Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort

OBJECTIVES To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. RESULTS Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). CONCLUSIONS Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice

High-resolution computed tomography of the chest for the screening, re-screening and follow-up of systemic sclerosis-associated interstitial lung disease: a EUSTAR-SCTC survey

OBJECTIVES: High-resolution computed tomography (HRCT) of the chest is the gold standard to diagnose interstitial lung disease (ILD). A prior survey reported that fewer than 60% of SSc-treating rheumatologists order an HRCT for ILD screening in newly diagnosed SSc patients. Since then, efforts were initiated to increase awareness of HRCT as a screening tool. Aim of the present study was to assess efficacy of these awareness programs. METHODS: European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members answered a survey about the use of HRCT at diagnosis, the re-screening of patients with a negative baseline HRCT, and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected. RESULTS: Among 205 physician responders, 95.6% would perform an HRCT at SSc diagnosis: 64.9% as routine screening for ILD (65.4% of SSc referral and 63.6% of non-referral physicians) and 30.7% upon clinical suspicion (95.2% in case of crackles on auscultation). Among non-screening physicians, clinical and ethical concerns were major driving factors for not ordering HRCTs. During follow-up, 79.0% of responders would repeat HRCTs in baseline negative cases: 14.1% as routine screening and 64.9% for diagnostic purposes. Finally, 93.2% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.6% as yearly routine and 56.6% according to clinical evaluation. CONCLUSIONS: The use of baseline HRCT for the screening of SSc-ILD has slightly increased, but awareness programs should be adapted for further improvement. HRCT use in re-screening and follow-up may benefit from validated algorithms

Intelligibility and Comprehensibility in English as a Lingua Franca: Nativized English in Japanese

The present study examines international intelligibility and comprehensibility of nativized English lexis from Japanese as determined by tertiary student listeners in four countries. After an overview of nativized English in Japanese, form and attitudes, the study queries which linguistic features of Japanized English lexis and short expressions reduce intelligibility and comprehensibility for listeners from Indonesia, the Philippines, South Korea, and the United States. The results indicate that morphological and semantic modifications tend to be more challenging to the Indonesian, Filipino, and US listener groups than phonological ones, while South Korean listeners had an advantage with nativized expressions. Rank orders of the difficulty of individual items tended to be shared by the Filipino and US groups. Listener factors were identified including first language (L1) influence, English proficiency, and sociocultural background. Further considered are linguistic complexity, cultural, and historical linguistic flows, Englishes as dialectal variation, and ELF pronunciation pedagogy

Intravenous versus oral cyclophosphamide for lung and/or skin fibrosis in systemic sclerosis: an indirect comparison from EUSTAR and randomised controlled trials

OBJECTIVES: Both intravenous (IV) and oral (PO) cyclophosphamide (CYC) showed beneficial effects on skin and lung involvement in systemic sclerosis (SSc) in placebo-controlled randomised clinical trials and observational studies. Our goal was to compare the relative efficacy and safety of PO- versus IV-CYC for treating interstitial lung disease and/or skin involvement in SSc. METHODS: Patients were derived from the EUSTAR centres and the Scleroderma Lung Studies I and II. A minimum of 6 months of CYC treatment and 12 months follow-up were required. Serious (SAEs) and non-serious adverse events and efficacy data (change in FVC%, DLCO%, mRSS) were analysed at the end of CYC treatment (EoT) and at follow-up (FU). Analysis included descriptive statistics and linear regressions. RESULTS: Differences in ethnicity, previous DMARD exposure, previous and concomitant steroid exposure/dosage were observed in the PO (n=149) and IV (n=153) CYC groups. Adjusted and unadjusted changes in FVC%, DLCO% and mRSS were similar irrespective of mode of administration. PO patients had more leukopenia (p<0.001), haemorrhagic cystitis (p=0.011) and alopecia (p<0.001) at the EoT visit, while the IV group had more SAEs (p=0.025) and need for oxygen supplementation at FU (p=0.049). CONCLUSIONS: In a comparison of PO- to IV-CYC for SSc, we found no differences in lung function or cutaneous sclerosis after one year. Some differences in side effects were seen. The results need to be considered as preliminary; however, because we needed to use a combination of RCT and registry data, with some differences in demographics and concomitant medications, well-controlled studies are warranted

Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study.

Objective To determine whether joint synovitis and tendon friction rubs (TFRs) can predict the progression of systemic sclerosis (SSc) over time. Patients and methods We performed a prospective cohort study that included 1301 patients with SSc from the EUSTAR database with disease duration 643 years at inclusion and with a follow-up of at least 2 years. Presence or absence at clinical examination of synovitis and TFRs was extracted at baseline. Outcomes were skin, cardiovascular, renal and lung progression. Overall disease progression was defined according to the occurrence of at least one organ progression. Results Joint synovitis (HR: 1.26, 95% CI 1.01 to 1.59) and TFRs (HR: 1.32, 95% CI 1.03 to 1.70) were independently predictive of overall disease progression, as were also the diffuse cutaneous subset (HR: 1.30, 95% CI 1.05 to 1.61) and positive antitopoisomerase-I antibodies (HR: 1.25, 95% CI 1.02 to 1.53). Regarding skin progression, joint synovitis (HR: 1.67, 95% CI 1.06 to 2.64) and TFRs (HR: 1.69, 95% CI 1.02 to 2.77) were also independently predictive of worsening of the modified Rodnan skin score. For cardiovascular progression, joint synovitis was predictive of the occurrence of new digital ulcer(s) (HR: 1.45, 95% CI 1.08 to 1.96) and decreased left ventricular ejection fraction (HR: 2.20, 95% CI 1.06 to 4.57); TFRs were confirmed to be an independent predictor of scleroderma renal crisis (HR: 2.33, 95% CI 1.03 to 6.19). Conclusions Joint synovitis and TFRs are independent predictive factors for disease progression in patients with early SSc. These easily detected clinical markers may b

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort.

OBJECTIVES Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. METHODS We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. RESULTS We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p &lt;0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1&ndash;12) Swiss vs 6.0 years (2&ndash;12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. CONCLUSION This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis