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1.
Arthritis Rheumatol ; 72(1): 125-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31342624

RESUMO

OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

2.
J Rheumatol ; 46(2): 176-183, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30275260

RESUMO

OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc). METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration. RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations. CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

3.
PLoS One ; 13(1): e0189498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293537

RESUMO

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Humanos , Polimorfismo de Nucleotídeo Único
5.
Clin Exp Rheumatol ; 35 Suppl 106(4): 106-113, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27908301

RESUMO

OBJECTIVES: To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc). METHODS: PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients. RESULTS: 172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001). CONCLUSIONS: NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.


Assuntos
Hipertensão Pulmonar/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Escleroderma Sistêmico/complicações , Idoso , Progressão da Doença , Feminino , Hemodinâmica , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Sistema de Registros , Escleroderma Sistêmico/sangue
6.
Lancet Respir Med ; 4(9): 708-719, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27469583

RESUMO

BACKGROUND: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. METHODS: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. FINDINGS: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). INTERPRETATION: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.


Assuntos
Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/administração & dosagem , Escleroderma Sistêmico/complicações , Adulto , Idoso , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Escleroderma Sistêmico/fisiopatologia , Resultado do Tratamento
8.
Arthritis Rheumatol ; 68(10): 2384-93, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27110949

RESUMO

OBJECTIVE: Alterations in the microbiome, including the periodontal microbiome, may be a risk factor for rheumatoid arthritis (RA). Most studies that have analyzed this association are relatively small, focus primarily on a single periodontal pathogen (Porphyromonas gingivalis), and are not population based. This study was undertaken to investigate the association between elevated serum levels of IgG antibodies to 19 periodontal species and the prevalence of rheumatoid factor (RF) in a large nationally representative sample of adults. METHODS: The Third National Health and Nutrition Examination Survey (NHANES-III) is a cross-sectional sample of the noninstitutionalized US population (n = 33,994). Our study population included all dentate participants who were 60 years and older, did not have RA as defined by a modified version of the American College of Rheumatology 1987 criteria, and had complete data for both serum IgG antibodies against periodontal bacteria and serum RF antibody titer (n = 2,461). RESULTS: Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) summarizing the relationship between the 19 periodontal serum IgG antibodies and RF seropositivity ranged from 0.53 (95% CI 0.29-0.97) to 1.27 (95% CI 0.79-2.06), and 17 of the 19 observed ORs were <1.0. The ORs for RF seropositivity among participants with elevated Prevotella intermedia (0.53 [95% CI 0.29-0.97]) and Capnocytophaga ochracea (0.54 [0.31-0.95]) IgG levels were statistically significant. CONCLUSION: Our findings indicate that elevated levels of IgG antibodies to periodontal bacteria are mostly unassociated with RF seropositivity in the nationally representative NHANES-III. Elevated levels of antibodies to P intermedia and C ochracea are associated with lower odds of RF seropositivity.


Assuntos
Anticorpos Antibacterianos/imunologia , Imunoglobulina G/imunologia , Microbiota/imunologia , Periodonto/microbiologia , Fator Reumatoide/imunologia , Idoso , Capnocytophaga/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Doenças Periodontais , Índice Periodontal , Porphyromonas gingivalis/imunologia , Prevotella intermedia/imunologia , Estudos Soroepidemiológicos , Estados Unidos
9.
Arthritis Res Ther ; 18: 20, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26792595

RESUMO

BACKGROUND: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc. METHODS: A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc. RESULTS: We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (ß = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (ß = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (ß = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort. CONCLUSIONS: Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Pneumonias Intersticiais Idiopáticas/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Escleroderma Sistêmico/diagnóstico
10.
J Immunol ; 196(5): 2051-2062, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26826243

RESUMO

Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell-associated cytokines in response to innate stimulation in the absence of Ag. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as group 1 ILC (ILC1) contains CD4(+) CD8(-), CD4(-) CD8(+), and CD4(-) CD8(-) populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4(+) ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4(+) ILC1 and NKp44(+) group 3 ILC, but not CD4(-) ILC1 or group 2 ILC, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology, as well as immune dysregulation. Furthermore, we demonstrate that CD4(+) and CD4(-) ILC1 are functionally divergent based on their IL-6Rα expression and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4(+) and CD4(-) ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases, such as SSc.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Escleroderma Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Separação Celular , Citometria de Fluxo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
11.
Semin Arthritis Rheum ; 44(6): 680-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25578738

RESUMO

OBJECTIVE: To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS: SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS: This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS: In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.


