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

OBJECTIVE: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. METHODS: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. RESULTS: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. CONCLUSION: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

• Publikační typ
• časopisecké články 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

OBJECTIVES: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. METHODS: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians' and the patients' global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. RESULTS: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. CONCLUSION: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.

• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (SSc) patients in the international juvenile SSc inception cohort, and to compare these characteristics between the classically defined juvenile diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) subtypes and among those with overlap features. METHODS: A cross-sectional study was performed using baseline visit data. Information on demographic characteristics, organ system evaluation, treatment, and patient- and physician-reported outcomes was extracted and summary statistics applied. Comparisons between juvenile dcSSc and lcSSc subtypes and patients with and without overlap features were performed using chi-square and Mann-Whitney U tests. RESULTS: At data extraction, 150 juvenile SSc patients were enrolled across 42 centers; 83% were White, 80% were female, juvenile dcSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between juvenile dcSSc and juvenile lcSSc regarding modified Rodnan skin thickness score, the presence of Gottron's papules, digital tip ulceration, results of the 6-minute walk test, and composite pulmonary and cardiac involvement. All of these were more frequent in dcSSc except for cardiac involvement. Juvenile dcSSc patients had significantly worse scores for physician-rated disease activity and damage. A significantly higher occurrence of Gottron's papules and musculoskeletal and composite pulmonary involvement, and a significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features. CONCLUSION: Results from a large international juvenile SSc cohort demonstrate significant differences between juvenile dcSSc and juvenile lcSSc patients, including more globally severe disease and increased frequency of interstitial lung disease in juvenile dcSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease.

• MeSH
• difuzní sklerodermie * diagnóza   MeSH
• intersticiální plicní nemoci * MeSH
• kožní vředy * MeSH
• lidé MeSH
• lokalizovaná sklerodermie MeSH
• průřezové studie MeSH
• systémová sklerodermie * diagnóza   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Systémová progresivní skleróza je autoimunitní onemocnění nejasné etiologie charakterizované vaskulopatií a fibrózou. Výskyt maligních nádorů u pacientů s tímto závažným onemocněním je vyšší než u běžné populace. Příčina této predispozice není dosud jasně definována. V naší práci uvádíme případ pacientky se systémovou progresivní sklerózou, u níž byl diagnostikován orofaryngeální karcinom. Cílem práce je upozornit na komplikace v diagnostické rozvaze a terapii u souběžně probíhajícího systémového autoimunitního a nádorového onemocnění.

Systemic progressive sclerosis is an autoimmune disease of unclear etiology characterized by vasculopathy and fibrosis. The incidence of malignancies in patients with this serious disease is higher than in the general population. The cause of this predisposition is not yet clearly defined. In our case we present a patient with systemic progressive sclerosis who was diagnosed with oropharyngeal carcinoma. The aim of this work is to draw attention to the complications in differential diagnosis and therapy in concurrent systemic autoimmune and cancer.

• MeSH
• difuzní sklerodermie * komplikace   MeSH
• jazyk patologie   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• nádory orofaryngu * chirurgie   diagnostické zobrazování   komplikace   radioterapie   MeSH
• obličej patologie   MeSH
• odmítnutí terapie pacientem MeSH
• PET/CT MeSH
• poruchy polykání MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

• MeSH
• C-reaktivní protein metabolismus   MeSH
• cyklofosfamid terapeutické užití   MeSH
• dermatitida metabolismus   MeSH
• difuzní kapacita plic účinky léků   MeSH
• dospělí MeSH
• imunosupresiva terapeutické užití   MeSH
• intersticiální plicní nemoci krev   farmakoterapie   etiologie   MeSH
• kůže patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• oxid uhelnatý metabolismus   MeSH
• plíce patofyziologie   MeSH
• prospektivní studie MeSH
• proteiny tepelného šoku HSP90 krev   MeSH
• průřezové studie MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie krev   komplikace   farmakoterapie   MeSH
• vitální kapacita účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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

