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BACKGROUND: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc). METHODS: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression. RESULTS: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups. CONCLUSION: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals.
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Extensive extracellular matrix production and increased cell-matrix adhesion by bone marrow stromal cells (BMSCs) are hallmarks of fibrotic alterations in the vertebral bone marrow known as Modic type 1 changes (MC1). MC1 are associated with non-specific chronic low-back pain. To identify treatment targets for MC1, in vitro studies using patient BMSCs are important to reveal pathological mechanisms. For the culture of BMSCs, fibroblast growth factor 2 (FGF2) is widely used. However, FGF2 has been shown to suppress matrix synthesis in various stromal cell populations. The aim of the present study was to investigate whether FGF2 affected the in vitro study of the fibrotic pathomechanisms of MC1-derived BMSCs. Transcriptomic changes and changes in cell-matrix adhesion of MC1-derived BMSCs were compared to intra-patient control BMSCs in response to FGF2. RNA sequencing and quantitative real-time polymerase chain reaction revealed that pro-fibrotic genes and pathways were not detectable in MC1-derived BMSCs when cultured in the presence of FGF2. In addition, significantly increased cell-matrix adhesion of MC1-derived BMSCs was abolished in the presence of FGF2. In conclusion, the data demonstrated that FGF2 overrides key pro-fibrotic features of MC1 BMSCs in vitro. Usage of FGF2-supplemented media in studies of fibrotic mechanisms should be critically evaluated as it could override normally dominant biological and biophysical cues.
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Fator 2 de Crescimento de Fibroblastos , Células-Tronco Mesenquimais , Medula Óssea , Células da Medula Óssea , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Células EstromaisRESUMO
Modic type 1 changes (MC1) are painful vertebral bone marrow lesions frequently found in patients suffering from chronic low-back pain. Marrow fibrosis is a hallmark of MC1. Bone marrow stromal cells (BMSCs) are key players in other fibrotic bone marrow pathologies, yet their role in MC1 is unknown. The present study aimed to characterise MC1 BMSCs and hypothesised a pro-fibrotic role of BMSCs in MC1. BMSCs were isolated from patients undergoing lumbar spinal fusion from MC1 and adjacent control vertebrae. Frequency of colony-forming unit fibroblast (CFU-F), expression of stem cell surface markers, differentiation capacity, transcriptome, matrix adhesion, cell contractility as well as expression of pro-collagen type I alpha 1, α-smooth muscle actin, integrins and focal adhesion kinase (FAK) were compared. More CFU-F and increased expression of C-X-C-motif-chemokine 12 were found in MC1 BMSCs, possibly indicating overrepresentation of a perisinusoidal BMSC population. RNA sequencing analysis showed enrichment in extracellular matrix proteins and fibrosis-related signalling genes. Increases in pro-collagen type I alpha 1 expression, cell adhesion, cell contractility and phosphorylation of FAK provided further evidence for their pro-fibrotic phenotype. Moreover, a leptin receptor high expressing (LEPRhigh) BMSC population was identified that differentiated under transforming growth factor beta 1 stimulation into myofibroblasts in MC1 but not in control BMSCs. In conclusion, pro-fibrotic changes in MC1 BMSCs and a LEPRhigh MC1 BMSC subpopulation susceptible to myofibroblast differentiation were found. Fibrosis is a hallmark of MC1 and a potential therapeutic target. A causal link between the pro-fibrotic phenotype and clinical characteristics needs to be demonstrated.
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Fibrose/fisiopatologia , Células-Tronco Mesenquimais/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiologia , Feminino , Fibrose/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/fisiologia , Fenótipo , Transdução de Sinais/fisiologiaRESUMO
A 30-year-old patient presented with bilateral shoulder pain, hematoma of the upper arm and livid discoloration of the tongue. Blood analysis showed an increase in creatine kinase and inflammatory markers. Screening for immunological and infection markers were negative. Under the suspicion of systemic vasculitis, a positron emission tomography-computed tomography (PET-CT) scan was performed, which instead revealed fractures of the greater tuberosities of both humeri and a suspicious brain lesion. A secondary generalized epileptic seizure due to a World Health Organization (WHO) grade III astrocytoma with subsequent traumatic luxation and fracture of both shoulders, hemarthrosis and tongue bite was diagnosed.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Dor de Ombro , Adulto , Diagnóstico Diferencial , Humanos , Dor de Ombro/diagnósticoRESUMO
OBJECTIVE: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years' duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. METHOD: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud's SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud's phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31-59, and ≥ 60 years. We performed descriptive and bivariate analyses. RESULTS: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud's. CONCLUSION: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice.
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Sistema de Registros , Escleroderma Sistêmico/epidemiologia , Adulto , Distribuição por Idade , Fatores Etários , Idade de Início , Estudos Transversais , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Escleroderma Sistêmico/diagnóstico , Distribuição por SexoRESUMO
Systemic sclerosis is a rare rheumatologic disease that is characterised by skin and organ fibrosis as well as vascular changes and the occurrence of specific autoantibodies. It has a high morbidity and mortality while its manifestations show significant heterogeneity in patients. Thus, diagnosis and follow-up of patients with systemic sclerosis has to be extensive, the more so because treatment must be adapted to organ manifestations. Although specific therapies for gastrointestinal, pulmonary or vascular complications exist, patients respond only partly to these and new therapeutic approaches are still needed.
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Escleroderma Sistêmico , Autoanticorpos , Fibrose , Humanos , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , PeleRESUMO
Systemic sclerosis is a rare rheumatologic disease that is characterised by skin and organ fibrosis as well as vascular changes and the occurrence of specific autoantibodies. It has a high morbidity and mortality while its manifestations show significant heterogeneity in patients. Thus, diagnosis and follow-up of patients with systemic sclerosis has to be extensive, the more so because treatment must adapted to organ manifestations. Although specific therapies for gastrointestinal, pulmonary or vascular complications exist, patients respond only partly to these and new therapeutic approaches are still needed.
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Escleroderma Sistêmico , Autoanticorpos , Fibrose , Humanos , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , PeleRESUMO
Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.
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Classificação Internacional de Doenças/normas , Reumatologia/normas , Escleroderma Sistêmico/classificação , Escleroderma Sistêmico/diagnóstico , Terminologia como Assunto , Tradução , Alemanha , Guias de Prática Clínica como AssuntoRESUMO
Objectives: Modic type 1 changes (MC1) are vertebral endplate bone marrow (BM) lesions observed on magnetic resonance images in sub-populations of chronic low back pain (CLBP) patients. The etiopathogenesis remains unknown and treatments that modify the underlying pathomechanisms do not exist. We hypothesized that two biological MC1 subtypes exist: a bacterial and a non-bacterial. This would have important implications for developing treatments targeting the underlying pathomechanisms. Methods: Intervertebral disc (IVD) samples adjacent to MC1 (n â= â34) and control (n â= â11) vertebrae were collected from patients undergoing spinal fusion. Cutibacterium acnes (C.acnes) genome copy numbers (GCNs) were quantified in IVD tissues with 16S qPCR, transcriptomic signatures and cytokine profiles were determined in MC1 and control BM by RNA sequencing and immunoassay. Finally, we assessed if C.acnes GCNs are associated with blood plasma cytokines. Results: IVD tissues from control levels had <870 âC.acnes GCNs/gram IVD. MC1-adjacent IVDs had either "low" (<870) or "high" (>870) C.acnes GCNs. MC1 patients with "high" C.acnes GCNs had upregulated innate immune cell signatures (neutrophil, macrophage/monocyte) and pro-inflammatory cytokines related to neutrophil and macrophage/monocyte function in the BM, consistent with a host defense against bacterium. MC1 patients with "low" C.acnes GCNs had increased adaptive immune cell signatures (T-and B-cell) in the BM and elevated IL-13 blood plasma levels. Conclusion: Our study provides the first evidence for the existence of bacterial (C.acnes "high") and non-bacterial (C.acnes "low") subtypes in MC1 patients with CLBP. This supports the need for different treatment strategies.
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BACKGROUND: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) reported in systemic sclerosis (SSc). Especially due to low prevalence, the clinical relevance of NOR90 in SSc remains uncertain. OBJECTIVES: To analyze the clinical associations of NOR90 in patients with SSc in a multicentric cohort. METHODS: Post-hoc, cross-sectional study of prospectively collected data from the European Scleroderma Trials and Research (EUSTAR) database, with additional information on NOR90. Further, we performed a systematic literature search, using the terms "systemic sclerosis" and "NOR90" across three databases: Medline via PubMed, Scopus, and Thomson Reuters' Web of Science Core Collection, from inception to November 1st, 2023. RESULTS: Overall, 1318 patients with SSc were included (mean age 58.3 ± 13.7 years, 81.3 % female), of whom 44 (3.3 %) were positive for NOR90. Of these, 32 were also positive for one of the SSc-criteria antibodies: 9/44 (20.5 %) for anti-topoisomerase I, 18/42 (42.9 %) for anti-centromere, and 5/40 (12.5 %) for anti-RNA polymerase III. NOR90-positive patients were more frequently female, had lower modified Rodnan skin score (mRSS), and lower prevalence of upper and lower gastrointestinal (GI) symptoms compared to NOR90-negative patients. In multivariable analysis, NOR90 remained significantly associated with lower mRSS and less frequent GI symptoms. The literature search identified 17 articles, including a total number of 87 NOR90-positive out of 3357 SSc patients, corresponding to an overall prevalence of 2.6 %. CONCLUSION: To our best knowledge, this is the largest SSc cohort tested for NOR90 to date, confirming the NOR90 prevalence in SSc patients is around 3 %.
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Anticorpos Antinucleares , Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/imunologia , Anticorpos Antinucleares/sangue , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Estudos Transversais , Adulto , Europa (Continente) , DNA Topoisomerases Tipo I/imunologia , Relevância ClínicaRESUMO
Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Of the numerous organ manifestations, involvement of the upper and lower gastrointestinal tract (GIT) appears to be the most frequent with regard to the clinical symptoms. However, as the frequency and clinical relevance of GI involvement in patients with SSc are not known in detail, the German network of the systemic sclerosis (DNSS) has developed a detailed questionnaire to evaluate the extent and profile of gastrointestinal involvement in SSc patients. The multi-symptom questionnaire was used at baseline and after 1 year in registered patients of the DNSS. In addition, the results were compared with gastrointestinal disorders in patients with SSc and other rheumatic diseases, as well as with the medical history of the patients. In total, 90 patients were included in the study. The results of the study show that in reality, a much higher (nearly all) percentage of (98,9%) patients than expected suffer from GI-symptoms, regardless of the stage of their disease. Of these, meteorism (87,8%) was the most common followed by coughing/sore voice (77,8%), heartburn (daytime 68,9%, nighttime 53,3%), diarrhea (67,8%), stomach ache (68,9%) and nausea (61,1%). Although SSc patients were treated according to the respective recommendations, only limited improvements with regard to GI-symptoms could be achieved after 1 year of follow-up. In addition, the study revealed that the multi-symptom questionnaire is a useful tool to contribute to identify the gastrointestinal sequelae in systemic sclerosis.
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Gastroenteropatias/epidemiologia , Doença Mista do Tecido Conjuntivo/epidemiologia , Esclerodermia Difusa/epidemiologia , Esclerodermia Limitada/epidemiologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Gastroenteropatias/diagnóstico , Gastroenteropatias/terapia , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença Mista do Tecido Conjuntivo/terapia , Prognóstico , Sistema de Registros , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/terapia , Esclerodermia Limitada/diagnóstico , Esclerodermia Limitada/terapia , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de TempoRESUMO
OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.