Assuntos
Anticorpos Antinucleares/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Nefropatias/etiologia , Pulmão/fisiopatologia , Síndromes de Malabsorção/etiologia , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar , Fibrose Pulmonar/etiologia , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Fatores Sexuais , Úlcera Cutânea/etiologia , Telangiectasia/etiologia
12.
Semin Arthritis Rheum ; 44(1): 55-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24709277

RESUMO

OBJECTIVES: PHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc). METHODS: "At-risk" pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40 mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan-Meier estimate of time to PH diagnosis. RESULTS: A total of 251 "at-risk" subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 ± 1.2 years. The mean age at entry was 56.7 ± 11.0 and disease duration was 9.9 ± 8.7 years. Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the "at-risk" and new PH groups. Using Kaplan-Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than "at-risk" PAH group. CONCLUSIONS: A low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.


Assuntos
Hipertensão Pulmonar/etiologia , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Risco
13.
Arthritis Care Res (Hoboken) ; 66(3): 489-95, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23983198

RESUMO

OBJECTIVE: To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US. METHODS: The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses. RESULTS: In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality. CONCLUSION: This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.


Assuntos
Hipertensão Pulmonar/mortalidade , Sistema de Registros , Escleroderma Sistêmico/complicações , Idoso , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estados Unidos/epidemiologia
15.
Ann Rheum Dis ; 71(8): 1335-42, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22307943

RESUMO

BACKGROUND: Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21-24 mm Hg) are "at risk" of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. METHODS: PHAROS is a multicentre prospective longitudinal cohort of patients with SSc "at risk" or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. RESULTS: 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS). CONCLUSIONS: Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Cateterismo Cardíaco , Feminino , Seguimentos , Hemodinâmica , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fibrose Pulmonar/complicações , Fibrose Pulmonar/fisiopatologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico
16.
Curr Opin Rheumatol ; 24(1): 76-83, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22157415

RESUMO

PURPOSE OF REVIEW: Castleman disease can occur in association with autoimmune connective tissue disease and confound the clinical picture, resulting in delayed diagnosis and suboptimal treatment. This review focuses on the intersection of Castleman disease and autoimmunity with an emphasis on shared pathology and mutually beneficial treatments. RECENT FINDINGS: Targeting CD-20, interleukin-6, and the nuclear factor-κB pathway has shown promise in achieving long-term remission in patients with Castleman disease and associated autoimmune features. SUMMARY: Advances in understanding of pathogenic cell types and cytokines in Castleman disease have allowed the development of targeted therapies successful in the treatment of both Castleman disease and associated autoimmune disease.


Assuntos
Doenças Autoimunes/complicações , Hiperplasia do Linfonodo Gigante/complicações , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Humanos
17.
J Clin Periodontol ; 38(11): 998-1006, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22092471

RESUMO

AIMS: Infection may be a rheumatoid arthritis (RA) risk factor. We examined whether signs of periodontal infection were associated with RA development in the First National Health and Nutrition Examination Survey and its epidemiological follow-up study. MATERIAL AND METHODS: In 1971-1974, 9702 men and women aged 25-74 were enrolled and surveyed longitudinally (1982, 1986, 1987, 1992). Periodontal infection was defined by baseline tooth loss or clinical evidence of periodontal disease. Baseline (n = 138) and incident (n = 433) RA cases were defined via self-report physician diagnosis, joint pain/swelling, ICD-9 codes (714.0-714.9), death certificates and/or RA hospitalization. RESULTS: Adjusted odds ratios (ORs) (95% CI) for prevalent RA in gingivitis and periodontitis (versus healthy) were 1.09 (0.57, 2.10) and 1.85 (0.95, 3.63); incident RA ORs were 1.32 (0.85, 2.06) and 1.00 (0.68, 1.48). The ORs for prevalent RA among participants missing 5-8, 9-14, 15-31 or 32 teeth (versus 0-4 teeth) were 1.74 (1.03, 2.95), 1.82 (0.81, 4.10), 1.45 (0.62, 3.41) and 1.30 (0.48, 3.53); ORs for incident RA were 1.12 (0.77, 1.64), 1.67 (1.12, 2.48), 1.40 (0.85, 2.33) and 1.22 (0.75, 2.00). Dose-responsiveness was enhanced among never smokers. The rate of death or loss-to-follow-up after 1982 was two- to fourfold higher among participants with periodontitis or missing ≥9 teeth (versus healthy participants). CONCLUSIONS: Although participants with periodontal disease or ≥5 missing teeth experienced higher odds of prevalent/incident RA, most ORs were non-statistically significant and lacked dose-responsiveness. Differential RA ascertainment bias complicated the interpretation of these data.


