IntroductionThe rarity of systemic sclerosis (SSc) and its widely heterogeneous presentation and disease course are the main limitations for clinical research. The European Scleroderma Trials and Research group (EUSTAR) was launchegd in 2004, aiming to unify research efforts in the field of SSc. The central EUSTAR database has grown exponentially over the years, promoting new research and clinical trials, shedding new light on SSc diagnosis, its clinical course and providing new ideas for state-of-the-art therapy.Areas covered: The authors summarized the key findings of the main EUSTAR studies by reviewing PubMed and Web-of-Science databases through July 2020. The authors focused on the very early diagnosis of SSc, the prediction of disease course and mortality, the evaluation of disease activity and quality of life, the general management and therapy.Expert opinionThe findings elucidated in EUSTAR studies have substantially improved the diagnostic and therapeutic approach to SSc in the last 15 years. Further efforts are warranted to identify early prognostic markers of the disease and stratify patients who may benefit most from vasoactive, immunosuppressive, and/or antifibrotic therapy. This will be particularly important in leading the future of SSc toward precision medicine and to promote more targeted clinical trials.

•Squamous Cell Carcinoma Antigen (SCCA-IgM) is associated with interstitial lung disease (ILD) in systemic sclerosis (SSc).•SCCA-IgM seems able to improve the diagnostic performance of total lung capacity (TLC), identifying patients with a very low risk of SSc-ILD.•SCCA-IgM could be particularly useful in the early assessment of SSc-ILD.

ObjectiveTo determine the prevalence of lower urinary tract symptoms (LUTS) in systemic sclerosis (SSc), to find specific risk factors, and to assess their impact on quality of life (QoL).MethodsIn a multicenter study, 334 patients completed a self‐administered questionnaire on LUTS and QoL. LUTS were classified into 3 main categories: storage, voiding, and post‐micturition symptoms. Digestive symptoms burden was captured by a visual analog scale, divided into 5 equal categories. Multivariable logistic regressions were performed to test association between risk factors and LUTS categories. Linear regression adjusted the association between LUTS and QoL.ResultsLUTS were recorded in 311 SSc patients (96.0%) and classified as severe in 120 (38.0%). The storage category of LUTS was the most prevalent (91.9%), followed by voiding (72.2%) and then by post‐micturition symptoms (49.8%). Risk factors identified in the multivariable models were higher than the median Health Assessment Questionnaire disability index (HAQ DI; odds ratio [OR] 4.2 [95% confidence interval (95% CI) 1.4–12.9]) in the storage category; higher than the median HAQ DI (OR 2.4 [95% CI 1.2–4.9]) for digestive symptoms burden (OR 1.9 [95% CI 1.3–2.7]) and synovitis (OR 4.8 [95% CI 1.0–22.6) in the voiding category; and higher for digestive symptoms burden (OR 1.2 [95% CI 1.0–1.5]) in the post‐micturition category of symptoms. These factors also increased the odds of having further severe symptoms. QoL was affected by the 3 categories of LUTS and decreased progressively with increasing frequency of symptoms.ConclusionSelf‐reported LUTS are among the most frequent symptoms in SSc and are associated with digestive symptoms. SSc patients with LUTS have lower QoL.

Cyclopentadienone-based iron complexes were used for the first time to successfully catalyze the diastereoselective hydrogenation of enantiopure imines. Chiral amines, including valuable biologically active products, were obtained often as enantiomerically pure compounds. Computational studies helped to elucidate the chemical and stereochemical aspects of the iron-catalyzed reaction.

Objectives:The aim of this study was to explore the association between urinary incontinence (UI) and the main clinical and serological subsets of SSc, to assess risk factors for UI and its impact on quality of life (QoL).Methods:UI and QoL were assessed through self-administered questionnaires in 334 patients with SSc from five European tertiary centres. Logistic regressions were performed to test the association between clinical forms, serological status and UI and to adjust for confounders. Further independent predefined SSc risk factors for UI were tested through a multivariable logistic model.Results:The prevalence of UI was 63% (95% CI: 60, 68%). lcSSc and ACAs were both significantly associated with UI even after adjusting for age, sex, disability, diabetes, BMI, caffeine consumption, dyspnoea, faecal incontinence, abnormal bowel movement, presence of overlapping rheumatological disease and pulmonary hypertension [adjusted odds ratio (OR) = 2.4; 95% CI: 1.2, 4.7]. ACA and lcSSc doubled the risk of frequent and heavy urinary leaks. Factors independently associated with UI were as follows: lcSSc (OR = 2.2; 95% CI: 1.1, 3.2), ACA (OR = 2.8; 95% CI: 1.4, 5.8), female sex (OR = 10.8; 95% CI: 2.8, 41.3), worsening of dyspnoea (OR = 6.8; 95% CI: 1.2, 36.7), higher HAQ-DI (OR = 3.2; 95% CI: 1.5, 6.7), BMI (OR = 1.1; 95% CI: 1.0, 1.1) and active finger ulceration (OR = 0.3; 95% CI: 0.1, 0.7). Patients suffering from UI had decreased QoL.Conclusion:Self-reported UI is frequent in SSc and disproportionally affects the limited cutaneous form of the disease and patients positive for ACA.Trial registration:ClinicalTrials.gov, http://clinicaltrials.gov, NCT01971294.

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.

An S-(2,2,2-trifluoroethyl) 1,3-dithiane-2-carbothioate has been successfully employed as acyl anion synthon in the organocatalytic enantioselective addition to enones promoted by quinine- and quinidine-derived tertiary/primary diamines. By proper selection of a co-catalyst and by optimization of the reaction parameters, convenient experimental conditions were found that allowed to obtain the highly functionalized products in up to 90% yield and 98% ee in short reaction times. These compounds, featuring selectively removable functionalities, proved to be versatile synthetic intermediates, which could be transformed into different derivatives without any erosion of the stereochemical integrity of the molecules.

The mechanism of a recently reported, highly chemoselective metal-free protocol of wide general applicability for the reduction of aromatic and aliphatic nitro-derivatives to amines has been investigated. The reaction is supposed to occur through the generation of a Si(II) reducing species; quantum mechanical calculations, and spectroscopic and experimental data strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.

The stereoselective direct aldol reaction of S-phenyl thioesters and aromatic aldehydes promoted by tetrachlorosilane was realized for the first time; the proposed mechanism involves the formation of a chiral cationic hypervalent silicon species and requires the presence of catalytic amounts of a Lewis base, like a chiral phosphine oxide. The reaction affords syn -hydroxy thioesters as major isomers in good yields, high diastereoselectivity (up to 99:1), and up to 92% enantiomeric excess. The absolute configuration of the major isomer was established by converting the product into the corresponding -hydroxy ester. The scope of the reaction was also investigated by employing differently substituted thioesters in combination with different aromatic aldehydes.