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Escleroderma Sistêmico/diagnóstico , Anticorpos Antinucleares/sangue , Técnica Delphi , Diagnóstico Diferencial , Diagnóstico Precoce , Edema/etiologia , Dedos , Humanos , Angioscopia Microscópica , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Dermatopatias/etiologiaRESUMO
Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins. Unexpectedly, protease inhibitors also inhibited the secretion of apolipoprotein B. This was associated with inhibition of cholesteryl-ester synthesis and microsomal triglyceride transfer-protein activity. However, in the presence of oleic acid, which stimulates neutral-lipid biosynthesis, protease-inhibitor treatment increased secretion of apolipoprotein B-lipoproteins above controls. These findings suggest a molecular basis for protease-inhibitor-associated hyperlipidemia, a serious adverse effect of an otherwise efficacious treatment for HIV infection.
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Apolipoproteínas B/metabolismo , Cisteína Endopeptidases/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Hiperlipidemias/etiologia , Complexos Multienzimáticos/efeitos dos fármacos , Animais , Transporte Biológico , Ésteres do Colesterol/metabolismo , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/efeitos adversos , Humanos , Hiperlipidemias/induzido quimicamente , Lipoproteínas/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Ácido Oleico/farmacologia , Complexo de Endopeptidases do Proteassoma , Ratos , Inibidores da Transcriptase Reversa/farmacologia , Triglicerídeos/metabolismo , Células Tumorais CultivadasRESUMO
Systemic sclerosis (SSc) is a fibrosing connective tissue disease with significantly increased mortality. Therapeutic options to treat fibrosis are limited. The small molecule tyrosine kinase inhibitor imatinib and related drugs such as dasatinib and nilotinib target simultaneously two of the major profibrotic pathways, TGFbeta- and PDGF- signaling. Imatinib, dasatinib and nilotinib inhibit collagen synthesis in cultured fibroblasts and have potent anti-fibrotic effects in animal models of different fibrotic diseases. Moreover, several case reports, case series and uncontrolled studies on patients with SSc, mixed connective tissue disease, nephrogenic systemic fibrosis and in particular sclerodermatous graft versus host disease (cGvHD) report regression of fibrosis and good tolerability. However, the results of larger controlled trials, which are currently ongoing, are needed before any conclusions on efficacy and tolerability can be drawn. Until the results of these trials are available, we discourage off-label use of Imatinib in single patients.
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Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Escleroderma Sistêmico/tratamento farmacológico , Benzamidas , Fibrose/tratamento farmacológico , Humanos , Mesilato de Imatinib , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Pirimidinas/uso terapêutico , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidoresRESUMO
OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.
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Escleroderma Sistêmico/complicações , Disfunção Ventricular Esquerda/etiologia , Adulto , Fatores Etários , Idoso , Bloqueadores dos Canais de Cálcio/uso terapêutico , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Feminino , Dedos , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/complicações , Miosite/epidemiologia , Escleroderma Sistêmico/epidemiologia , Fatores Sexuais , Úlcera Cutânea/complicações , Úlcera Cutânea/epidemiologia , Volume Sistólico , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/prevenção & controleRESUMO
Systemic sclerosis (scleroderma, SSc) and mixed connective tissue disease (MCTD) are chronic autoimmune diseases characterised by a broad spectrum of clinical manifestations including different forms of musculoskeletal involvement, skin and vascular changes, as well as internal organ complications. Clinical course and outcomes might vary from mild forms with good clinical prognosis to severe rapidly progressive life-threatening diseases. At present, immunosuppressive therapies are considered a cornerstone in the treatment of MCTD, and are frequently used in clinical practice in SSc despite limited evidence from clinical trials. The aim of the present review is to discuss available data concerning efficacy of methotrexate therapy in SSc and MCTD.
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Anti-Inflamatórios/uso terapêutico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Doença Mista do Tecido Conjuntivo/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Medicina Baseada em Evidências , Humanos , Resultado do TratamentoRESUMO
Scleroderma (synonyms: systemic sclerosis, systemic scleroderma) is a systemic disease which affects the skin as well as internal organs such as the lungs, gastrointestinal tract, kidneys, and the heart. Pathogenetically a distinction should be made between uncontrolled formation of extracellular matrix proteins (fibrosis) and vasculopathy. In addition to organ fibrosis, this leads to a clinical picture of vascular manifestations. These include fingertip ulcers, pulmonary arterial hypertension, and acute renal crisis. Localized forms of scleroderma, such as morphea, which do not involve organ complications, should be differentiated from systemic sclerosis. Due to its clinical heterogeneity and high rate of morbidity and mortality, systemic sclerosis poses an enormous diagnostic and therapeutic challenge in everyday clinical practice. This review article summarizes the current status of classification and epidemiology, pathogenesis, and the most important clinical manifestations such as interstitial fibrosis, pulmonary arterial hypertension, acute renal crisis, and peripheral vasculopathy and provides an overview of current and future treatment options.
