RESUMO
OBJECTIVES: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). METHODS: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. RESULTS: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. CONCLUSION: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.
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Doenças Pulmonares Intersticiais/epidemiologia , Úlcera por Pressão/epidemiologia , Esclerodermia Difusa/patologia , Adulto , Feminino , Mãos/fisiopatologia , Humanos , Imunossupressores/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/complicações , Esclerodermia Difusa/tratamento farmacológico , Pele/patologia , Capacidade VitalRESUMO
OBJECTIVE: To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. METHODS: A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. RESULTS: Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. CONCLUSION: Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population.
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Esclerodermia Difusa/sangue , Pele/patologia , Adulto , Sedimentação Sanguínea , Progressão da Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/patologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To evaluate the efficacy and safety of tacrolimus in adult patients with rheumatoid arthritis (RA) by using the GRADE approach. METHODS: We searched PubMed, Japana Centra Revuo Medicina Web (Ichu-shi web), and the Cochrane Database of Systematic Reviews. Articles fulfilling the predefined inclusion criteria were appraised and used for meta-analysis. The primary outcomes were American College of Rheumatology 20 (ACR20) and serum creatinine elevation. Other outcomes included ACR50, ACR70, changes in C-reactive protein, modified Health Assessment Questionnaire Disability Index, gastrointestinal disorders, metabolic and nutritional disorders, and infections and infestations. RESULTS: We identified five randomized controlled studies, four of which compared tacrolimus to placebo and were included in the meta-analysis. The risk ratio of ACR20 achievement was 1.71 (95% confidence interval [CI] 1.20-2.42) for 1-2 mg/day and 2.30 (95% CI 1.79-2.96) for 3 mg/day. The risk ratio of creatinine elevation was 1.95 (95% CI 1.18-3.23) for 1-2 mg/day and 3.81 (95% CI 2.43-5.99) for 3 mg/day. CONCLUSION: Tacrolimus is effective with acceptable safety in the management of RA.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Tacrolimo/uso terapêutico , Antirreumáticos/efeitos adversos , Humanos , Tacrolimo/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14â 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.
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Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Japão/epidemiologia , Polimorfismo de Nucleotídeo Único , Fator 1 de Ligação ao Domínio I Regulador Positivo , Escleroderma Sistêmico/etnologiaRESUMO
OBJECTIVE: Patients' values and preferences are among the key factors that determine the strength of recommendations presented in clinical practice guidelines (CPG). The aim of this study was to summarize the integration process for patients' perceptions into the development of CPG for rheumatoid arthritis (RA) management in Japan. METHODS: We used a mixed-methods approach. Questionnaires that could be self-administered were mailed to 2222 RA patients randomly selected from the Japan Rheumatism Friendship Association (JRFA) membership list that was age- and prefecture-stratified. A focus group with five JRFA executive members was formed to verify the results of the questionnaire. RESULTS: A total of 1470 patients aged 20-79 years old returned the questionnaire. Analysis of the questionnaire data revealed that the topics selected by the CPG task force met the patients' needs. The focus group participants showed reluctance to use the term 'preference' because patients would not want to take any medications but would have to take them out of necessity. CONCLUSIONS: We confirmed that the new CPG successfully addressed clinical issues that were important to both rheumatologists and patients. Clinicians should understand patients' reluctance to take medications and explain the role of each medication well to increase adherence.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Pacientes/psicologia , Percepção , Guias de Prática Clínica como Assunto , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/psicologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan. METHODS: The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients. RESULTS: Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined. CONCLUSIONS: Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Gerenciamento Clínico , Medicina Baseada em Evidências/normas , Guias de Prática Clínica como Assunto/normas , Reumatologia/normas , Técnica Delphi , Humanos , JapãoRESUMO
OBJECTIVES: To evaluate, through a systematic review of the literature, the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and surgical site infection (SSI) or wound healing delay after orthopedic surgery in patients with rheumatoid arthritis (RA). METHODS: A systematic review of articles indexed in the Cochrane Library, PubMed, and Web of Science from 1992 to 2012 was performed. The search aimed to identify studies describing SSI or wound healing delay in patients with RA treated with or without bDMARDs. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality was appraised. RESULTS: There was no Cochrane review on this subject. We found 75 articles through specific searches of PubMed and Web of Science, and hand searching. After inclusion and exclusion by full-text review, 10 articles were found for SSI, and 5 articles for delayed wound healing. The use of bDMARDs appeared to increase the rate of SSI slightly, especially in large joint-replacement surgery. Delayed wound healing was not increased by the use of bDMARDs. However, the definitions of SSI and delayed wound healing varied between the reviewed articles. Most of the articles focused on tumor necrosis factor-α inhibitors. CONCLUSION: bDMARDs slightly increase the relative risk of SSI but not that of delayed wound healing after orthopedic surgery and should be used with appropriate caution.
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Antirreumáticos/farmacologia , Artrite Reumatoide/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Infecção da Ferida Cirúrgica/etiologia , Cicatrização/efeitos dos fármacos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , HumanosRESUMO
Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.
Assuntos
Predisposição Genética para Doença , Escleroderma Sistêmico , Humanos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Receptores de IgG/genética , Estratificação de Risco Genético , Escleroderma Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fatores Reguladores de Interferon/genética , Loci GênicosRESUMO
OBJECTIVE: To assess the utility of serum chemokine levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Seventy Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicenter, observational study. Concentrations of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 in serum samples from all patients were measured using cytometric beads array. In 33 patients, chemokine levels were measured each year for 4 years. The ability of baseline chemokine levels to predict changes in clinical features were evaluated statistically by multiple regression analysis. RESULTS: At their first visit, serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were significantly elevated in patients with SSc compared with healthy controls. There were significant associations between CCL2 and CXCL8 levels and between CXCL9 and CXCL10 levels in patients. The initial serum CXCL8 levels were significantly associated with the HAQ-DI at the fourth year while the %VC of baseline tended to be negatively associated with HAQ-DI at the fourth year. Initial chemokine levels were not associated with other clinical features including skin thickness score and the respiratory function. CONCLUSION: Serum CXCL8 level may serve as a prognostic indicator of the physical dysfunction in SSc. Further longitudinal studies of larger populations are needed to confirm these findings.
Assuntos
Quimiocinas/sangue , Escleroderma Sistêmico/diagnóstico , Adolescente , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Escleroderma Sistêmico/sangueRESUMO
OBJECTIVE: To clarify the clinical course of SSc in Japanese patients with early-onset disease. It is well known that ethnic variations exist in the clinical features and severity of SSc. However, neither the clinical course nor prognostic factors have been thoroughly investigated in the Japanese population. METHODS: Ninety-three Japanese patients of early-onset SSc (disease duration: <3 years) with diffuse skin sclerosis and/or interstitial lung disease were registered in a multi-centre observational study. All patients had a physical examination with laboratory tests at their first visit and at each of the three subsequent years. Factors that could predict the severity of skin sclerosis and lung involvement were examined statistically by multiple regression analysis. RESULTS: Two patients died from SSc-related myocardial involvement and four patients died from other complications during the 3-year study. Among various clinical data assessed, the initial modified Rodnan total skin thickness score (MRSS) and maximal oral aperture were associated positively and negatively with MRSS at Year 3, respectively. Additionally, initial ESR tended to be associated with final MRSS. Pulmonary vital capacity (VC) in the third year was significantly associated with initial %VC. Furthermore, patients with anti-topo I antibody tended to show reduced %VC at Year 3. CONCLUSIONS: Several possible prognostic factors for skin sclerosis and lung function were detected in Japanese patients with early SSc. Further longitudinal studies of larger populations will be needed to confirm these findings.
Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Escleroderma Sistêmico/diagnóstico , Adolescente , Adulto , Idoso , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Sedimentação Sanguínea , Criança , Pré-Escolar , DNA Topoisomerases Tipo I/imunologia , Progressão da Doença , Diagnóstico Precoce , Métodos Epidemiológicos , Feminino , Humanos , Japão , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Boca/patologia , Prognóstico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Pele/patologia , Capacidade Vital/fisiologia , Adulto JovemRESUMO
We aimed to clarify the clinical features of Japanese patients with systemic sclerosis (SSc), especially with reference to organ involvement and autoantibodies. A cohort of 405 patients with SSc who attended our institution from 1973 to 2008 was identified retrospectively. Data on clinical features, including autoantibodies, organ involvement, and overlap of other connective tissue diseases, were obtained by following the medical records until 2009. The percentage of male patients during or after 1990 was greater than that before 1990 (3.9 vs. 10.6%, respectively). Limited cutaneous SSc (lSSc) was twice as frequent as diffuse cutaneous SSc (dSSc). About half of the patients had lung involvement (50.4%), while only 3.2% had scleroderma renal crisis. Male gender was associated with lung involvement, and dSSc was associated with most organ involvements except for pulmonary arterial hypertension (PAH). Anti-Scl-70 antibody was associated with lung or heart involvement, while anti-U1-RNP antibody was only associated with PAH. Conversely, patients with anti-centromere antibody had less organ involvement. SSc-Sjögren overlap syndrome was related to lSSc, further overlapping systemic lupus erythematosus (SLE), and less lung or heart involvement. In conclusion, these results not only confirmed previous reports but revealed several other findings, such as the increased proportion of male patients in recent years and the relationships between clinical features.
Assuntos
Pneumopatias/patologia , Insuficiência Renal/patologia , Esclerodermia Difusa/patologia , Esclerodermia Limitada/patologia , Dermatopatias/patologia , Autoanticorpos/sangue , Biomarcadores/sangue , Centrômero/imunologia , Estudos de Coortes , DNA Topoisomerases Tipo I , Feminino , Humanos , Pneumopatias/etiologia , Pneumopatias/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/imunologia , Insuficiência Renal/etiologia , Insuficiência Renal/imunologia , Estudos Retrospectivos , Ribonucleoproteína Nuclear Pequena U1/imunologia , Esclerodermia Difusa/complicações , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/complicações , Esclerodermia Limitada/imunologia , Fatores Sexuais , Dermatopatias/etiologia , Dermatopatias/imunologiaRESUMO
OBJECTIVE: Adipokines may influence inflammatory and/or immune responses. This study was undertaken to examine whether adiponectin affects the production of prostaglandin E(2) (PGE(2)) by rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. Fibroblast-like cells from the third or fourth passage were used as RASFs. Expression of adiponectin receptor messenger RNA (mRNA) and protein was detected. PGE(2) (converted from arachidonic acid) was measured by enzyme-linked immunosorbent assay (ELISA). Expression of mRNA and protein for cyclooxygenase 2 (COX-2) and membrane-associated PGE synthase 1 (mPGES-1), key enzymes involved in PGE(2) synthesis, was detected in RASFs. The effects of RNA interference (RNAi) targeting the adiponectin receptor genes and the receptor signal inhibitors were examined. The influence of adiponectin on NF-kappaB activation in RASFs was measured with an ELISA kit. RESULTS: Adiponectin receptors were detected in RASFs. Adiponectin increased both COX-2 and mPGES-1 mRNA and protein expression by RASFs in a time- and concentration-dependent manner. PGE(2) production by RASFs was also increased by the addition of adiponectin, and this increase was inhibited by RNAi for the adiponectin receptor gene, or coincubation with the receptor signal inhibitors. Enhancement of NF-kappaB activation by adiponectin as well as by interleukin-1beta was observed in RASFs. CONCLUSION: Our findings indicate that adiponectin induces COX-2 and mPGES-1 expression, resulting in the enhancement of PGE(2) production by RASFs. Thus, adiponectin may play a role in the pathogenesis of synovitis in RA patients.
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Adiponectina/metabolismo , Artrite Reumatoide/metabolismo , Dinoprostona/biossíntese , Fibroblastos/metabolismo , Membrana Sinovial/metabolismo , Adiponectina/genética , Adiponectina/farmacologia , Artrite Reumatoide/genética , Western Blotting , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Prostaglandina-E Sintases , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacosRESUMO
Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.
Assuntos
Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/metabolismo , Dinoprostona/metabolismo , Receptores de Prostaglandina E/metabolismo , Sarcoma 180/irrigação sanguínea , Sarcoma 180/metabolismo , Animais , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/prevenção & controle , Inibidores de Ciclo-Oxigenase/farmacologia , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfocinas/genética , Linfocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/deficiência , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E Subtipo EP3 , Sarcoma 180/patologia , Sarcoma 180/prevenção & controle , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
OBJECTIVE: To evaluate the clinical usefulness of measuring anti-RNA polymerase (RNAP) III antibody with a commercially available ELISA in Japanese patients with SSc. METHODS: This multicentre study involved 354 patients with SSc, 245 with non-SSc CTDs and 102 healthy controls. ELISAs were used to detect anti-RNAP III antibody, anti-topo I antibody and ACA. The presence of anti-RNAP III antibody in selected serum samples was confirmed by immunoprecipitation (IP) assay. RESULTS: By ELISA, anti-RNAP III antibody was detected in 38 (10.7%) patients with SSc, 3 (1.2%) with non-SSc CTD and no healthy controls. The clinical specificity for SSc was excellent (98.8%), although a small number of false positives occurred. The sensitivity of the anti-topo I and ACA ELISAs for SSc was 59.9%, which increased to 68.2% without a reduction in specificity when the anti-RNAP III measurement was added. Clinical features associated with positivity for the anti-RNAP III antibody include dcSSc, a high total skin score and a trend towards high prevalence of renal crisis, consistent with previous studies that used an IP assay. Furthermore, on clinical severity scales, SSc patients with anti-RNAP III antibody scored highest for skin and renal involvement among patients subgrouped by the presence of individual SSc-related antibodies. CONCLUSIONS: The measurement of anti-RNAP III antibody by ELISA is useful in routine clinical practice, because it helps diagnose SSc and identify a disease subset with severe skin and renal involvement.
Assuntos
Anticorpos Antinucleares/sangue , RNA Polimerase III/imunologia , Escleroderma Sistêmico/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Doenças do Tecido Conjuntivo/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoprecipitação , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia , Índice de Gravidade de DoençaRESUMO
Henoch-Schönlein purpura is a systemic vasculitis of small vessels characterized by purpura, arthralgias, glomerulonephritis and gastrointestinal involvements which can cause intestinal perforation. A 75-year-old man with renal dysfunction and palpable purpura (petechiae) of which dermal specimen showed leukocytoclastic vasculitis was diagnosed as Henoch-Schönlein purpura. Corticosteroid and cyclosporine were effective, but subsequently he developed pneumocystis pneumonia. After he improved by treatment with trimethoprim-sulfamethoxazole, he presented sudden abdominal pain, caused by perforation of the gallbladder. Histological analysis revealed infiltration of inflammatory cells with bleeding in the gallbladder wall at the site of perforation. It is suggested that inflammatory disruption of capillary walls might lead to the perforation of the gallbladder.
Assuntos
Vesícula Biliar/patologia , Vasculite por IgA/complicações , Perfuração Intestinal/complicações , Abdome/diagnóstico por imagem , Dor Abdominal/complicações , Dor Abdominal/etiologia , Idoso , Colecistectomia , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/cirurgia , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/patologia , Perfuração Intestinal/etiologia , Tempo de Internação , Masculino , Alta do Paciente , Lavagem Peritoneal , Resultado do Tratamento , UltrassonografiaRESUMO
We conducted a pilot study to investigate whether tacrolimus was effective for treating patients with systemic lupus erythematosus (SLE) without renal involvement. Ten SLE patients with symptoms such as arthritis and erythema, but no active nephritis, were treated with tacrolimus. They included 8 women and 2 men aged from 24 to 62 years [mean +/- standard deviation (SD): 42.1 +/- 11.3 years]. Tacrolimus was administered at doses of 1-3 mg daily, and efficacy was assessed from the SLE Disease Activity Index (SLEDAI) after 1 year. Two patients ceased treatment due to adverse reactions (after 4 days for chest pain and 7 months for recurrent infections). The other 8 patients completed 1 year of treatment, and significant improvement of disease activity was observed in 6 of them. The mean (+/-SD) SLEDAI showed a significant decrease after 1 year of tacrolimus therapy, from 6.8 +/- 3.1 to 3.4 +/- 0.9; p < 0.05 by Student's paired t test. The mean (+/-SD) dose of prednisolone also decreased significantly, from 16.8 +/- 8.6 to 9.3 +/- 4.6 mg/day; p < 0.05. Although a prospective controlled study will be necessary to confirm, tacrolimus might be a treatment option for active SLE without renal involvement.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Tacrolimo/administração & dosagem , Adulto , Anti-Inflamatórios/uso terapêutico , Estudos de Coortes , Complemento C3/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunoglobulina G/sangue , Imunossupressores , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Projetos Piloto , Prednisolona/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Tacrolimo/efeitos adversos , Resultado do TratamentoRESUMO
Pulmonary involvement is a common future in patient with collagen diseases. Some of the pulmonary involvements are a resistant of current available treatment and a fetal condition. These conditions include interstitial pneumonitis in scleroderma, acute diffuse alveolar damage (DAD) in polymyositis/dermatomyositis (PM/DM), alveolar hemorrhage, and pulmonary hypertension in collagen disease. Intensive immunosuppressive treatment in early stage of interstitial pneumonitis may be effective for an intractable condition. Oral cyclophosphamide therapy is effective for non specific interstitial pneumonitis of scleroderma in a randomized control trial. Acute interstitial pneumonitis, so called DAD in patients with PM/DM is a resistant of steroid therapy and a poor prognostic complication. Combination therapy with high dose corticosteroids and immunosuppressive drugs (cyclosporin A, cyclophosphamide) is sometimes available therapy. Diffuse alveolar hemorrhage sometimes occurred in collagen disease including antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis, systemic lupus erythematosus. Intensive treatment need to inhibit hemorrhage.
Assuntos
Doenças do Colágeno/complicações , Doenças Pulmonares Intersticiais/etiologia , Corticosteroides/uso terapêutico , Ciclofosfamida/uso terapêutico , Dermatomiosite/complicações , Quimioterapia Combinada , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Pneumopatias/etiologia , Pneumopatias/terapia , Doenças Pulmonares Intersticiais/terapia , Polimiosite/complicações , Alvéolos Pulmonares , Escleroderma Sistêmico/complicaçõesRESUMO
We report two cases presenting focal neurological deficits with high intensity lesions in fluid attenuated inversion recovery (FLAIR) images on brain magnetic resonance imaging (MRI), which almost completely improved by corticosteroid therapy. Marked elevation of cerebrospinal fluid IL-6 was also noted when these patients showed neurological deficits. As far as we explored, there have been thirteen published case reports of systemic lupus erythematosus patients with reversible focal neurological deficits. The neurological symptoms varied from case to case, but could be attributed to the lesions on MRI scans. The completely reversible feature of neurological manifestations as well as MRI findings on corticosteroid therapy is distinct from any other disorder, including cerebrovascular disease and demyelinating syndrome, in the 1999 American College of Rheumatology nomenclature. Therefore, we propose that reversible focal neurological deficits should be added to the 1999 nomenclature and classification and case definitions.
Assuntos
Lúpus Eritematoso Sistêmico/complicações , Doenças do Sistema Nervoso/etiologia , Adulto , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Doenças do Sistema Nervoso/patologiaRESUMO
Lipoxin A(4) (LXA(4)) is an eicosanoid which is produced via lipoxygenases and characteristic of its anti-inflammatory effect in many metabolites of arachidonic acid, which are mostly pro-inflammatory. Glucocorticoids are well known also for their strong anti-inflammatory action but induce 5-lipoxygenase, essential to synthesize leukotrienes, which are pro-inflammatory. To elucidate the interaction of glucocorticoids and lipoxin A(4) for anti-inflammation, we analyzed in vitro expression of lipoxin A(4) receptor (ALX) on human neutrophils and the in vivo anti-inflammatory effect of glucocorticoids and LXA(4) using a dermal inflammation mouse model. ALX mRNA was up-regulated by dexamethasone (Dex) in human neutrophils. A glucocorticoid receptor antagonist, mifepristone, suppressed up-regulation of ALX induced by Dex. LXA(4) and/or Dex decreased CD11b expression on human neutrophils and suppressed mouse dermatitis induced by LTB(4). These results suggest that anti-inflammatory effects of glucocorticoids depend at least partly on up-regulation of ALX and that the lipoxin system could be a negative feedback regulator for LTB(4).
Assuntos
Glucocorticoides/metabolismo , Lipoxinas/metabolismo , Receptores de Formil Peptídeo/genética , Receptores de Lipoxinas/genética , Adulto , Antígeno CD11b/genética , Primers do DNA , Humanos , Inflamação/fisiopatologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis and excessive collagen deposition in the skin and various internal organs. In early stages of SSc, the dermis reveals infiltration of inflammatory cells associated with increased collagen synthesis. SKL-2841 was initially synthesized as a novel small molecule antagonist of MCP-1. In this study, we indicated that SKL-2841 also exerts anti-chemotactic activity for MIP-1 beta in mouse spleen cells. In the early stages of bleomycin-induced skin lesions, immunohistochemical analysis showed the expression of both MCP-1 and MIP-1 beta in dermal inflammatory cells. Moreover, intraperitoneal administration of SKL-2841 suppressed the infiltration of inflammatory mononuclear cells and polymorphonuclear cells in the acute phase and also significantly suppressed fibrillization in the chronic phase in bleomycin-induced scleroderma, compared with PBS treatment. These findings suggest that SKL-2841 has potential as a compound for the treatment of conditions associated with skin fibrosis such as SSc.