On the early stages of localised atmospheric corrosion of magnesium–aluminium alloys

The surface film on pure magnesium and two aluminium-containing magnesium alloys was characterised after 96\ua0h at 95% RH and 22\ua0\ub0C. The concentration of CO2 was carefully controlled to be either 0 or 400\ua0ppm. The exposed samples were investigated using X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and electron microscopy. The results showed that when the alloys were exposed to the CO2-containing environment, aluminium cations (Al3+) was incorporated into a layered surface film comprising a partially “hydrated” MgO layer followed by Mg(OH)2, and magnesium hydroxy carbonates. The results indicated that aluminium-containing magnesium alloys exhibited considerably less localised corrosion in humid air than pure magnesium. Localised corrosion in the materials under investigation was attributed to film thinning by a dissolution/precipitation mechanism

Interstitial pneumonia with autoimmune features: a new classification still on the move.

IPAF classification criteria include several autoimmune conditions with different evolution. The progression into established CTD is common and a continuous up-to-date process of classification criteria of both IPAF and CTD is mandator

Determination of the Partial Contributions to the Electrical Conductivity of TiO2 - SiO2 - Al2O3 - MgO - CaO Slags: Role of the Experimental Processing Conditions

The electrical transport properties of molten TiO2–SiO2–Al2O3–MgO–CaO slags were determined as a function of temperature and oxygen partial pressure. To avoid the corrosion of crucible materials by this slag at ultra high temperatures, the pendant droplet technique was used inside a modified floating zone furnace. Electronic and ionic transference numbers were estimated using stepped-potential chronoamperometry experiments to quantify the contribution of the electronic/ionic conductivity to the total electric conductivity. The results show that these slags are mixed conductors, where current is carried by ionic and electronic carriers. The oxygen partial pressure dependence of the electronic transference numbers, te, indicated a semiconducting mechanism in the molten slag. The ratio of the different valences of the transition metal ions had a predominant effect on the te. The TiO2 content also favoured electronic conduction, while the effect of temperature and structure was less noticeable within the temperature and composition range studied

Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group

Introduction: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. Method: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. Results: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. Conclusions: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed

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

Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.

The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort.Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables.Based on our selection criteria, 1476 patients were included in the analysis; 87\% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31\% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of 50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95\% CI 1.035, 3.247) and HR 0.973 (95\% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95\% CI 1.91, 4.78) for sPAP ≥36 mmHg.An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization

Smoking in Systemic Sclerosis: a Longitudinal European Scleroderma Trials and Research Group Study

Data on the role of tobacco exposure in systemic sclerosis (SSc) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations in the EUSTAR database

Effects of nintedanib in patients with limited cutaneous systemic sclerosis and interstitial lung disease

OBJECTIVES: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib. RESULTS: Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (SE) of decline in FVC (mL/year) over 52 weeks was -74.5 (19.2) in the placebo group and -49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI -28.9, 79.6]). Among 249 patients with data at week 52, mean (SE) changes in FVC at week 52 were -86.4 (21.1) mL in the placebo group and -39.1 (22.2) mL in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -41.5 (24.0) mL in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and -45.1 (19.1) mL in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON. CONCLUSION: Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD. TRIAL REGISTRATION: ClinicalTrials.gov (https://www.clinicaltrials.gov), NCT02597933 and NCT03313180

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. FINDINGS: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). INTERPRETATION: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. FUNDING: F Hoffmann-La Roche Ltd