OBJECTIVE: The objective of this study is to evaluate whether adding oral glucocorticoids to immunosuppressive therapy improves skin scores and ensures safety in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We performed an emulated randomized trial comparing the changes from baseline to 12 ± 3 months of the modified Rodnan skin score (mRSS: primary outcome) in patients with early dcSSc receiving either oral glucocorticoids (≤20 mg/day prednisone equivalent) combined with immunosuppression (treated) or immunosuppression alone (controls), using data from the European Scleroderma Trials and Research Group. Secondary end points were the difference occurrence of progressive skin or lung fibrosis and scleroderma renal crisis. Matching propensity score was used to adjust for baseline imbalance between groups. RESULTS: We matched 208 patients (mean age 49 years; 33% male; 59% anti-Scl70), 104 in each treatment group, obtaining comparable characteristics at baseline. In the treated group, patients received a median prednisone dose of 5 mg/day. Mean mRSS change at 12 ± 3 months was similar in the two groups (decrease of 2.7 [95% confidence interval {95% CI} 1.4-4.0] in treated vs 3.1 [95% CI 1.9-4.4] in control, P = 0.64). Similar results were observed in patients with shorter disease duration (≤ 24 months) or with mRSS ≤22. There was no between-group difference for all prespecified secondary outcomes. A case of scleroderma renal crisis occurred in both groups. CONCLUSION: We did not find any significant benefit of adding low-dose oral glucocorticoids to immunosuppression for skin fibrosis, and at this dosage, glucocorticoid did not increase the risk of scleroderma renal crisis.

• MeSH
• aplikace orální MeSH
• databáze faktografické MeSH
• difuzní sklerodermie * farmakoterapie   patologie   diagnóza   MeSH
• dospělí MeSH
• fibróza MeSH
• glukokortikoidy * aplikace a dávkování   škodlivé účinky   MeSH
• imunosupresiva * aplikace a dávkování   škodlivé účinky   MeSH
• kombinovaná farmakoterapie MeSH
• kůže * patologie   účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prednison * aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa MeSH

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

• MeSH
• biologické markery * krev   MeSH
• biopsie MeSH
• difuzní sklerodermie * farmakoterapie   patologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fibróza farmakoterapie   MeSH
• guanosinmonofosfát cyklický krev   metabolismus   MeSH
• kůže * patologie   účinky léků   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pyrazoly * terapeutické užití   MeSH
• pyrimidiny * terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year. METHODS: Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762. FINDINGS: In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease. INTERPRETATION: No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study. FUNDING: Bayer and Merck Sharp & Dohme.

• MeSH
• difuzní sklerodermie * farmakoterapie   MeSH
• lidé MeSH
• pacienti MeSH
• pyrazoly škodlivé účinky   MeSH
• pyrimidiny * MeSH
• výzkumný projekt MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Early stage of osteoarthritis (OA) is characterized by joint stiffness and pain as well as by subclinical structural changes that may affect cartilage, synovium, and bone. At the moment, the lack of a validated definition of early osteoarthritis (EOA) does not allow to make an early diagnosis and adopt a therapeutic strategy to slow disease progression. Also, no questionnaires are available to evaluate the early stage, and therefore this remains an unmet need. OBJECTIVE: Therefore, the purpose of the technical experts panel (TEP) of 'International Symposium of intra-articular treatment' (ISIAT) was to create a specific questionnaire to evaluate and monitor the follow-up and clinical progress of patients affected by early knee OA. DESIGN: The items for the Early Osteoarthritis Questionnaire (EOAQ) were identified according to the following steps: items generation, items reduction, and pre-test submission. METHODS: During the first step, literature has been reviewed and a comprehensive list of items about pain and function in knee EOA was drafted. Then, during the ISIAT (5th edition 2019), the draft has been discussed by the board, which reformulated, deleted, or subdivided some of the items. After the ISIAT symposium, the draft was submitted to 24 subjects affected by knee OA. A score based on the importance and the frequency was created and the items with a score ⩾0.75 were selected. After intermediate evaluation made by a sample of patients, the second and final version of the questionnaire EOAQ was submitted to the whole board for final analysis and acceptance in a second meeting (29 January 2021). RESULTS: After an exhaustive elaboration, the final version of the questionnaire contains two domains (Clinical Features and Patients Reported Outcome) with respectively 2 and 9 questions, for a total of 11 questions. Questions mainly explored the fields of early symptoms and patients reported outcomes. Marginally, the need of the symptoms treatment and the use of painkillers were investigated. CONCLUSIONS: Adoption of diagnostic criteria of early OA is strongly encouraged and a specific questionnaire for the whole management of the clinical features and patients' outcome might really improve the evolution of OA in the early stages of the disease, when the treatment is expected to be more effective.

• Publikační typ
• časopisecké články MeSH

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

• MeSH
• aktivátory enzymů aplikace a dávkování   MeSH
• difuzní sklerodermie farmakoterapie   patologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hodnocení rizik MeSH
• imunohistochemie MeSH
• internacionalita MeSH
• jehlová biopsie MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• neúspěšná terapie MeSH
• pyrazoly aplikace a dávkování   MeSH
• pyrimidiny aplikace a dávkování   MeSH
• respirační funkční testy MeSH
• rozvrh dávkování léků MeSH
• stupeň závažnosti nemoci MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

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.

• MeSH
• časové faktory MeSH
• databáze faktografické MeSH
• lidé středního věku MeSH
• lidé MeSH
• příčina smrti MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• rizikové faktory MeSH
• senioři MeSH
• systémová sklerodermie mortalita   MeSH
• úmrtní listy MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Francie MeSH

• MeSH
• systémová sklerodermie diagnóza   komplikace   patofyziologie   terapie   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• revmatologie
• dermatovenerologie

• MeSH
• dítě MeSH
• dospělí MeSH
• klinické lékařství MeSH
• lokalizovaná sklerodermie diagnóza   klasifikace   terapie   MeSH
• nemoci kůže a pojivové tkáně terapie   MeSH
• Raynaudova nemoc farmakoterapie   MeSH
• systémová sklerodermie diagnóza   klasifikace   terapie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• dermatovenerologie
• revmatologie

• MeSH
• atrofie klasifikace   MeSH
• Borrelia burgdorferi imunologie   MeSH
• genetické nemoci vrozené MeSH
• klinické lékařství MeSH
• lokalizovaná sklerodermie genetika   imunologie   patofyziologie   MeSH
• myalgický syndrom s eozinofilií MeSH
• systémová sklerodermie genetika   imunologie   patofyziologie   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• dermatovenerologie
• revmatologie