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Padrões de Prática Médica/tendências , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , HumanosRESUMO
OBJECTIVES: To investigate the effect of ACE inhibitors (ACEi) on the incidence of scleroderma renal crisis (SRC) when given prior to SRC in the prospectively collected cohort from the European Scleroderma Trial and Research Group (EUSTAR). METHODS: SSc patients without prior SRC and at least one follow-up visit were included and analyzed regarding SRC, arterial hypertension, and medication focusing on antihypertensive medication and glucocorticoids (GC). RESULTS: Out of 14,524 patients in the database, we identified 7648 patients with at least one follow-up. In 27,450 person-years (py), 102 patients developed SRC representing an incidence of 3.72 (3.06-4.51) per 1000 py. In a multivariable time-to-event analysis adjusted for age, sex, disease severity, and onset, 88 of 6521 patients developed SRC. The use of ACEi displayed an increased risk for the development of SRC with a hazard ratio (HR) of 2.55 (95% confidence interval (CI) 1.65-3.95). Adjusting for arterial hypertension resulted in a HR of 2.04 (95%CI 1.29-3.24). There was no evidence for an interaction of ACEi and arterial hypertension (HR 0.83, 95%CI 0.32-2.13, p = 0.69). Calcium channel blockers (CCB), angiotensin receptor blockers (ARB), endothelin receptor antagonists, and GC-mostly in daily dosages below 15 mg of prednisolone-did not influence the hazard for SRC. CONCLUSIONS: ACEi in SSc patients with concomitant arterial hypertension display an independent risk factor for the development of SRC but are still first choice in SRC treatment. ARBs might be a safe alternative, yet the overall safety of alternative antihypertensive drugs in SSc patients needs to be further studied.
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Injúria Renal Aguda/diagnóstico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão Renal/diagnóstico , Escleroderma Sistêmico/tratamento farmacológico , Injúria Renal Aguda/epidemiologia , Idoso , Europa (Continente)/epidemiologia , Feminino , Humanos , Hipertensão Renal/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Systemic sclerosis (SSc) is a severe multi-organ disease with interstitial lung disease (ILD) being the major cause of death. While targeted therapies are emerging, biomarkers for sub-stratifying patients based on individual profiles are lacking. Herein, we investigated how levels of serum metabolites correlated with different stages of SSc and SSc-ILD. Serum samples of patients with SSc without ILD, stable and progressive SSc-ILD as well as of healthy controls (HC) were analysed using liquid targeted tandem mass spectrometry. The best discriminating profile consisted of 4 amino acids (AA) and 3 purine metabolites. L-tyrosine, L-tryptophan, and 1-methyl-adenosine distinguished HC from SSc patients. L-leucine, L-isoleucine, xanthosine, and adenosine monophosphate differentiated between progressing and stable SSc-ILD. In SSc-ILD, both, L-leucine and xanthosine negatively correlated with changes in FVC% predicted. Additionally, xanthosine was negatively correlated with changes in DLco% predicted and positively with the prognostic GAP index. Validation of L-leucine and L-isoleucine by an enzymatic assay confirmed both the sub-stratification of SSc-ILD patients and correlation with lung function and prognosis score. Serum metabolites may have potential as biomarkers for discriminating SSc patients based on the presence and severity of ILD. Confirmation in larger cohorts will be needed to appreciate their value for routine clinical care.
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Doenças Pulmonares Intersticiais/sangue , Escleroderma Sistêmico/sangue , Idoso , Biomarcadores/sangue , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicaçõesRESUMO
INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points ⢠The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. ⢠More than half of the patients with recurrent DU received bosentan and/or sildenafil. ⢠However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.