Microparticles: potential new contributors to the pathogenesis of systemic sclerosis?

Abstract Background Microparticles (MPs) are membrane-derived vesicles released from cells undergoing activation or apoptosis with diverse proinflammatory and prothrombotic activities, that have been implicated in the pathogenesis of systemic sclerosis (SSc). We aimed to evaluate the plasma levels of platelet-derived microparticles (PMPs), endothelial cell-derived microparticles (EMPs), and monocyte-derived microparticles (MMPs) in SSc patients, and the association between MPs and the clinical features of SSc. Methods In this cross-sectional study, 70 patients with SSc and 35 age- and sex-matched healthy controls were evaluated. Clinical and nailfold capillaroscopy (NFC) data were obtained from all patients. Plasma levels of PMPs (CD42+/31+), EMPs (CD105+), and MMPs (CD14+) were quantified by flow cytometry. Results Patients were mainly females (90%), with a mean age of 48.9 years old. PMP, EMP, and MMP levels were significantly increased in SSc patients compared to controls (79.2% ± 17.3% vs. 71.0% ± 19.8%, p = 0.033; 43.5% ± 8.7% vs. 37.8% ± 10.4%, p = 0.004; and 3.5% ± 1.3% vs. 1.1% ± 0.5%, p < 0.0001, respectively). PMP levels were significantly higher in patients with positive anti-topoisomerase-I antibodies (p = 0.030) and in patients with a disease duration > 3 years (p = 0.038). EMP levels were lower in patients with a higher modified Rodnan skin score (p = 0.015), and in those with an avascular score > 1.5 in NFC (p = 0.042). Conclusion The increased levels of PMPs, EMPs and MMPs in scleroderma patients might indicate a possible role for these agents in the pathogenesis of this challenging disease.

Anti-annexin V autoantibodies and vascular abnormalities in systemic sclerosis: a longitudinal study

Abstract Background: Annexins are a group of conserved proteins which exert several regulatory functions on various cellular activities. Increased frequency and levels of antibodies against annexin V have already been observed in several autoimmune diseases including systemic sclerosis (SSc), but their role as a vascular biomarker is unknown. The aim of this study was to determine the serum levels and the dynamical behavior of anti-annexin V antibodies over a 24 months follow-up in patients with SSc. Methods: In this bicentric cross-sectional study, 70 patients with SSc were consecutively selected from March 2016 to April 2017. Demographic and clinical features, including the presence of active DUs, were collected. Serum anti-annexin V IgG and IgM antibodies were measured at baseline and after 6, 12 and 24 months of follow-up. Videocapillaroscopy was performed in all patients. Results: Among the 70 SSc patients included anti-annexin V IgG was found in 11 patients (15.7%) (range of 15.88-39.48 U/mL) and anti-annexin V IgM in 10 patients (14.3%) (range of 14.16-22.69 U/mL) at baseline. During follow-up, the number of patients who were positive for anti-annexin V IgG and IgM remained stable over 24 months. Among the patients with positive anti-annexin V IgG at baseline the frequency of patients with necrosis or amputation of extremities, forced vital capacity less than 70% and pulmonary arterial hypertension (PAH) was significantly higher than in patients with negative anti-annexin V IgG antibodies. Patients with anti-annexin V IgG had also a higher Raynaud's Condition Score and a higher Health Assessment Questionnaire Disability Index (HAQ-DI) than patients without these antibodies at baseline. Patients with positive anti-annexin V IgM at baseline presented a higher frequency of PAH, compared to those with negative anti-annexin V IgM at baseline. Conclusions: Anti-annexin V antibodies are stable and do not change their positivity during a 24 month follow-up in SSc patients. Anti-annexin V IgG was associated with more severe interstitial lung involvement and digital microangiopathy, and patients with anti-annexin V IgG or IgM had a higher occurrence of PAH indicating an association of these biomarker with more severe disease.(AU)

Position article and guidelines 2018 recommendations of the Brazilian Society of Rheumatology for the indication, interpretation and performance of nailfold capillaroscopy

Abstract Nailfold capillaroscopy (NFC) is a reproducible, simple, low-cost, and safe imaging technique used for morphological analysis of nail bed capillaries. It is considered to be extremely useful for the investigation of Raynaud's phenomenon and for the early diagnosis of systemic sclerosis (SSc). The capillaroscopic pattern typically associated with SSc, scleroderma ("SD") pattern, is characterized by dilated capillaries, microhemorrhages, avascular areas and/or capillary loss, and distortion of the capillary architecture. The aim of these recommendations is to provide orientation regarding the relevance of NFC, and to establish a consensus on the indications, nomenclature, the interpretation of NFC findings and the technical equipments that should be used. These recommendations were formulated based on a systematic literature review of studies included in the database MEDLINE (PubMed) without any time restriction.

Nailfold capillaroscopy as a risk factor for pulmonary arterial hypertension in systemic lupus erythematosus patients

Abstract Background: Pulmonary arterial hypertension (PAH) is a rare and severe complication of systemic lupus erythematosus (SLE). This study aimed to evaluate clinical and laboratory risk factors associated with PAH in SLE patients. Methods: This was a retrospective case-control study in which patients with SLE with PAH (SLE-PAH) confirmed by right heart catheterization (RHC) were compared with SLE patients without PAH. Clinical and demographic variables related to SLE and PAH and nailfold capillaroscopy were evaluated by reviewing the medical records of the patients. Results: Twenty-one patients with SLE-PAH and 44 patients with SLE without PAH matched for sex and disease duration were included. The scleroderma (SD) pattern on nailfold capillaroscopy was more frequently found in patients with SLE-PAH than in those without PAH (56.3% versus 15.9%, respectively, p = 0.002). By univariate analysis, Raynaud's phenomenon, history of abortion, and SD pattern on capillaroscopy were associated with PAH. Arthritis was a protective factor for PAH development. Multivariate analysis showed that the SD pattern on capillaroscopy was the only variable associated with a significantly higher risk of PAH, with an odds ratio of 6.393 (95% confidence interval, 1.530-26.716; p = 0.011). Conclusion: In this study, SD pattern was associated with a 6.3-fold increased risk for PAH development in SLE patients, suggesting that nailfold capillaroscopy might be useful as a screening method to identify SLE patients with a high risk of developing this severe complication.

Risk of digital ulcers occurrence in systemic sclerosis: a cross-sectional study

Abstract Background/objective: Digital ulcers (DUs) represent a frequent complication of systemic sclerosis (SSc). The aim of this study was to evaluate clinical, serological and capillaroscopy features that are associated with DUs in patients with SSc. Methods: In this bicentric cross-sectional study, 70 patients with SSc were consecutively selected from March 2016 to April 2017. Demographic and clinical features, including the presence of active DUs, were collected. Videocapillaroscopy was performed in all patients. Results: Among the 70 patients included (mean age of 46.8 years, mean disease duration of 9.41 years), 14 (20%) had active DUs. Based on multivariate analysis, the presence of anti-Scl-70 antibodies, the HAQ-DI score, and the capillary loss score were independently associated with DUs with odds ratios of 7.96 (95% CI 1.32-47.99), 55.77 (95% CI 1.76-1764.28), and 16.66 (95% CI 2.07-133.81), respectively. Conclusions: The presence of avascular areas in capillaroscopy, elevation of HAQ-DI score and anti-Scl-70 antibodies were independent factors associated with DUs in patients with SSc.

Neuropsychiatric Lupus in clinical practice / Lúpus neuropsiquiátrico na prática clínica

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options.

RESUMO Lúpus eritematoso sistêmico (LES) é uma doença autoimune crônica que envolve múltiplos órgãos e sistemas, caracterizada pela produção de auto anticorpos e lesão tecidual. A etiologia do LES é parcialmente conhecida e envolve interação entre fatores genéticos e ambientais. Até 50% dos pacientes com LES apresentam envolvimento neurológico no decorrer da doença. Manifestações neurológicas estão associadas a prejuízo na qualidade de vida e altas taxas de mortalidade e morbidade. Foram identificadas 19 síndromes neuropsiquiátricas em pacientes com LES, divididas entre manifestações do sistema nervoso central e periférico. O objetivo deste artigo é revisar as manifestações neuropsiquiátricas mais importantes. Serão abordadas as características clínicas, os aspectos radiológicos e opções de tratamento dos eventos neuropsiquiátricos.

Capilaroscopia periungueal: relevância para a prática reumatológica / Nailfold capillaroscopy: relevance to the practice of rheumatology

A capilaroscopia periungueal é um método simples, de baixo custo, e de extrema relevância na avaliação de pacientes com fenômeno de Raynaud ou portadores de doenças do espectro da esclerose sistêmica (ES). Além de sua importância para o diagnóstico precoce da ES, constitui instrumento útil na identificação de pacientes esclerodérmicos com risco elevado para o desenvolvimento de complicações vasculares, viscerais e de óbito. A inclusão da capilaroscopia nos novos critérios para classificação da ES do Colégio Americano de Reumatologia (ACR) e da Liga Europeia Contra o Reumatismo (Eular) dá novo impulso para a utilização e disseminação do método. No presente artigo, pretendemos apresentar uma revisão didática, não sistemática, sobre o tema, com ênfase nos avanços recentemente descritos.

Nailfold capillaroscopy is a simple, low-cost method, that is extremely important in the evaluation of patients with Raynaud's phenomenon and of patients with systemic sclerosis (SSc) spectrum diseases. Besides its importance for the early diagnosis of SSc, nailfold capillaroscopy is a useful tool to identify scleroderma patients with high risk for development of vascular and visceral complications and death. The inclusion of capillaroscopy in the new classification criteria for SSc of the American College of Rheumatology (ACR) and European League Against Rheumatism (Eular) gives a new impetus to the use and dissemination of the method. In this paper, we present a didactic, non-systematic review on the subject, with emphasis on advances recently described.

N-acetilcisteína oral no tratamento do fenômeno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo-controlado e duplo-cego / Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: A randomized, double-blind, placebo-controlled clinical trial

Objetivo Avaliar a segurança e a eficácia da N-acetilcisteína (NAC) por via oral sobre o fluxo sanguíneo da microcirculação digital em pacientes com fenômeno de Raynaud (FRy) secundário à esclerose sistêmica (ES). Métodos Este foi um estudo randomizado, duplo-cego e placebo-controlado, no qual 42 pacientes com ES receberam NAC oral na dose de 600 mg, três vezes ao dia (21 pacientes, idade média 45,6±9,5 anos) ou placebo (21 pacientes, idade média 45,0±12,7 anos) durante quatro semanas. O desfecho primário do estudo foi: melhora no fluxo sanguíneo da microcirculação cutânea antes e após estímulo frio avaliado pelo laser Doppler imaging (LDI) nas semanas 0 e 4. A frequência e a gravidade do FRy e o número de úlceras digitais também foram avaliados nas semanas 0 e 4. Os efeitos adversos foram registrados na quarta semana. Resultados Não houve mudança significativa no fluxo sanguíneo digital avaliado pelo LDI antes ou depois do estímulo frio após quatro semanas de NAC ou placebo. Ambos os grupos apresentaram melhora significativa na frequência e gravidade dos ataques de FRy, sem diferença entre os dois. O grupo placebo apresentou três úlceras digitais enquanto o grupo NAC não apresentou úlceras ao final do estudo. NAC foi bem tolerada e nenhum paciente descontinuou o tratamento. Conclusões NAC por via oral na dose de 1.800mg/dia não demonstrou efeito vasodilatador sobre a microcirculação das mãos após quatro semanas de tratamento em pacientes com FRy secundário à ES. .

Objective To evaluate the safety and efficacy of oral N-acetylcysteine (NAC) on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). Methods This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. Results There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. Conclusions NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands’ microcirculation after four weeks of treatment in patients with RP secondary to SSc. .

Esclerose sistêmica e o fenômeno de Raynaud: manejo terapêutico / Systemic sclerosis and Raynaud's phenomenon: therapeutic management

O fenômeno de Raynaud (FRy) caracteriza-se por episódios reversíveis de vasoespasmos de extremidades, que ocorrem usualmente após estresse ou exposição ao frio. O FRy pode ser primário ou secundário a uma série de condições, principalmente a doenças do espectro da esclerose sistêmica (ES). Na ES, o FRy costuma ser mais grave, e lesões isquêmicas de extremidades são frequentes. Nos últimos anos, avanços no estudo da fisiopatologia do FRy e da doença vascular na ES propiciaram o surgimento de novas opções terapêuticas para esta manifestação. Os bloqueadores de canal de cálcio devem ser utilizados como tratamento de primeira escolha para o FRy. Novas drogas, como os inibidores da fosfodiesterase V e os prostanoides, podem ser utilizados em pacientes com FRy grave, e a bosentana (antagonista do receptor da endotelina-1) é indicada para a prevenção de úlceras digitais recorrentes.

Raynaud's phenomenon (RP) is characterized by episodic vasospasm of the extremities, usually in response to stress or cold exposure. It can be primary or secondary to several conditions, especially systemic sclerosis-related diseases. In systemic sclerosis (SSc), RP is usually more severe and digital ischemic lesions are a frequent problem. In recent years, advances in the understanding of the pathophysiology of RP and of SSc vasculopathy led to the development of new therapeutic options for this condition. Calcium-channel blockers are the first choice for the treatment of RP. New drugs including phosphodiesterase type V inhibitors and prostanoids can be used for severe RP, and bosentan (endothelin-1 receptor antagonist) for prevention of recurrent digital ulcers.

Thymopoiesis and regulatory T cells in healthy children and adolescents

OBJECTIVES: The purpose of this study was to investigate the association between T cell receptor excision circle levels in peripheral blood mononuclear cells and regulatory T cells that co-express CD25 and Foxp3 in healthy children and adolescents of different ages. MATERIALS AND METHODS: The quantification of signal-joint T-cell receptor excision circle levels in the genomic DNA of peripheral blood mononuclear cells was performed using real-time quantitative PCR. The analysis of CD4, CD8, CD25, and Foxp3 expression was performed using flow cytometry. RESULTS: Ninety-five healthy controls (46 females and 49 males) ranging in age from 1 to 18 years were analyzed. The mean T-cell receptor excision circle count in all individuals was 89.095¡36.790 T-cell receptor excision circles per microgram of DNA. There was an inverse correlation between T-cell receptor excision circles counts and age (r = -0.846; p<0.001) as well as between the proportion of CD4+CD25+Foxp3+ T cells and age (r = -0.467; p = 0.04). In addition, we observed a positive correlation between the amount of CD4+CD25+Foxp3+ T cells and the amount of Tcell receptor excision circles per microgram of DNA in individuals of all ages (r = -0.529; p = 0.02). CONCLUSIONS: In this study, we observed a decrease in the thymic function with age based on the fact that the level of T-cell receptor excision circles in the peripheral blood positively correlated with the proportion of regulatory T cells in healthy children and adolescents. These findings indicate that although T-cell receptor excision circles and regulatory T cells levels decrease with age, homeostasis of the immune system and relative regulatory T cells population levels are maintained in the peripheral blood.

IL-2, IL-5, TNF-α and IFN-γ mRNA expression in epidermal keratinocytes of systemic lupus erythematosus skin lesions

OBJECTIVE: To analyze cytokine gene expression in keratinocytes from patients with systemic lupus erythematosus (SLE). INTRODUCTION: Keratinocytes represent 95 percent of epidermal cells and can secrete several cytokines. METHODS: Keratinocytes were obtained by laser microdissection from 21 patients with SLE (10 discoid and 11 acute lesions) at involved and uninvolved sites. All patients were receiving a low/moderate prednisone dose and 18 were receiving chloroquine diphosphate. IL-2, IL-5, TNF-α and IFN-γ gene expression was evaluated by real-time PCR and expressed as the ratio (R) to a pool of skin samples from 12 healthy volunteers. RESULTS: Heterogeneity in cytokine gene expression was found among patients with SLE. Eighteen of 38 valid SLE samples (47 percent) presented overexpression (R>1) of at least one cytokine. Lesional skin samples tended to show higher cytokine expression than samples from uninvolved skin (p = 0.06). IL-5 and IFN-γ were the most commonly overexpressed cytokines. Samples with cytokine overexpression corresponded to more extensive and severe lesions. Prednisone dose did not differ between samples without cytokine overexpression (15.71±3.45 mg/day) and those with overexpressed cytokines (12.68±5.41 mg/day) (p = 0.216). Samples from all patients not receiving diphosphate chloroquine had at least one overexpressed cytokine. CONCLUSIONS: The heterogeneous keratinocyte cytokine gene expression reflects the complex immunological and inflammatory background in SLE. Patients with severe/extensive skin lesions showed a higher frequency of cytokine gene overexpression. Increased IFN-γ and IL-5 expression suggests that Th1 and Th2 cells are involved in SLE skin inflammation. The possibility that prednisone and antimalarial drugs may have contributed to low cytokine gene expression in some samples cannot be ruled out.

Laser Doppler Imaging para quantificação do fluxo sanguíneo de polpa digital em condições basais e após estímulo frio em pacientes com esclerose sistêmica / Quantification of basal digital blood flow and after cold stimulus by laser doppler imaging in patients with systemic sclerosis

OBJETIVO: Determinar o comportamento dinâmico do fluxo sanguíneo da microcirculação digital, antes e após dois estímulos frios (EF) de diferentes intensidades, utilizando o método do Laser Doppler Imaging (LDI) em pacientes com esclerose sistêmica (ES) e controles saudáveis. MÉTODOS: Foram incluídos 14 pacientes com ES (51,2 ± 5,5 anos de idade) e 12 controles saudáveis (44,8 ± 9,9 anos). Foram realizados dois protocolos alternativos de EF (submersão das mãos em água a 10 ºC ou 15 ºC, durante 1 minuto). O fluxo médio das quatro polpas digitais da mão esquerda (FPD) foi mensurado com a utilização do LDI (Moor LDI-VR), em condições basais, nos períodos de 1, 4, 10, 25 e 40 minutos após EF. RESULTADOS: O fluxo basal foi significativamente menor em ambos os protocolos em pacientes com ES comparados a controles (312,9 ± 102,7 versus 465,4 ± 135,4 PU, P = 0,006, no protocolo a 15 ºC; 305,2 ± 121,0 versus 437,9 ± 119,8 PU, P = 0,01, no protocolo a 10 ºC). Nos controles houve declínio significativo do FPD após EF, em comparação aos valores basais apenas no tempo de um minuto após EF a 15 ºC (P = 0,001) e nos tempos de 1 e 25 minutos após EF a 10 ºC (P = 0,005; P = 0,001, respectivamente). Nos pacientes com ES, houve declínio significativo do FPD nos tempos de 1, 4 e 10 minutos após ambos EFs (P < 0,000; P = 0,002; P = 0,014, EF a 15 ºC; P < 0,000; P = 0,004; P = 0,001, EF a 10 ºC, respectivamente). CONCLUSÃO: LDI demonstrou baixa perfusão em polpa digital em condições basais e elevado declínio de perfusão com retardo na recuperação após EF na ES. A quantificação do fluxo sanguíneo pelo LDI pode ser útil para o seguimento longitudinal da doença e para a monitoração de intervenções terapêuticas na ES.

OBJECTIVES: The objective of this study was to investigate the dynamic behavior of the blood flow of the microvascular circulation of the fingertips before and after two cold stimuli (CS), using Laser Doppler Imaging with different intensities in patients with systemic sclerosis (SSc) and in healthy individuals. PATIENTS AND METHODS: Fourteen SSc patients (51.2 ± 5.5 years) with Raynaud's phenomenon and 12 healthy controls (44.8 ± 9.0 years) were included in this study. Two CS protocols (submersion of the hands in water at 10 ºC or 15 ºC for 1 minute) were performed on the same day. Mean fingertip blood flow (FBF) of four digits of the left hand was measured using LDI (Moor LDI-VR, Moor Instruments) at baseline and at 1, 4, 10, 25, and 40 minutes after CS. RESULTS: Baseline blood flow was significantly lower in both CS protocols in SSc patients when compared to controls (312.9 ± 102.7 vs 465.4 ± 135.4 PU, P = 0.006 at 15 ºC; 305.2 ± 121.0 vs 437.9 ± 119.8 PU; P = 0.01 at 10 ºC). In the control group, a significant decrease in FBF after CS, when compared to baseline, was observed 1 minute (P = 0.001) after CS at 15 ºC and at 1 (P = 0.005) and 25 minutes (P = 0.001) after CS at 10 ºC. In SSc patients, a significant decrease in FBF was observed in both CS protocols at 1, 4, and 10 minutes (P < 0.000; P = 0.002; P = 0.014, after CS at 15 ºC; P < 0.000; P = 0.004; P = 0.001, after CS at 10 ºC). CONCLUSIONS: Laser Doppler Imaging showed lower baseline fingertip perfusion and further reduction after CS in SSc patients compared to controls. Quantification of fingertip blood flow by LDI may be useful in the longitudinal monitoring of the disease status and therapeutic interventions in SSc.

Bosentan in the treatment of refractory extremities ulcers in systemic sclerosis / Bosentana no tratamento de úlceras de extremidades refratárias na esclerose sistêmica

INTRODUÇÃO: Acometimento vascular é uma manifestação central da esclerose sistêmica (ES) e pode levar a complicações como úlceras, gangrena ou amputação de extremidades. Bosentana é um medicamento antagonista dos receptores da endotelina utilizado na prevenção de úlceras digitais na ES. OBJETIVO: Avaliar a eficácia de bosentana em úlceras de extremidades recorrentes e refratárias em pacientes com ES. PACIENTES E MÉTODOS: Realizamos estudo aberto e observacional em três pacientes com diagnóstico de ES provenientes do Ambulatório de ES da UNIFESP com idades de 31, 58 e 61 anos. Todas apresentavam uma ou mais úlceras de extremidades ativas que não haviam respondido ao tratamento convencional: paciente P1 com uma úlcera digital; P2 com três úlceras em membro inferior direito; e P3 com úlcera em dígito, perna, e calcanhar direitos e maléolo esquerdo. Bosentana foi administrado na dose de 62,5 mg VO duas vezes ao dia por quatro semanas, seguido por 125 mg duas vezes ao dia por mais quatro ou oito semanas. As pacientes foram avaliadas quanto ao número e ao diâmetro das úlceras em três momentos: no início deste estudo, após quatro semanas e após oito semanas. A paciente mais grave foi também avaliada após 12 semanas. RESULTADOS: Após tratamento com bosentana, todas apresentaram cicatrização ou diminuição no diâmetro das úlceras. Nenhuma paciente apresentou surgimento de novas úlceras. CONCLUSÃO: O tratamento com bosentana se mostrou eficaz na prevenção do surgimento de novas úlceras em curto prazo e na cicatrização de úlceras de extremidades em três pacientes com ES. Sugere-se assim, que a droga possa ser uma opção terapêutica nos pacientes com acometimento vascular grave.

INTRODUCTION: Vasculopathy is a hallmark of systemic sclerosis (SSc) and may lead to complications such as ischemic ulcers, necrosis or amputation of fingers or lower limbs. Bosentan is a dual endothelin receptor antagonist currently used for prevention of digital ulcers in SSc. OBJECTIVE: To evaluate the efficacy of bosentan in the treatment of recurrent and refractory extremity ulcers in patients with SSc. PATIENTS AND METHODS: An open and observational study was performed with three patients from the Rheumatology Division of UNIFESP aged 31, 58 and 61 years with diagnosis of SSc. All patients presented one or more active extremity ulcer refractory to conventional treatment. The first one (P1) presented one digital ulcer; P2 presented three ulcers on the right lower limb; and P3 presented an ulcer on the right digit, leg and heel, and on left maleolar region. Bosentan was prescribed in a dose regimen of 62.5 mg twice a day for 4 weeks, followed by 125 mg twice a day for additional 4 or 8 weeks. All patients were evaluated regarding the number and diameter of the ulcers in weeks 0, 4, and 8, and one of them in week 12 as well. RESULTS: After the treatment with bosentan all patients presented complete resolution or reduction in the diameter of the ulcers. None of the patients presented a new ulcer. CONCLUSION: Bosentan was an effective treatment in refractory extremities ulcers and in the prevention of new ulcers in three SSc patients suggesting that this medication could be an option for patients with severe vascular involvement.

Fenômeno de Raynaud: [revisão] / Raynaud's phenomenon: [review]

O fenômeno de Raynaud (FRy) caracteriza-se por episódios reversíveis de vasoespasmos de extremidades, associados a palidez, seguido por cianose e rubor de mãos e pés, que ocorrem usualmente após estresse ou exposição ao frio. O FRy primário é um evento funcional benigno e não está associado a nenhuma doença ou condição subjacente. Já o FRy secundário pode estar associado a uma série de condições, principalmente a doenças reumáticas autoimunes. Na esclerose sistêmica (ES), o FRy é a manifestação inicial mais frequente. No FRy secundário às doenças do espectro da ES, complicações como lesões isquêmicas de extremidades são frequentes. Nos últimos anos, avanços no estudo da fisiopatologia do FRy e da doença vascular na ES propiciaram o surgimento de opções terapêuticas bastante promissoras para essa manifestação. Nesta revisão pretendemos discorrer principalmente sobre a patogênese, a investigação clínica e o tratamento do FRy, com ênfase nos novos tratamentos disponíveis.

Raynaud's phenomenon (RP) is an episodic vasospasm of the peripheral arterioles, causing pallor followed by cyanosis and redness of the fingers and toes, usually in response to stress or cold exposure. Primary Raynaud's phenomenon is a benign event and occurs without an underlying disease. In contrast, secondary Raynaud's phenomenon can occur in association with several underlying diseases or conditions, mostly autoimmune rheumatic diseases. In systemic sclerosis (SSc), RP is the most frequent initial manifestation. In RP secondary to SSc-related diseases, digital ischemic lesions are a frequent problem. In recent years, advances in the understanding of the physiopathology of RP have favored the development of novel promising therapeutic alternatives for this clinical condition. This article presents a review of the pathogenesis, clinical investigation and treatment of RP, with special emphasis in novel therapeutic modalities.

Síndrome de Werner associada a quadro esclerodermiforme: relato de caso e revisão da literatura / Werner's syndrome associated with scleroderma-like syndrome: case report and literature revision

A síndrome de Werner é uma doença autossômica recessiva rara associada a envelhecimento precoce, cujo quadro cutâneo deve ser distinguido daquele encontrado na esclerose sistêmica (ES). Descrevemos aqui o caso de uma paciente de 39 anos de idade, portadora de síndrome de Werner, encaminhada ao nosso serviço com hipótese diagnóstica inicial de ES. A paciente apresentava várias manifestações associadas à síndrome de Werner, incluindo cabelos precocemente grisalhos, voz estridente, baixa estatura, alterações cutâneas esclerodermiformes, diabetes melito, catarata, hipogonadismo, hipotireoidismo e hiperlipidemia. Não apresentava fenômeno de Raynaud, manifestações viscerais típicas da ES, alterações capilaroscópicas periungueais ou auto-anticorpos. O diagnóstico de síndrome de Werner, apesar de raro, deve ser lembrado no diagnóstico diferencial de ES, principalmente na presença de manifestações atípicas e na ausência de alterações típicas da ES.

Werner's syndrome is a rare autosomal recessive disease associated with premature ageing. Skin alteration must be distinguished from cutaneous manifestation of systemic sclerosis (SSc). We describe a case of a 39 years old patient with Werner's syndrome admitted with an initial diagnostic hypothesis of SSc. The patient had many characteristic features associated with Werner's syndrome including gray hair, hoarseness, short stature, scleroderma-like skin changes, diabetes mellitus, cataracts, hypogonadism, hypothyroidism, and hyperlipidemia. There was no Raynaud's phenomenon, other typical visceral manifestation of SSc, nailfold capillary alterations or autoantibodies. Werner's syndrome diagnosis notwithstanding rare, should be remember in the differential diagnosis of SSc, mainly in the presence of atypical manifestations and in the absence of typical features of SSc.