RESUMO
INTRODUCTION: We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). METHODS: We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. RESULTS: uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. CONCLUSIONS: uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.
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Fator Ativador de Células B/urina , Lúpus Eritematoso Sistêmico/urina , Nefrite Lúpica/urina , Adolescente , Adulto , Idoso , Austrália , Biomarcadores/urina , Estudos de Casos e Controles , Quimiocina CCL2/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/urina , Adulto JovemRESUMO
BACKGROUND: Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is now standard care in this disease. The existing Australian Scleroderma Interest Group algorithm (ASIGSTANDARD ) is based on transthoracic echocardiography (TTE) and pulmonary function tests (PFT). Recently, ASIG has derived and validated a new screening algorithm (ASIGPROPOSED ) that incorporates N-terminal pro-B-type natriuretic peptide level together with PFT in order to decrease reliance on TTE, which has some limitations. Right heart catheterisation (RHC) remains the gold standard for the diagnosis of PAH in patients who screen 'positive'. AIM: To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms. METHODS: We applied both ASIGSTANDARD and ASIGPROPOSED algorithms to 643 screen-naïve SSc patients from the Australian Scleroderma Cohort Study (ASCS), assuming a PAH prevalence of 10%. We compared the costs of screening, the number of TTE required and both the total number of RHC required and the number of RHC needed to diagnose one case of PAH, and costs, according to each algorithm. We then extrapolated the costs to the estimated total Australian SSc population. RESULTS: In screen-naïve patients from the ASCS, ASIGPROPOSED resulted in 64% fewer TTE and 10% fewer RHC compared with ASIGSTANDARD , with $1936 (15%) saved for each case of PAH diagnosed. When the costs were extrapolated to the entire Australian SSc population, there was an estimated screening cost saving of $946 000 per annum with ASIGPROPOSED , with a cost saving of $851 400 in each subsequent year of screening. CONCLUSIONS: ASIGPROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIGSTANDARD .
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Algoritmos , Redução de Custos/métodos , Hipertensão Pulmonar/economia , Programas de Rastreamento/economia , Escleroderma Sistêmico/economia , Idoso , Estudos de Coortes , Ecocardiografia/economia , Ecocardiografia/métodos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Testes de Função Respiratória/economia , Testes de Função Respiratória/métodos , Escleroderma Sistêmico/diagnósticoRESUMO
BACKGROUND/AIM: To determine the epidemiology and clinical features of biopsy-proven giant cell arteritis (GCA) in South Australia (SA). METHODS: Patients with biopsy-proven GCA were identified from pathology reports of temporal artery biopsies at SA Pathology laboratories, from 1 January 1992, to 31 July 2011. Epidemiological data were collected through patient questionnaires and standardised case note reviews. Incidence was estimated using Australian Bureau of Statistics population data for SA. Seasonality was analysed by Cosinor analysis, and time-to- event analysis was performed for the duration of steroid use. RESULTS: There were 314 cases of biopsy-proven GCA (72% female). The mean age at diagnosis of GCA was 78 years (interquartile range 72-82). The estimated population incidence for people over 50 was 3.2 per 100,000 person years. The female : male incidence ratio was 2.3 (P < 0.001), and incidence increased with each age decade. There was evidence of seasonal variation (P = 0.015), with higher rates observed in the summer months. Clinical data were available for 163 patients (68% female, median age 78 years). The most common presenting clinical features were temporal headache (74%), visual disturbance (68.4%), jaw claudication (59.3%) and symptoms of polymyalgia rheumatica (56%). The median initial steroid dose was 60 mg, with median duration of steroid use 4.5 years. Corticosteroid side-effects were common, affecting 89%, with 34% reporting five or more. CONCLUSIONS: This is the first epidemiological study of Australian biopsy-proven GCA patients. Age at onset and gender associations were similar to other Western populations. There was a high burden of steroid use in these patients.
Assuntos
Arterite de Células Gigantes/epidemiologia , Artérias Temporais/patologia , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Comorbidade , Feminino , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/patologia , Humanos , Incidência , Masculino , Sistema de Registros , Fatores de Risco , Estações do Ano , Austrália do Sul/epidemiologia , Avaliação de SintomasRESUMO
BACKGROUND: The role of inflammasomes in chronic inflammation has been the subject of intense research in recent years. Chronic rhinosinusitis (CRS), a persistent inflammatory disease, continues to be investigated hoping that a clearer pathophysiologic description will guide discovery of future treatment modalities. This study investigates the role of inflammasome complexes in CRS patients with Staphylococcus aureus biofilm infection, a key culprit associated with disease severity and recalcitrance. METHODOLOGY: Sinonasal tissue samples were collected from CRS patients with (P+) and without (P-) polyps and controls. S. aureus biofilm status was obtained using fluorescence in situ hybridization and classified as biofilm positive (B+) or negative (B-). RNA was analysed using a Human Inflammasome PCR array, profiling the expression of 84 genes involved in inflammasome function. RESULTS: Sixteen samples were obtained: 5 B+P+, 5 B-P- and 6 controls. Comparing B+P+ vs. controls showed the greatest number of differentially expressed genes. In particular, Absent in Melanoma 2 (AIM2) was consistently and significantly up-regulated in the B+P+ vs. B-P- and controls. In contrast, when comparing the B-P- vs. controls, no genes showed significant changes. CONCLUSION: Our results indicate the involvement of inflammasome complexes and their signalling pathways in CRS patients with polyps and S. aureus biofilms. In particular, AIM2, activated by intracellular double-stranded DNA, is up-regulated in this group, implying that S. aureus may play a role in intracellular triggering of the inflammasome response. Studies with further patient stratification and assessing corresponding protein expression are needed to further characterize the role of inflammasomes in CRS.
Assuntos
Biofilmes , Inflamassomos/metabolismo , Rinite/etiologia , Sinusite/etiologia , Infecções Estafilocócicas/etiologia , Staphylococcus aureus/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Inflamassomos/genética , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/etiologia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , RNA Mensageiro/metabolismo , Rinite/metabolismo , Rinite/patologia , Sinusite/metabolismo , Sinusite/patologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/patologiaRESUMO
OBJECTIVE: The RCA alpha block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA alpha block haplotype associations with both disease susceptibility and diversification of the anti-Ro/La autoantibody response in primary Sjögren syndrome (pSS). METHODS: 115 patients with pSS and 98 controls were included in the study. 93 of 109 (85%) of the patients with pSS were seropositive for Ro/La autoantibodies. The Genomic Matching Technique (GMT) was used to define RCA alpha block ancestral haplotypes (AH). RESULTS: RCA alpha block haplotypes, AH1 and AH3, were both associated with autoantibody-positive pSS (p = 0.0003). Autoantibody associations with both HLA DR3 and DR15 have been previously defined. There was an epistatic interaction (p = 0.023) between RCA alpha AH1 and HLA DR3, and this genotypic combination was present in 48% of autoantibody-positive patients with pSS compared with 8% of controls. This epistasis is most simply attributable to an interaction between C4 and its receptor, CR1, encoded within the RCA alpha block. Both DR3 and a relative C4 deficiency are carried on the major histocompatibility complex 8.1 ancestral haplotype. Only four of 92 (4%) autoantibody-positive patients with pSS did not carry any risk RCA alpha or HLA haplotype, compared with 36 of 96 (38%) controls, and there were differences in haplotype frequencies within autoantibody subsets of pSS. CONCLUSIONS: Normal population variation in the RCA alpha block, in addition to the major histocompatibility complex, contributes genetic susceptibility to systemic autoimmune disease and the autoantibody response. This finding provides evidence for the role of regulation of complement activation in disease pathogenesis.
Assuntos
Epistasia Genética , Genes MHC da Classe II , Receptores de Complemento 3b/genética , Síndrome de Sjogren/genética , Autoanticorpos/sangue , Autoantígenos/imunologia , Estudos de Casos e Controles , Complemento C4/imunologia , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Ribonucleoproteínas/imunologia , Síndrome de Sjogren/imunologia , Antígeno SS-BRESUMO
OBJECTIVE: To investigate the association between haplotypes in the 5' regulatory region of the B-lymphocyte activating factor (BAFF) gene, disease susceptibility and serum BAFF (s-BAFF) levels in Caucasian primary SS (pSS) patients. METHODS: Case-control study in an established pSS cohort with PCR-RFLP genotyping for four SNPs (-2841 T-->C, -2704 T-->C, -2701 T-->A, -871 C-->T), which tag a haplotype block in the 5' regulatory region of the BAFF gene and s-BAFF determination by ELISA. RESULTS: s-BAFF levels were elevated in Ro/La-positive pSS patients (n = 85, 1770 pg/ml) compared with both Ro/La-negative pSS patients (n = 27, 1193 pg/ml) and controls (n = 59, 1171 pg/ml), P < 0.001. s-BAFF increased with diversification of the anti-Ro/La antibody response, but was not correlated with age, RF or immunoglobulin G levels. There were four common BAFF haplotypes. While the CTAT haplotype was associated with Ro/La-positive pSS [odds ratio (OR) 2.6; 95% CI 1.7, 4.1; P = 0.00004], the TTTT haplotype was associated with elevated s-BAFF in autoantibody-positive pSS (n = 85; 88% females; P = 0.008). The shared -871 T allele had no independent contribution to disease susceptibility or s-BAFF. CONCLUSIONS: Disease susceptibility for Ro/La-positive pSS is increased with the CTAT haplotype, but not associated with high s-BAFF levels. Elevated s-BAFF levels in pSS are associated with the TTTT haplotype and may be a secondary phenomenon in Ro/La-positive pSS. While both haplotypes carry the -871 T allele, this allele is not independently associated with disease susceptibility.
Assuntos
Autoanticorpos/sangue , Fator Ativador de Células B/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren/genética , Anticorpos Antinucleares/sangue , Autoantígenos/imunologia , Fator Ativador de Células B/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Ribonucleoproteínas/imunologia , Síndrome de Sjogren/imunologia , Antígeno SS-BRESUMO
OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.
Assuntos
Autoanticorpos/imunologia , Escleroderma Sistêmico/imunologia , Idoso , Antígenos Nucleares/imunologia , Austrália , Autoantígenos/imunologia , Proteína Centromérica A , Proteína B de Centrômero/imunologia , Proteínas Cromossômicas não Histona/imunologia , Estudos de Coortes , Contratura/etiologia , Contratura/imunologia , DNA Topoisomerases Tipo I/imunologia , Proteínas de Ligação a DNA/imunologia , Transtornos da Motilidade Esofágica/etiologia , Transtornos da Motilidade Esofágica/imunologia , Exorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo/imunologia , Feminino , Ectasia Vascular Gástrica Antral/etiologia , Ectasia Vascular Gástrica Antral/imunologia , Humanos , Immunoblotting , Autoantígeno Ku , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Proteínas Pol1 do Complexo de Iniciação de Transcrição/imunologia , Análise de Componente Principal , RNA Polimerase III/imunologia , Proteínas de Ligação a RNA/imunologia , Doença de Raynaud/etiologia , Doença de Raynaud/imunologia , Receptores do Fator de Crescimento Derivado de Plaquetas/imunologia , Ribonucleoproteínas/imunologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/epidemiologia , Fatores Sexuais , Fumar/epidemiologia , Telangiectasia/etiologia , Telangiectasia/imunologiaRESUMO
Autoimmunity to La(SS-B) and Ro(SS-A) is a paradigm for understanding the normal mechanisms of B cell and T cell tolerance and development of autoimmunity to clinically important sequestered autoantigens. Epitope mapping experiments have indicated that the autoantibody response is largely self antigen-driven but have failed to elucidate why these particular autoantigens are selected. Abnormal trafficking of La or Ro peptides in polarised epithelial cells and their presentation to autoreactive T cells, or selective release of ribonucleoproteins by injured epithelial cells, could explain the targeting of salivary and lacrimal epithelium in Sjogren's syndrome. There appears to be little, if any, immune tolerance to La in the T helper and B cell compartments. Both intra-and inter-molecular spreading of the autoimmune response have been observed for La. We present a model of recruited autoimmunity whereby capture and internalisation of La/Ro ribonucleoproteins by B cells and subsequent presentation of La or Ro determinants to autoreactive T cells could lead to inter-molecular spreading of the response.
Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , RNA Citoplasmático Pequeno , Ribonucleoproteínas/imunologia , Humanos , Antígeno SS-BRESUMO
Characterisation of autoantibodies and their target autoantigens in primary Sjögren's syndrome (SS) is an important entry point for studying this common systemic autoimmune disease. Diversification of anti-Ro/La responses is believed to occur by a process of determinant spreading following initiation of an autoimmune response to one component, possibly 52-kD Ro (Ro52). Recent evidence supports the ER-resident chaperone Grp78 as a potential candidate in the initiation of an autoimmune response against Ro52, by binding to a Grp78 binding motif in the COOH-terminal region of Ro52. The subsequent diversification of the anti-Ro/La response is influenced by distinct HLA class II alleles. Anti-salivary duct autoantibodies have been revisited and shown to be mimicked by cross-reactive isoantibodies to AB blood group antigens. Identification of autoantibodies that act as antagonists at M3-muscarinic receptors represents an important advance. As well as contributing to the sicca symptoms, the functional effects of these autoantibodies may explain associated features of autonomic dysfunction in patients with SS. Anti-M3 receptor autoantibodies occur in both primary and secondary SS and allow Sjögren's syndrome to be viewed as a disorder of anti-receptor autoimmunity.
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Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Síndrome de Sjogren/imunologia , Animais , Anticorpos Antinucleares/genética , Especificidade de Anticorpos , Carbacol/metabolismo , Chaperona BiP do Retículo Endoplasmático , Haplorrinos , Camundongos , Receptores Muscarínicos/imunologia , Receptores Muscarínicos/metabolismo , Ductos Salivares/imunologia , Síndrome de Sjogren/patologiaRESUMO
Anti-Ro (SS-A) antibodies are important diagnostic markers for primary Sjögren's syndrome and systemic lupus erythematosus, but their detection by indirect immunofluorescence (IF) in the diagnostic laboratory is hindered by the low cellular abundance of 60kDa Ro protein (Ro60). The approach we used to overcome this problem was to transfect and over-express the Ro60 gene into HEp-2 cells. In this study we have used a mixture of Ro60 transfectants and untransfected HEp-2 cells (HEp-Ro60) as a substrate for IF-antinuclear antibody (ANA) testing in a hospital laboratory. Screening of 240 routine serum specimens identified 14 Ro transfectant-positive sera which were confirmed by counterimmunoelectrophoresis (CIE); 3 of these sera were ANA-negative on untransfected cells and regular HEp-2. A comparison of HEp-Ro60 and regular HEp-2 showed strong concordance of the different ANA patterns between the 2 substrates. No increase in background staining was observed on the Ro transfectants when reacted with normal human sera. A comparison between HEp-Ro60 and CIE for 53 sera from patients with primary Sjögren's syndrome showed that HEp-Ro60 were a sensitive and specific substrate for detection of anti-Ro antibodies. Masking of positive Ro transfectants was observed rarely in sera containing multiple ANA specificities, but the Ro60 staining on these transfectants were unmasked at higher serum dilutions. We conclude that HEp-Ro60 are a suitable substrate for IF-ANA in the routine laboratory and that they have the additional advantage over regular HEp-2 slides of being able to detect anti-Ro in ANA-negative sera. HEp-RO60 are also a valuable confirmatory test for sera giving equivocal precipitin reactions or ELISA results.
Assuntos
Anticorpos Antinucleares/análise , Autoantígenos/imunologia , RNA Citoplasmático Pequeno , Ribonucleoproteínas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imunoeletroforese Bidimensional , Masculino , Pessoa de Meia-Idade , Ribonucleoproteínas/genética , Sensibilidade e Especificidade , Transfecção/imunologia , Células Tumorais CultivadasRESUMO
OBJECTIVE: To determine associations between sicca symptoms, chronic rhinosinusitis (CRS) symptoms and asthma in a community survey. METHODS: Data was obtained from the Spring 2009 South Australian Health Omnibus Survey which sampled, via interviewer administered questionnaire, 3007 individuals aged 15 years and over whose socio-demographic distribution corresponded to South Australian population estimates. Respondents were asked a range of questions relating to the presence of persistent dry eyes or dry mouth, CRS and medically diagnosed nasal polyps and asthma. Relationships between symptoms were explored using maximum likelihood dependency tree analysis. RESULTS: THE RESPECTIVE POPULATION PREVALENCES WERE: dry mouth (5.9%), dry eyes (8.6%), nasal polyps (3.8%), CRS (13.2%) and asthma (12.0%). The overall prevalence of sicca symptoms (dry eyes or dry mouth) was 12.4%. Dependency tree analysis revealed the expected symptom clustering between (1) sicca symptoms and their association with female gender and increasing age and (2) CRS, nasal polyps and asthma (one airway hypothesis). However there was also an association between dry eyes and CRS (OR 2.5, 95% CI 1.9, 3.4), which was in fact stronger than the association between CRS and asthma (OR 1.9, 95% CI 1.4, 2.5). CONCLUSIONS: Sicca symptoms are common in the community. Our novel finding of a strong association between dry eyes and CRS suggests that further research into the relationship between airway inflammation and sicca symptoms is required. These findings may have particular relevance to Sjögren's syndrome (SS) in both its primary and secondary forms.
RESUMO
OBJECTIVE: Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes. METHODS: In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose. RESULTS: Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen. CONCLUSION: Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Biomarcadores/sangue , Cartilagem/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Placebos , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival. AIM: To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients. METHODS: Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma. RESULTS: Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT. CONCLUSION: Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.
Assuntos
Hipertensão Pulmonar/etiologia , Esclerodermia Limitada/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Esclerodermia Limitada/mortalidade , Austrália do Sul , Análise de SobrevidaRESUMO
OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. METHODS: Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. RESULTS: Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by approximately 50%. Sera from these patients also inhibited the action of neuronally released acetylcholine at M3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. CONCLUSION: Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients.
Assuntos
Autoanticorpos/sangue , Sistema Nervoso Parassimpático/imunologia , Receptores Muscarínicos/imunologia , Síndrome de Sjogren/imunologia , Transmissão Sináptica/imunologia , Acetilcolina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/farmacologia , Carbacol/farmacologia , Feminino , Humanos , Imunoglobulina G/farmacologia , Técnicas In Vitro , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Agonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/metabolismo , Receptor Muscarínico M3 , Síndrome de Sjogren/sangue , Transmissão Sináptica/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacosRESUMO
In systemic autoimmunity, the human B cell response to the La (SS-B) autoantigen is polyclonal and directed to both conserved and human-specific epitopes. This study has further characterized the B cell epitope(s) present within the conserved central region of the La protein, LaC (amino acids 111-242) containing the RNA recognition motif (RRM, aa 111-187). Ten overlapping and non-overlapping protein fragments spanning LaC were expressed in bacteria as NH2-terminal fusions with glutathione-S-transferase. The fusion proteins were tested by ELISA for reactivity with a panel of human anti-La sera in order to define the nature of the epitopes. Ninety-two percent of patient sera containing anti-La antibodies reacted with the region of La containing the RRM. Fine mapping of this reactivity using deletion mutants indicated that the deletion of 19 amino acids from either the NH2-terminal or COOH-terminal region of the RRM was associated with loss of antibody reactivity, suggesting that the immunodominant epitope expressed in this region is discontinuous. Autoantibodies affinity-purified from the La RRM fragment to remove other specificities immunoprecipitated newly synthesized native La (SS-B)/Ro (SS-A) complexes, providing additional evidence that autoantibodies were recognizing a conformational epitope. The findings indicate that the human autoantibody response to La involves recognition of a conformational determinant involving the conserved RRM region without necessarily interfering with the RNA-dependent association of the La/Ro ribonucleoprotein.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Epitopos/imunologia , RNA Citoplasmático Pequeno , Ribonucleoproteínas/imunologia , Autoanticorpos/metabolismo , Autoantígenos/metabolismo , Sequência de Bases , Mapeamento de Epitopos/normas , Epitopos/metabolismo , Humanos , Dados de Sequência Molecular , Testes de Precipitina , Ribonucleoproteínas/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Antígeno SS-BRESUMO
A case of giant cell arteritis presenting in an atypical fashion with respiratory and upper limb ischaemic symptoms is described. The subclavian and axillary arterial involvement is demonstrated in this case, and followed up with repeated angiographic examinations over the next 3 yr. Despite resolution of all symptoms and return of pulses and a recordable blood pressure in the ischaemic upper limb, there was no angiographic evidence of resolution of the axillary artery stenoses.
Assuntos
Braço/irrigação sanguínea , Tosse/etiologia , Arterite de Células Gigantes/complicações , Isquemia/etiologia , Doença Crônica , Feminino , Seguimentos , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/patologia , Humanos , Pessoa de Meia-Idade , RadiografiaRESUMO
The immunoglobulin kappa (Km) light chain gene is polymorphic and is believed to play a role in the pathology of infectious and autoimmune diseases. Polymorphisms within the constant region of the Km gene encode three alleles designated Km1, Km1,2 and Km3. Previous studies using serological detection of Km allotypes reported associations between specific Km allotypes, systemic lupus erythematosus and the presence of anti-La antibodies, yet these findings were not confirmed in other studies. In order to more precisely define any associations between Km alleles and anti-Ro/La antibodies we used the polymerase chain reaction and restriction fragment length polymorphisms for Km genotyping in a large cohort of patients with primary Sjögren's syndrome (SS). No associations were observed between specific Km alleles and primary SS when compared with a control population, nor within serologically defined subsets of SS patients. We conclude that Km alleles are not associated with primary SS or the Ro/La autoantibody response.
Assuntos
Predisposição Genética para Doença , Cadeias kappa de Imunoglobulina/genética , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Frequência do Gene , Humanos , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
BACKGROUND: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). OBJECTIVE: To examine genetic variation in the promoter region of the Fas gene in pSS. METHODS: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. RESULTS: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). CONCLUSION: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.
Assuntos
Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Síndrome de Sjogren/genética , Receptor fas/genética , Anticorpos Antinucleares/sangue , Frequência do Gene , Genótipo , Humanos , Síndrome de Sjogren/imunologiaRESUMO
OBJECTIVE: We evaluated the clinical relevance and pathogenic significance of anti-salivary duct autoantibodies (ASDA) in Sjögren's syndrome (SS) and rheumatoid arthritis (RA) by examining (1) their frequency in healthy controls, patients with sicca symptoms, and patients with various autoimmune and infective disorders; (2) their localization by confocal microscopy; and (3) their tissue distribution and cross reactivity with blood group antigens. METHODS: Indirect immunofluorescence (IF) was performed on commercial cryostat sections of monkey parotid salivary gland. Sections were examined by fluorescence and confocal laser scanning microscopy. Sera giving positive staining on the ducts were tested by IF on a range of monkey tissues and salivary glands from several mammalian species. Blocking experiments were performed with human erythrocytes of different ABO blood groups and AB antigens. RESULTS: We identified 2 distinct ductal staining patterns. The first resembled ASDA described in earlier studies and showed patchy bright staining of the apical (luminal) surfaces of the ducts and staining of apical cytoplasmic vesicles. The other was only observed with anti-mitochondrial antibody positive sera and stained the mitochondrial-rich ductal epithelium in a distinctive punctate pattern. Antibodies staining the apical surface of ducts were detected rarely in patients with antiRo/La autoantibody-positive primary SS (1/76) and RA (1/36) and were found in only 1115 with RA and secondary SS. ASDA were detected in sera from 13/51 (25.5%) of patients referred to our clinic with limited sicca symptoms who were anti-Ro/La antibody-negative and had no typical clinical or laboratory features of classical primary SS. The apical ductal staining pattern was not observed with sera from 63 healthy controls without sicca symptoms or in patients with autoimmune and infective disorders. Twelve of the 13 patients whose sera gave ASDA-like staining were blood group O and one group A. Ductal staining was abolished in all sera after absorption with blood group AB erythrocytes or AB antigen. In 5 patients ductal staining was removed by absorption with B erythrocytes but not with A erythrocytes; in the remainder ductal reactivity was abolished by both A and B erythrocytes. CONCLUSION: ASDA seem to occur rarely in patients with primary SS and RA. However, isotype-switched IgG AB blood group antibodies cross react with primate salivary ducts and may produce false positive ASDA staining. Detection of ASDA may be of value in identifying a subset of patients who present with mild sicca symptoms without other autoimmune features.