RESUMO
OBJECTIVE: To assess the role of thrombocytopaenia as an independent predictor of outcome in patients with systemic lupus erythematosus (SLE). METHODS: This was a single-centre, retrospective, matched case-control study (1:2). Fifty consecutive Greek SLE patients were selected at random who had developed thrombocytopaenia during the disease course (cases) were compared with 100 SLE patients with no history of thrombocytopaenia, and matched for age, sex and disease duration (controls). Overall damage was assessed at the end of follow-up, using Systemic Lupus International Collaborating Clinics index. Total number of irreversible organ-damage events for both groups were recorded. Rates for specific outcomes and incidence-rate ratios (IRRs) for damage were estimated. Multivariate analysis estimating influential clinical and immunological factors for outcome, including thrombocytopaenia, was performed. RESULTS: After 583 person-years of follow-up for cases and 1155 for controls, we found that thrombocytopaenic individuals have a higher risk for damage (IRR 1.96, 1.52-2.53) compared with their matched controls and this effect persists throughout the course of their disease. They also have a predilection to certain types of damage involving heart and kidneys. Among other significant factors associated with damage in multivariate analysis (disease activity, serositis, anti-cardiolipin antibodies, central nervous system involvement), thrombocytopaenia appears as the most influential. CONCLUSION: Thrombocytopaenia is a quantitive and qualitative marker of impending damage in SLE patients.
Assuntos
Lúpus Eritematoso Sistêmico/sangue , Trombocitopenia/imunologia , Adolescente , Adulto , Anticorpos Anticardiolipina/imunologia , Autoanticorpos/imunologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Análise Multivariada , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren's syndrome (pSS) from different European countries. PATIENTS AND METHODS: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169-190aa and p211-232aa) and La/SSB (p147-154aa, p291-302aa, p301-318aa, and p349-364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies. RESULTS: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10-37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58-86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349-364aa, were significantly positively associated with longer disease duration (p<0.05), recurrent or permanent parotid gland enlargement (p<0.005), and a higher proportion of non-exocrine manifestations (p<0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p<0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59-69aa of DQB1 first domain (p<0.01, respectively). CONCLUSIONS: Autoantibodies against La/SSB, binding to four synthetic peptides, derived from the sequence of the La protein were identified with increased frequency in sera of patients with pSS. The formation of autoantibodies against B cell epitope analogues of La/SSB in European patients with pSS may be dependent on the presence of a permissive HLA-DQ heterodimer, most prominently represented by the HLA-DQA1*0501/DQB1*0201 heterodimer, suggesting that a model of HLA restricted presentation of La/SSB peptide determinants is crucial for the autoimmune response against La/SSB.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/imunologia , RNA Citoplasmático Pequeno , Ribonucleoproteínas/imunologia , Síndrome de Sjogren/imunologia , Idoso , Suscetibilidade a Doenças , Epitopos/imunologia , Europa (Continente) , Feminino , Genótipo , Antígenos HLA-DQ , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Antígeno SS-BRESUMO
BACKGROUND: Pulmonary capillary endothelium-bound (PCEB) angiotensin-converting ectoenzyme (ACE) activity alteration is an early, sensitive, and quantifiable lung injury index in animal models. We hypothesized that (1) PCEB-ACE alterations can be found in patients with acute lung injury (ALI) and (2) PCEB-ACE activity correlates with the severity of lung injury and may be used as a quantifiable marker of the underlying pulmonary capillary endothelial dysfunction. METHODS AND RESULTS: Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis of the synthetic ACE substrate (3)H-benzoyl-Phe-Ala-Pro (BPAP) in 33 mechanically ventilated, critically ill patients with a lung injury score (LIS) ranging from 0 (no lung injury) to 3.7 (severe lung injury) and calculated the kinetic parameter A(max)/K(m). Both parameters decreased early during the ALI continuum and were inversely related to APACHE II score and LIS. Hydrolysis decreased with increasing cardiac output (CO), whereas 2 different patterns were observed between CO and A(max)/K(m). CONCLUSIONS: PCEB-ACE activity decreases early during ALI, correlates with the clinical severity of both the lung injury and the underlying disease, and may be used as a quantifiable marker of underlying pulmonary capillary endothelial dysfunction.
Assuntos
Endotélio Vascular/enzimologia , Pulmão/enzimologia , Peptidil Dipeptidase A/metabolismo , Síndrome do Desconforto Respiratório/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gasometria , Endotélio Vascular/citologia , Feminino , Hemodinâmica , Humanos , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/metabolismo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Respiração Artificial , Síndrome do Desconforto Respiratório/diagnóstico , Taxa de Sobrevida , TrítioRESUMO
BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. METHODS: The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). RESULTS: Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. CONCLUSIONS: Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.
Assuntos
Transtornos da Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/genética , Peptidil Dipeptidase A/genética , Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/genética , Feminino , Genótipo , Humanos , Hipertensão/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
BACKGROUND: Sjögren's syndrome (SS) is one of the most common systemic autoimmune diseases in middle-aged women. The present study had the aim to examine the dental and periodontal condition in patients with SS in comparison with disease controls and to evaluate the influence of reduced salivary flow in the periodontal tissues. METHOD: We examined 24 patients with primary or secondary SS in comparison with 27 patients who had another autoimmune disease but no signs or symptoms of SS, as well as with 29 subjects who had a subjective feeling of xerostomia or xerophthalmia without exhibiting an underlying disease. The clinical evaluation included examination of the oral mucosa, determination of missing, decayed and filled teeth, fixed or removable prosthetic appliances, plaque index, gingival index, probing pocket depth, probing attachment level, oral hygiene habits and frequency of dental visits. Statistical analysis was performed using the 2-tailed Fisher exact and Kruskal-Wallis tests. RESULTS: No significant difference was found in the dental or periodontal condition of the 3 groups. The number of teeth, feelings and distal or mesial decay lesions correlated negatively with age, while the number of fixed prosthetic appliances correlated positively. The salivary flow was statistically lower in patients with SS and exhibited a negative correlation with the number of cervical decay lesions. It was also found that SS patients had better oral hygiene habits than subjects of the control groups. CONCLUSIONS: No significant,difference could be detected concerning the dental and periodontal status of SS patients, compared with that of patients with other immune diseases as well as with that of controls who had subjective xerostomia.
Assuntos
Doenças Periodontais/classificação , Síndrome de Sjogren/complicações , Doenças Dentárias/classificação , Fatores Etários , Doenças Autoimunes/complicações , Doenças Autoimunes/fisiopatologia , Estudos de Casos e Controles , Índice CPO , Assistência Odontológica , Índice de Placa Dentária , Dentaduras/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Higiene Bucal , Perda da Inserção Periodontal/classificação , Índice Periodontal , Bolsa Periodontal/classificação , Análise de Regressão , Cárie Radicular/classificação , Saliva/metabolismo , Taxa Secretória/fisiologia , Síndrome de Sjogren/fisiopatologia , Colo do Dente/patologia , Xeroftalmia/complicações , Xerostomia/complicaçõesRESUMO
OBJECTIVE: Description of Greek patients with scleroderma with reference to (a) major organ disease, (b) autoantibodies, (c) survival rate, and (d) HLA associations. METHODS: The clinical files of 254 patients were analysed retrospectively and a standardised clinical chart was completed with age at disease onset, sex, date of first and last visit, clinical and serological findings, organs affected, reasons for death, and HLA class II alleles. HLA class II alleles (DRB1, DQA1, DQB1, DPB1) were determined by polymerase chain reaction amplification using oligopeptide probes. DNA was extracted from 98 patients and 130 Greek controls. RESULTS: 124 patients (49%) had limited systemic sclerosis (lSSc), 114 (45%) had diffuse systemic sclerosis (dSSc), and 16 (6%) had overlap syndromes. Patients with dSSc, compared with lSSc, were characterised by a higher prevalence of lung disease (p=0.0011), oesophageal, heart, and peripheral vessel disease (p=0.027, p=0.0025, and p=0.012, respectively). Anticentromere antibodies (ACA) occurred exclusively in lSSc (34%), whereas antibodies to topoisomerase I (anti-topo I) were associated with dSSc (p<0.0001). Anti-topo I were associated with interstitial pulmonary fibrosis, oesophageal and peripheral vessel disease (p=0.028, p=0.012, and p=0.01, respectively). The HLA-DRB1*1104 allele was associated with the disease (p<0.0001) and anti-topo I (p<0.001), whereas it was not associated with ACA serum reactivity (p<0.001). Renal disease occurred in 4% of patients with SSc. The estimated survival probability for this cohort of patients with SSc, four years after the first visit, is 94.8%. CONCLUSION: SSc among Greek subjects has the same pattern of organ disease as in other white populations. However, the prevalence of kidney disease is low. The HLA class II DRB1*1104 allele is associated with the disease, with anti-topo I, and not associated with ACA serum reactivity.
Assuntos
Alelos , Antígenos HLA-DR/sangue , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/mortalidade , Adulto , Autoanticorpos/sangue , Causas de Morte , Feminino , Seguimentos , Grécia/epidemiologia , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/imunologia , Taxa de SobrevidaRESUMO
OBJECTIVE: Several reports have noted an increased incidence of malignant lymphoma in patients with Sjögren's syndrome (SS). Each case series has consisted of a limited number of patients with malignant non-Hodgkin's lymphoma (MNHL). In this report, we describe the disease characteristics, the clinical course, and the evolution in 33 patients followed up in 9 European medical centers. METHODS: The pool of MNHL patients from participating centers in a European Concerted Action on SS were analyzed. We report on the disease characteristics, its evolution, prognosis, current treatment practices, and survival. RESULTS: The MNHLs in this study were primarily situated in the marginal zone (48.5%), with the manifestations mostly extranodal (78.8%) and most often identified in the salivary glands (54.6%). Lymphadenopathy (65.6%), skin vasculitis (33.3%), peripheral nerve involvement (24.2%), low-grade fever (25.0%), anemia (48.1%), and lymphopenia (78.6%) were observed significantly more frequently than in the general SS population. Patients with high-to-intermediate grade lymphoma had significantly worse survival (P = 0.041). The presence of B symptoms (fever, night sweats, and weight loss) and a large tumor diameter (>7 cm) were additional independent risk factors for death. CONCLUSION: The novel observations of this study were those related to the type of MNHL, the survival prognosis, and the very high frequency of skin vasculitis, peripheral nerve involvement, anemia, and lymphopenia. Some of the previously reported results on extranodal manifestations were confirmed.
Assuntos
Linfoma não Hodgkin/complicações , Síndrome de Sjogren/complicações , Seguimentos , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
This study investigates the treatment management and survival of inoperable advanced non-small cell lung cancer (NSCLC) patients. The objective was to treat all patients with induction chemotherapy and then to stratify them for surgery, radiotherapy, second-line chemotherapy or supportive treatment. Of the 359 patients enrolled in the study, 336 fulfilled the study criteria and were classified as follows: 90 stage IIIa, 135 stage IIIb and 111 stage IV. Histological types included 131 squamous cell, 123 adenocarcinomas, 53 undifferentiated non-small, 15 large cell, 3 adenosquamous, 3 bronchoalveolar and 8 unclassified. For all patients induction therapy involved Cisplatin (CDDP) combined chemotherapy and 84% of the patients were also treated with Vindesine and Epirubicin. The mean number of courses was 4 (minimum 2, maximum 11). The result of induction therapy was 49% complete and partial for at least 8 weeks; with minor response included, the total response rate was 67.6%. Fourteen patients (4.16%) achieved analytically complete response, 151 (45%) partial response and 62 (18.5%) minor response. The second-line treatment implemented was as follows: surgical excision, 22 patients (Group A); radiotherapy, 106 patients (Group B); chemotherapy, 91 patients (Group C) and supportive treatment, 117 patients (Group D). Median survival in months was 72 (range 5-120+), 12 (range 2-118), 15 (range 3-48) and 7 (range 3-120) for Groups A-D respectively. There was a statistically significant difference in survival in Group A patients (p < 0.001) but no difference was observed between Groups B and C. Group D patients had significantly lower survival than the other three groups. In conclusion, induction chemotherapy renders a reasonably high response rate in operable NSCLC patients and second-line radiotherapy treatment is not superior to second-line chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/tratamento farmacológico , Carcinoma/mortalidade , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/mortalidade , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Terapia Combinada , Epirubicina/administração & dosagem , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Indução de Remissão , Fatores de Tempo , Vindesina/administração & dosagemRESUMO
OBJECTIVE: In the present retrospective cohort study, the association of anti-Ro/SSA antibody with pregnancy loss and adverse pregnancy outcome in women with autoimmune diseases was investigated. MATERIALS AND METHODS: Obstetric histories of 154 anti-Ro/SSA-positive women with autoimmune diseases [78 systemic lupus erythematosus (SLE) and 76 non-SLE] were analysed and compared to a control group of 142 anti-Ro/SSA-negative women (71 SLE and 71 non-SLE) matched for disease diagnosis and age at the time of anti-Ro/SSA diagnosis. Obstetric history was also obtained and analysed from a group of healthy women, frequency matched to anti-Ro/SSA-positive women on age at study entry. RESULTS: The rate of pregnancy loss and adverse pregnancy outcome did not differ significantly between anti-Ro/SSA-positive women, anti-Ro/SSA-negative women and healthy controls. Anti-Ro/SSA-positive SLE women reported a significantly higher rate (18.0%) of therapeutic abortions compared to anti-Ro/SSA-negative women (5.6%, P=0.0244) and healthy controls (4.6%, P=0.0013). Anti-Ro/SSA non-SLE-positive women reported a significantly higher rate (23.7%) of recurrent pregnancy loss in comparison to anti-Ro/SSA-negative women (7.04%, P=0.0063) and healthy controls (6.4%, P=0.0004). CONCLUSIONS: Although anti-Ro/SSA antibody does not adversely affect pregnancy outcome in SLE patients, it appears to be associated with recurrent pregnancy loss in non-SLE patients.
Assuntos
Aborto Espontâneo/etiologia , Aborto Terapêutico , Anticorpos Antinucleares/análise , Artrite Reumatoide/complicações , Lúpus Eritematoso Sistêmico/complicações , Resultado da Gravidez , RNA Citoplasmático Pequeno , Escleroderma Sistêmico/complicações , Aborto Espontâneo/imunologia , Adulto , Artrite Reumatoide/imunologia , Autoantígenos/imunologia , Estudos de Coortes , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Ribonucleoproteínas/imunologia , Escleroderma Sistêmico/imunologiaRESUMO
In most clinical trials, markers are measured periodically with error. In the presence of measurement error, the naive method of using the observed marker values in the Cox model to evaluate the relationship between the marker and clinical outcome can produce biased estimates and lead to incorrect conclusions when evaluating a potential surrogate. We propose a two-stage approach to account for the measurement error and reduce the bias of the estimate. In the first stage, an empirical Bayes estimate of the time-dependent covariate is computed at each event time. In the second stage, these estimates are imputed in the Cox proportional hazards model to estimate the regression parameter of interest. We demonstrate through extensive simulations that this methodology reduces the bias of the regression estimate and correctly identifies good surrogate markers more often than the naive approach. An application evaluating CD4 count as a surrogate of disease progression in an AIDS clinical trial is presented.
Assuntos
Biometria/métodos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Resultado do Tratamento , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/imunologia , Fármacos Anti-HIV/uso terapêutico , Teorema de Bayes , Viés , Contagem de Linfócito CD4 , Humanos , Modelos Estatísticos , Modelos de Riscos Proporcionais , Análise de Regressão , Análise de SobrevidaRESUMO
OBJECTIVE: To define the prevalence of Sjögren's syndrome (SS) through an epidemiological survey in a closed rural community. The classification of SS is based on the validated criteria reported by a multicentre study performed in Europe and supported by the Epidemiology Committee of the European Community (EEC-COMAC Epidemiology). METHODS: The population under study consisted of 837 women aged 18 years or older, residing in the Astakos community of Aitoloakarnania, Greece. The study protocol was subdivided in two parts. In part I, an exhaustive epidemiological survey of these women was conducted in July and August of 1992. The validated questionnaire used in the survey assesses both ocular and oral involvement. In part II, 45 of the women reporting symptoms of both dry eye and dry mouth were approached for a full examination based on the validated set of classification criteria of SS. The full complement of the diagnostic tests was performed on 35 of these women. A subject is classified as a definite primary SS case if at least four of six items of the subject's test items are positive. If three of six items are positive the subject is classified as a probable primary SS case. RESULTS: The classification criteria for definite primary SS were satisfied by five women. This number corresponds to an estimated prevalence of 0.60% (exact 95% CI 0.19%, 1.39%). Probable primary SS was diagnosed for 25 women (prevalence = 2.99%). CONCLUSION: Because of the loss of follow up (10 of 45) and the use of slightly stricter criteria for inclusion of possible SS cases in part II of the study, we consider our estimate of the prevalence of SS to be conservative. This study concurring with other recent reports, suggests that SS is more prevalent than previously thought.