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1.
Clin Rheumatol ; 39(1): 93-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667644

RESUMO

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud's symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. KEY POINTS : • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

2.
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.

3.
Proc Natl Acad Sci U S A ; 117(1): 552-562, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871193

RESUMO

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

4.
Ann Rheum Dis ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767698

RESUMO

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

5.
J Rheumatol ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732551

RESUMO

OBJECTIVE: To evaluate whether a positive exercise echocardiogram (EE) predicts future development of pulmonary arterial hypertension (PAH) in a high-risk cohort of patients with systemic sclerosis (SSc). METHODS: Patients with SSc with features associated with an increased risk for PAH were recruited into a prospective, observational cohort. All patients underwent clinical assessment and EE. A positive EE was defined as an increase of ≥ 20 mmHg in the right ventricular systolic pressure with exercise. All patients with positive EE underwent right heart catheterization (RHC). RESULTS: The study included 85 patients. In the positive EE cohort, 10 of 43 patients (23%) developed resting pulmonary hypertension (PH) on RHC over a mean 4-year followup period [4 with PAH, 5 with pulmonary venous hypertension (PVH), and 1 with PH associated with interstitial lung disease]. In the persistently negative EE cohort, only 3 of 42 patients (7%) developed resting PH (1 PAH, 2 PVH; p = 0.04). Of the remaining 33 patients in the positive EE group who did not develop resting PH, 22 (67%) had a persistently positive EE over an average 5-year followup period. CONCLUSION: In this high-risk cohort of patients with SSc, a positive EE may predict the future development of resting PH. In addition, a majority of patients may have a persistently positive EE for years without progression to resting PH. Finally, a consistently negative EE may identify patients at low risk for future PH.

6.
Arthritis Res Ther ; 21(1): 202, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481106

RESUMO

BACKGROUND: To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). METHODS: Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). RESULTS: Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference - 0.24, 95% CI (- 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs. CONCLUSION: In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.

8.
Arthritis Rheumatol ; 71(10): 1691-1700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31066998

RESUMO

OBJECTIVE: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH). METHODS: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates. RESULTS: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups. CONCLUSION: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.

9.
Arthritis Care Res (Hoboken) ; 71(9): 1154-1163, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30821906

RESUMO

OBJECTIVE: African Americans with scleroderma have more severe disease and higher mortality than non-African Americans. Differences in rates of diffuse disease, autoantibody status, or socioeconomic status have not completely explained this phenomenon. Our study evaluates these risks at our site. METHODS: A retrospective study comparing African American and non-African American patients with scleroderma seen from 2008 to 2016 was performed. Groups were matched by sex, age at first visit, date of first visit, disease duration at first visit, and limited versus diffuse cutaneous disease. Demographic, serologic, and clinical features were compared. Mortality risks were assessed by a Cox proportional hazards model with covariates of race, marital status, education, employment, insurance, and imputed household income. RESULTS: African Americans comprised 202 of 402 patients. They demonstrated reduced forced vital capacity and diffusing capacity for carbon monoxide, more severe lung fibrosis, a higher prevalence of pulmonary hypertension, and more severe cardiac involvement. The autoantibody profile statistically differed between the 2 groups. Death during follow-up was 21% in African Americans versus 11% in non-African Americans (P = 0.005). African American race demonstrated an unadjusted hazard ratio for death during follow-up of 2.061 (P = 0.006) that declined with adjustment for socioeconomic covariates to 1.256 (P = 0.633). The only significant covariate was median income in tens of thousands of dollars by zip code (hazard ratio 0.845; P = 0.033). CONCLUSION: African American patients with scleroderma have more severe pulmonary disease and higher unadjusted mortality than matched non-African Americans. Following adjustment for socioeconomic factors, African American race was not a significant risk factor for mortality; however, independent of race, a lower median household income predicted increased mortality.

10.
Chest ; 155(3): 565-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660783

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) carries a poor prognosis if not promptly diagnosed and appropriately treated. The development and approval of 14 medications over the last several decades have led to a rapidly evolving approach to therapy, and have necessitated periodic updating of evidence-based treatment guidelines. This guideline statement, which now includes a visual algorithm to enhance its clinical utility, represents the fourth iteration of the American College of Chest Physicians Guideline and Expert Panel Report on Pharmacotherapy for PAH. METHODS: The guideline panel conducted an updated systematic review to identify studies published after those included in the 2014 guideline. A systematic literature search was conducted using MEDLINE via PubMed and the Cochrane Library. The quality of the body of evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations Assessment, Development and Evaluation approach. Graded recommendations and ungraded consensus-based statements were developed and voted on using a modified Delphi technique to achieve consensus. RESULTS: Two new recommendations on combination therapy and two ungraded consensus-based statements on palliative care were developed. An evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management, and to direct readers to the appropriate area of the document for more detailed information. CONCLUSIONS: Therapeutic options for the patient with PAH continue to expand through basic discovery, translational science, and clinical trials. Optimal use of new treatment options requires prompt evaluation at an expert center, utilization of current evidence-based guidelines, and collaborative care using sound clinical judgment.


Assuntos
Anti-Hipertensivos , Fármacos do Sistema Respiratório , Adulto , Anti-Hipertensivos/classificação , Anti-Hipertensivos/farmacologia , Técnicas de Diagnóstico do Sistema Respiratório , Monitoramento de Medicamentos/métodos , Medicina Baseada em Evidências , Tolerância ao Exercício/efeitos dos fármacos , Humanos , /etiologia , Pneumologia/métodos , Pneumologia/normas , Fármacos do Sistema Respiratório/classificação , Fármacos do Sistema Respiratório/farmacologia
11.
Arthritis Rheumatol ; 71(6): 964-971, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30614663

RESUMO

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.


Assuntos
Lesão Renal Aguda/classificação , Hipertensão Maligna/classificação , Rim/patologia , Escleroderma Sistêmico/complicações , Lesão Renal Aguda/etiologia , Anemia Hemolítica/classificação , Anemia Hemolítica/etiologia , Pressão Sanguínea , Técnica Delfos , Humanos , Hipertensão/classificação , Hipertensão/etiologia , Hipertensão Maligna/etiologia , Proteinúria/classificação , Proteinúria/etiologia , Índice de Gravidade de Doença
12.
Arthritis Rheumatol ; 71(2): 182-195, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604506
14.
Ann Rheum Dis ; 78(1): 122-130, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30409830

RESUMO

OBJECTIVE: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling. RESULTS: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data. CONCLUSION: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.


Assuntos
Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/mortalidade , Ácido Micofenólico/administração & dosagem , Escleroderma Sistêmico/mortalidade , Adulto , Monóxido de Carbono/análise , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Capacidade de Difusão Pulmonar , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
15.
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.

16.
Rheumatology (Oxford) ; 57(9): 1623-1631, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868924

RESUMO

Objectives: The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts. Methods: Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts. Results: Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN. Conclusion: Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.


Assuntos
Medidas de Resultados Relatados pelo Paciente , Satisfação do Paciente , Assistência Centrada no Paciente , Escleroderma Sistêmico/epidemiologia , Canadá/epidemiologia , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , Índice de Gravidade de Doença , Inquéritos e Questionários , Estados Unidos/epidemiologia
17.
Arthritis Rheumatol ; 70(10): 1654-1660, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29732714

RESUMO

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.


Assuntos
Afro-Americanos/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/etnologia , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/genética , Adenosina Trifosfatases/genética , Adulto , Grupo com Ancestrais do Continente Europeu/genética , Proteínas da Matriz Extracelular/genética , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Sequenciamento Completo do Exoma
18.
Chest ; 154(4): 862-871, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29777655

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH. METHODS: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of patients with SSc at high risk for or with incident pulmonary hypertension from right heart catheterization. Incident World Health Organization group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate Cox regression models identified predictors of mortality. RESULTS: Survival in 160 patients with incident SSc-PAH at 1, 3, 5, and 8 years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths from PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Men (hazard ratio [HR], 3.11; 95% CI, 1.38-6.98), diffuse disease (HR, 2.12; 95% CI, 1.13-3.93), systolic pulmonary artery pressure (PAP) on ECG (HR, 1.06 95% CI, 1.01-1.11), mean PAP on right heart catheterization (HR, 1.03; 95% CI, 1.001-1.07), 6-min walk distance (HR, 0.92; 95% CI, 0.86-0.99), and diffusing capacity for carbon monoxide (HR, 0.65; 95% CI, 0.46-0.92) significantly affected survival on multivariate analysis. CONCLUSIONS: Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than one-half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.


Assuntos
Hipertensão Pulmonar/etiologia , Escleroderma Sistêmico/complicações , Métodos Epidemiológicos , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Hipertensão Pulmonar/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Escleroderma Sistêmico/mortalidade , Estados Unidos/epidemiologia , Capacidade Vital/fisiologia
20.
Pulm Circ ; 8(2): 2045893218757404, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29468935

RESUMO

Group classification of pulmonary hypertension (PH) is based on pulmonary artery wedge pressure (PAWP) on right heart catheterization (RHC). How hemodynamics, particularly PAWP, change over time in systemic sclerosis (SSc)-PH patients is unknown. SSc-PH patients enrolled in the prospective observational PHAROS registry who had > 1 RHC (n = 120) were included in this analysis. Patients were considered to have a "PAWP class change" if they had a PAWP ≤ 15 mmHg on RHC-1 and then a PAWP > 15 on RHC-2 or had a PAWP > 15 on RHC-1 and then PAWP ≤ 15 on RHC-2. There was a median time of 1.4 years between RHC-1 and RHC-2 and 75% of patients had a PH medication added after their initial RHC. PAWP increased significantly (11 ± 5 versus 13 ± 6 mmHg, P = 0.01) between RHC-1 and RHC-2, particularly for patients who were started on PH medications. Overall, 30% of patients who had a repeat RHC experienced a PAWP class change between their initial and follow-up RHC, independent of whether a PH medication was added. Patients initially classified as World Health Organization group 2 PH were most likely to change PAWP class over time. In conclusion, PAWP values commonly change to a significant degree in SSc-PH, which highlights the challenges in using a single time-point PAWP to define clinical classification groups.

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