolism in adults with RA. These findings suggest that treatments to prevent bone loss or suppress PTH levels might positively affect the progression of bone erosions in RA.

Early identification of vascular damage in patients with systemic sclerosis.

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 (ß: 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 (ß: r = .46, P = .03; PWV: r = .50, P = .02), and anticentromere antibodies (ß: 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.