Souhrn: Úvod: Systémová sklerodermie (SSc – systemic sclerosis) je autoimunitní onemocnění s chronickým progresivním průběhem. Patogeneze SSc je charakterizována zánětem, vaskulopatií a fibrózou. Mezi nejčastěji postižené orgány patří gastrointestinální trakt, a to až u 90 % nemocných. Klinické projevy jsou spojeny s dysmotilitou všech částí gastrointestinálního traktu, vč. žaludku. Elektrogastrografie (EGG) je neinvazivní metoda pro vyšetření žaludeční myoeletrické aktivity. Cíl: Cílem této prospektivní studie bylo podrobně posoudit EGG u SSc, vč. analýzy jednominutových intervalů a plochy amplitud. Metoda: Do studie bylo zařazeno 33 pacientů splňujících klasifikační kritéria SSc podle ACR/EULAR (5 mužů, 28 žen; průměrný věk 60 let). Pacienti byli rozděleni na klinické podskupiny: difúzní kožní forma SSc (dSSc) (n = 17), limitovaná kožní forma (lSSc) (n = 13) a ostatní (n = 3). Žaludeční myoelektrická aktivita byla vyšetřována pomocí EGG (MMS, Enschede, Nizozemsko). Výsledky: Celkem bylo vyhodnoceno 855 jednominutových intervalů EGG, u každého z nich byla hodnocena dominantní frekvence a posouzena plocha amplitud. Pouze jeden pacient měl plně normální EGG záznam. U většiny pacientů se EGG vyznačovala bradygastrií (17 pacientů) nebo žaludeční arytmií s převahou bradygastrie (6 pacientů). Postprandiální plocha amplitud se výrazně snížila ve srovnání s hodnotami nalačno. Poměr ploch amplitud po jídle: před jídlem byl ve všech intervalech nízký. Závěr: Bradygastrie a postprandiální snížení plochy amplitud byly nejcharakterističtějšími nálezy. Tyto změny byly obzvlášť vyjádřené u skupiny dSSc.

Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a chronic progressive course. Inflammation, vasculopathy and fibrosis play an important role in the pathogenesis of SSc. Gastrointestinal tract belongs to the most commonly affected organ systems and its involvement can be observed in up to 90% of individuals. Clinical manifestations are associated with dysmotility of all segments of the gastrointestinal tract, including the stomach. Electrogastrography (EGG) is a non-invasive method used for the assessment of gastric myoelectrical activity. Aim: The aim of this prospective study was to investigate EGG in SSc patients in detail, including the analysis of one-minute intervals and assessment of EGG power. Method: The study included 33 patients that fulfilled SSc ACR/EULAR classification criteria (5 men, 28 women; mean age 60 years). Patients suffered from a diffuse cutaneous form of SSc (dSSc) (N = 17), limited cutaneous form (lSSc) (N = 13) or they belonged to other subgroups (N = 3). The gastric myoelectric activity was investigated by means of an EGG Stand (MMS, Enschede, The Netherlands). Results: Altogether 855 one-minute EGG intervals were evaluated, each one of them in dominant frequency, power and power ratio. Only one patient had a completely normal EGG. The EGG of most patients showed bradygastria (17 subjects) or gastric arrhythmia with a predominance of bradygastria (6 patients). The postprandial power decreased significantly. The power ratio was low in all intervals. Conclusion: Bradygastria and the postprandial decrease of power were the most characteristic features. These findings were confirmed especially in dSSc subgroup.

• Klíčová slova
• elektrogastrografie,
• MeSH
• diagnostické techniky gastrointestinální MeSH
• dospělí MeSH
• elektrodiagnostika * metody   MeSH
• gastrointestinální motilita fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• migrující myoelektrický komplex MeSH
• mladý dospělý MeSH
• pilotní projekty MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• systémová sklerodermie * diagnóza   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH