Assuntos
Infecções por Mycobacterium não Tuberculosas , Infecções por Mycobacterium , Mycobacterium chelonae , Dermatopatias Bacterianas , Humanos , Levofloxacino/uso terapêutico , Fluoroquinolonas/uso terapêutico , Dermatopatias Bacterianas/diagnóstico , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/microbiologia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Antibacterianos/uso terapêuticoRESUMO
Multiple primary malignant neoplasm (MPMN) is a rare disease with two or more malignant neoplasms in one patient. In less than 0.1% of cancer patients, four or more occur. MPMN is frequently associated with hereditary cancer syndrome, although in rare cases, it is not. A female patient developed 17 MPMNs. Although they were successfully treated with surgery, radiation, and adjuvant chemotherapy, the patient died from the recurrence of ovarian cancer. To explore genetic susceptibility to MPMN, immunohistochemical analysis, microsatellite instability analysis, germ line exome sequencing, and unscheduled DNA synthesis assays were performed. However, the results of immunohistochemical analysis and microsatellite instability indicated that there were no known hereditary cancer syndromes, and exome sequencing with 88 representative genes associated with hereditary cancer syndrome revealed no variants. An unscheduled DNA synthesis assay to rule out xeroderma pigmentosum was also performed, but the result was negative. While the presence of multiple neoplasms is rare, the present case represents 17 primary neoplasms with no associations with hereditary cancer syndrome. Although the cause of MPMN was not detected in this patient, careful follow-up and deliberate cancer screening enabled successful disease management over 17 years from the appearance of the first neoplasm.
Assuntos
Meato Acústico Externo , Neoplasias Primárias Múltiplas , Colo , Esôfago , Feminino , Humanos , Boca , Recidiva Local de Neoplasia , OvárioAssuntos
Amiloidose Familiar , Amiloidose , Síndrome de Sjogren , Dermatopatias Genéticas , Amiloide , Amiloidose/complicações , Amiloidose/diagnóstico , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnósticoRESUMO
Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.
Assuntos
Hiperemia/diagnóstico , Doenças Pulmonares Intersticiais/epidemiologia , Hipertensão Arterial Pulmonar/epidemiologia , Esclerodermia Difusa/complicações , Úlcera Cutânea/epidemiologia , Idoso , Endotélio Vascular/fisiopatologia , Feminino , Fibrose , Humanos , Hiperemia/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Pulso Arterial/métodos , Estudos Retrospectivos , Medição de Risco/métodos , Esclerodermia Difusa/patologia , Esclerodermia Difusa/fisiopatologia , Pele/irrigação sanguínea , Pele/patologia , Pele/fisiopatologia , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia , Vasodilatação/fisiologiaRESUMO
Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that presents with erythema and sterile pustules, pathologically characterized by Kogoj's spongiform pustules. GPP is sometimes accompanied by mucosal involvement, and the most common lesion is on the tongue. IL36RN mutation was found to contribute to the pathogenesis of GPP especially in patients who develop GPP without a past medical history of psoriasis vulgaris. The association of IL36RN mutation with mucosal involvement in GPP is controversial. We herein report a 60-year-old male GPP patient with no past history of plaque psoriasis presenting with not only severe skin lesions and arthritis but also severe mucosal involvements of pharyngeal and gastrointestinal lesions, which led to gastrointestinal bleeding. Our case did not have any mutation in the IL36RN gene. We should be aware that severe GPP can cause gastrointestinal bleeding. The relevancy of IL36RN mutation with mucosal involvement in GPP remains to be elucidated.
Assuntos
Fármacos Dermatológicos/uso terapêutico , Úlcera Duodenal/etiologia , Doenças do Esôfago/etiologia , Melena/etiologia , Psoríase/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Úlcera Duodenal/diagnóstico por imagem , Úlcera Duodenal/patologia , Endoscopia do Sistema Digestório , Transfusão de Eritrócitos , Doenças do Esôfago/diagnóstico por imagem , Doenças do Esôfago/patologia , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/patologia , Humanos , Interleucinas/genética , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Melena/diagnóstico por imagem , Melena/patologia , Melena/terapia , Pessoa de Meia-Idade , Mutação , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/patologia , Pele/patologia , Resultado do TratamentoRESUMO
There have been no established parameters to predict responsiveness to i.v. cyclophosphamide (IVCY) pulse therapy in combination with corticosteroids in patients with interstitial lung disease (ILD) related to systemic sclerosis (SSc). This retrospective study was conducted to determine predictive factors for efficacy of IVCY at the time of before and during the treatment. Thirty-two Japanese SSc patients, ever treated for ILD with IVCY in combination with prednisolone, were analyzed retrospectively. We performed detailed time-course analyses of parameters derived from blood samples and pulmonary function tests. With the exclusion of eight unclassified patients, 24 patients were classified into 14 good responders (GR) or 10 poor responders (PR) on the basis of changes in percent predicted diffusing capacity for carbon monoxide (DLco). Pretreatment percent predicted DLco was significantly reduced in PR compared with GR. In addition, serum parameters such as Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) and C-reactive protein were significantly higher in PR than in GR. Furthermore, our time-course analyses revealed a transient increase in serum KL-6 levels with a peak at 3 months after the first infusion of cyclophosphamide, which showed no relation to therapeutic efficacy. Moreover, continuously high serum KL-6 levels (>2000 U/mL) and rapid decrease in SP-D levels (<200 ng/mL) during IVCY were remarkably characteristic of PR and GR, respectively. ILD severity/activity before treatment and variability of serum KL-6 and SP-D levels during treatment may be useful to predict therapeutic effects of IVCY on SSc-ILD.
Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/complicações , Adulto , Idoso , Biomarcadores/sangue , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Infusões Intravenosas , Japão , Estudos Longitudinais , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Capacidade de Difusão Pulmonar , Pulsoterapia , Estudos Retrospectivos , Escleroderma Sistêmico/sangue , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Abscesso/imunologia , Anticorpos Monoclonais/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Psoríase/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/imunologia , Abscesso/diagnóstico por imagem , Abscesso/microbiologia , Abscesso/terapia , Adulto , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados , Drenagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Psoríase/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Infecções Cutâneas Estafilocócicas/diagnóstico por imagem , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/terapiaAssuntos
Antibacterianos/uso terapêutico , Hipertermia Induzida , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Mycobacterium marinum/isolamento & purificação , Idoso , Animais , Biópsia , Terapia Combinada/métodos , Antebraço , Mãos , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/patologia , Infecções por Mycobacterium não Tuberculosas/terapia , Pele/microbiologia , Pele/patologia , Resultado do TratamentoRESUMO
Localized scleroderma is an inflammatory disorder affecting the skin and underlying tissues, a certain subset of which develops other autoimmune diseases on the basis of a prominent autoimmune background. We here report a unique case of linear scleroderma presenting with a sclerotic plaque on the left thigh, multiple lymphadenopathy in bilateral inguinal and para-aortic lymph nodes, and hepatosplenomegaly, who later developed polymyositis. We describe the detailed disease course of our case and discuss the clinical significance of multiple lymphadenopathy in localized scleroderma based on a review of published work.
Assuntos
Doenças Autoimunes/patologia , Linfadenopatia/patologia , Linfedema/imunologia , Polimiosite/patologia , Esclerodermia Localizada/patologia , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Centríolos/imunologia , Eletromiografia , Fáscia/diagnóstico por imagem , Fáscia/patologia , Feminino , Glucocorticoides/uso terapêutico , Hepatomegalia/diagnóstico por imagem , Hepatomegalia/imunologia , Humanos , Linfonodos/patologia , Linfadenopatia/diagnóstico por imagem , Linfadenopatia/tratamento farmacológico , Linfadenopatia/imunologia , Linfedema/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Polimiosite/diagnóstico por imagem , Polimiosite/tratamento farmacológico , Polimiosite/imunologia , Prednisolona/uso terapêutico , Esclerodermia Localizada/diagnóstico por imagem , Esclerodermia Localizada/tratamento farmacológico , Esclerodermia Localizada/imunologia , Pele/patologia , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/imunologia , Tomografia Computadorizada por Raios XRESUMO
AIM: To determine serum galectin-1 levels and their clinical associations in patients with systemic sclerosis (SSc). METHOD: Serum galectin-1 levels were examined by enzyme-linked immunosorbent assay in 66 patients with SSc and 24 healthy individuals. RESULTS: No significant differences were observed in serum galectin-1 levels between patients with SSc (9.4 ± 5.6 ng/mL), and healthy individuals (8.9 ± 1.3 ng/mL). Among patients with SSc, no significant differences were seen in serum galectin-1 levels between those with diffuse cutaneous SSc (8.8 ± 5.7 ng/mL; n = 31) and those with limited cutaneous SSc (10.0 ± 5.4 ng/mL; n = 35). Patients with SSc who had increased galectin-1 levels less often had pitting scars/digital ulcers than those with normal galectin-1 levels (17% vs. 49%; P < 0.01). Consistently, galectin-1 levels were significantly lower in SSc patients with pitting scars/digital ulcers than in those without pitting scars/digital ulcers (6.9 ± 4.8 vs. 10.9 ± 5.5 ng/mL; P < 0.01). CONCLUSION: These results suggest that galectin-1 is a protective factor against the development of digital vasculopathy in SSc. In addition, measurement of serum galectin-1 levels may be useful for risk stratification for the development of digital vasculopathy in the early phase of SSc.
Assuntos
Cicatriz/etiologia , Galectina 1/sangue , Escleroderma Sistêmico/sangue , Úlcera Cutânea/etiologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Adulto JovemRESUMO
Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud's phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.
Assuntos
Antagonistas do Receptor de Endotelina A/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Doença de Raynaud/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Patients with systemic sclerosis (SSc) have an increased risk of malignancy compared with the general population. Recently, SSc patients with anti-RNA polymerase III antibody have been reported to have an increased risk of malignancy as compared with those with other disease-specific autoantibodies in US, European and Australian populations. Therefore, we studied the relationship between disease-specific autoantibodies and malignancy in 261 Japanese SSc patients. The prevalence of malignancy was significantly higher in patients with anti-RNA polymerase III antibody (7/22, 31.8%) than in those with anti-topoisomerase I antibody (2/82, 2.4%) and in those with anticentromere antibody (8/137, 5.8%). Importantly, among seven patients with anti-RNA polymerase III antibody and malignancy, three patients (42.9%) developed malignancy from 6 months before to 12 months after SSc onset. Thus, malignancy complication in Japanese SSc patients with anti-RNA polymerase III antibody is as high as that in other races, suggesting that SSc patients with anti-RNA polymerase III antibody share the same pathological process among different ethnic groups.
Assuntos
Anticorpos Antinucleares/sangue , Neoplasias/etnologia , RNA Polimerase III/imunologia , Escleroderma Sistêmico/sangue , DNA Topoisomerases Tipo I/imunologia , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologiaRESUMO
OBJECTIVES: Chemerin is a member of adipocytokines with a chemoattractant effect on plasmacytoid dendritic cells and macrophages and pro-angiogenic properties. We investigated the potential role of chemerin in the development of SSc. METHODS: Chemerin expression was evaluated by immunostaining and/or real-time quantitative RT-PCR in human and murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined using the gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by ELISA in 64 SSc patients and 19 healthy subjects. RESULTS: In SSc lesional skin, chemerin was up-regulated in small blood vessels, while it was down-regulated in fibroblasts surrounded with thickened collagen bundles. The decreased expression of chemerin was significantly reversed by TGF-ß1 antisense oligonucleotide in cultured SSc dermal fibroblasts and chemerin expression was markedly decreased in dermal fibroblasts of bleomycin-treated mice. Gene silencing of transcription factor Fli1, which binds to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1(+/-) mice exhibited elevated chemerin expression in dermal blood vessels. Serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. In SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without. CONCLUSION: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-ß, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc.
Assuntos
Quimiocinas/metabolismo , Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/complicações , Úlcera/etiologia , Úlcera/metabolismo , Idoso , Animais , Bleomicina/efeitos adversos , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Dedos , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/irrigação sanguínea , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo , Úlcera/induzido quimicamenteRESUMO
Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti-CD20 antibody, for SSc-associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti-topoisomerase I antibody levels. In addition, our detailed time-course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc-associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease-modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Doenças Pulmonares Intersticiais/terapia , Lúpus Eritematoso Sistêmico/terapia , Escleroderma Sistêmico/terapia , Anticorpos Monoclonais Murinos/administração & dosagem , Autoanticorpos/sangue , Linfócitos B/imunologia , DNA Topoisomerases Tipo I/imunologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Rituximab , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Resultado do TratamentoRESUMO
INTRODUCTION: Although the pathogenesis of systemic sclerosis (SSc) still remains unknown, recent studies have demonstrated that endothelins are deeply involved in the developmental process of fibrosis and vasculopathy associated with SSc, and a dual endothelin receptor antagonist, bosentan, has a potential to serve as a disease modifying drug for this disorder. Importantly, endothelin-1 (ET-1) exerts a pro-fibrotic effect on normal dermal fibroblasts and bosentan reverses the pro-fibrotic phenotype of SSc dermal fibroblasts. The purpose of this study was to clarify the details of molecular mechanisms underlying the effects of ET-1 and bosentan on dermal fibroblasts, which have not been well studied. METHODS: The mRNA levels of target genes and the expression and phosphorylation levels of target proteins were determined by reverse transcription real-time PCR and immunoblotting, respectively. Promoter assays were performed using a sequential deletion of human α2 (I) collagen (COL1A2) promoter. DNA affinity precipitation and chromatin immunoprecipitation were employed to evaluate the DNA binding ability of Fli1. Fli1 protein levels in murine skin were evaluated by immunostaining. RESULTS: In normal fibroblasts, ET-1 activated c-Abl and protein kinase C (PKC)-δ and induced Fli1 phosphorylation at threonine 312, leading to the decreased DNA binding of Fli1, a potent repressor of the COL1A2 gene, and the increase in type I collagen expression. On the other hand, bosentan reduced the expression of c-Abl and PKC-δ, the nuclear localization of PKC-δ, and Fli1 phosphorylation, resulting in the increased DNA binding of Fli1 and the suppression of type I collagen expression in SSc fibroblasts. In bleomycin-treated mice, bosentan prevented dermal fibrosis and increased Fli1 expression in lesional dermal fibroblasts. CONCLUSIONS: ET-1 exerts a potent pro-fibrotic effect on normal fibroblasts by activating "c-Abl - PKC-δ - Fli1" pathway. Bosentan reverses the pro-fibrotic phenotype of SSc fibroblasts and prevents the development of dermal fibrosis in bleomycin-treated mice by blocking this signaling pathway. Although the efficacy of bosentan for dermal and pulmonary fibrosis is limited in SSc, the present observation definitely provides us with a useful clue to further explore the potential of the upcoming new dual endothelin receptor antagonists as disease modifying drugs for SSc.