Assuntos
Artrite Reumatoide/complicações , Periodontite Crônica/complicações , Gengivite/complicações , Perda de Dente/complicações , Adulto , Fatores Etários , Idoso , Artrite Reumatoide/epidemiologia , Periodontite Crônica/epidemiologia , Estudos Transversais , Feminino , Gengivite/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Índice Periodontal , Prevalência , Fatores Sexuais , Fumar/epidemiologia , Perda de Dente/epidemiologia , Estados Unidos/epidemiologia
18.
J Rheumatol ; 38(8): 1622-30, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21572159

RESUMO

OBJECTIVE: Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc. METHODS: Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival. RESULTS: Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493). CONCLUSION: Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.


Assuntos
Afro-Americanos/genética , Anticorpos Antinucleares/genética , Anticorpos Antinucleares/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Proteínas Cromossômicas não Histona/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Proteínas Cromossômicas não Histona/genética , Feminino , Frequência do Gene , Cadeias HLA-DRB1/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunogenética/métodos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Análise de Sobrevida
19.
Clin Trials ; 7(1): 85-9, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20032002

RESUMO

BACKGROUND: Scleroderma Lung Study (SLS) was designed to evaluate the efficacy and safety of oral cyclophosphamide (CYC) versus placebo taken for 1 year for scleroderma-associated interstitial lung disease. An independent medication control officer (MCO), usually a physician, at each center was assigned to monitor laboratory and clinical toxicity of study medication and regulate its dosing based on these results. By having an MCO who watched and managed toxicity, the study investigators were free to care for study patients and to assess study outcomes without the potential bias of knowing toxicity data (toxicity from cyclophosphamide is distinctive - cytopenias and hematuria in particular). PURPOSE: To assess the usefulness of an MCO, whose chief role was to maintain safety while retaining the blinding in the clinical trial. METHODS: Patients had safety laboratory testing every 2-4 weeks and results were sent directly to the MCO within 2 days of the test. Other clinical adverse events (AEs) were reported by the patient to a nurse coordinator who reported them to the MCO who then managed the AEs to preserve the blinding of investigators caring for the patients. The MCO was provided pre-determined algorithms for dose adjustments of test medication based on the presence and severity of laboratory abnormalities. RESULTS: Safety monitoring by the MCO was effective in the early detection of drug toxicity with provision of appropriate medical intervention on a timely basis. At the same time, investigator blinding appeared to be maintained. LIMITATIONS: The testing of MCO effectiveness in maintaining blinding and consistency was not defined as an a priori hypothesis and thus complete data relating to the efficacy of the MCO were not collected in a prospective fashion. CONCLUSION: An MCO and pre-specified monitoring and dosing guidelines, coupled with uniform pre-specified responses to AEs, may be used effectively to preserve investigator blinding and provide consistency in response to AEs in a clinical trial setting, even when AEs of the test medication are distinctive.


Assuntos
Viés , Pneumopatias/tratamento farmacológico , Conduta do Tratamento Medicamentoso/organização & administração , Pesquisadores , Esclerodermia Localizada/tratamento farmacológico , Protocolos Clínicos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto/normas
20.
Minn Med ; 92(9): 42-4, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19877478

RESUMO

Systemic sclerosis, or scleroderma, is a rare condition that first presents with symptoms common to many other diseases. Because of this, diagnosing it can be difficult and take time.This article describes warning signs of possible incipient scleroderma as well as tests that can help the primary care provider identify this serious autoimmune disorder.


Assuntos
Escleroderma Sistêmico/diagnóstico , Anticorpos Antinucleares/sangue , Diagnóstico Diferencial , Diagnóstico Precoce , Humanos , Exame Físico , Atenção Primária à Saúde
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