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2.
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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31841265

RESUMO

OBJECTIVES: Digital ulcers (DUs) are a major cause of disease-related morbidity and difficult to treat vascular complication of systemic sclerosis (SSc). Demonstrating treatment efficacy has traditionally focussed upon clinician assessment of DUs alone. No existing patient reported outcome (PRO) instrument captures the multi-faceted impact of SSc-DU. We report the findings of a multi-centre qualitative research study exploring the patient experience of SSc-DU. METHODS: Patient focus groups (FGs) were conducted across 3 scleroderma units, following a topic guide devised by SSc patients, experts and experienced qualitative researchers. A purposive sampling framework ensured the experiences of a diverse group of patients were captured. FGs were audio recorded, transcribed, anonymised, and analysed using inductive thematic analysis. We continued FGs until thematic saturation was achieved. RESULTS: Twenty-nine SSc patients with a history of DU disease participated in 4 FGs across the UK (Bath, Manchester and London). Five major inter-related themes (and sub-themes) were identified which encompass the patient experience of SSc-DUs: 'Disabling pain and hypersensitivity', 'Deep and broad-ranging emotional impact', 'Impairment of physical and social activity', 'Factors aggravating occurrence, duration and impact' and 'Mitigating, managing and adapting'. CONCLUSION: The patient experience of SSc-DU is multi-faceted and comprises a complex interplay of experiences associated with significant pain and morbidity. Patient experiences of SSc-DU are not captured using existing SSc-DU outcomes. Our findings shall inform the development of a novel PRO instrument to assess the severity and impact of SSc-DUs for use in future SSc-DU clinical trials.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31680161

RESUMO

OBJECTIVES: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. METHODS: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. RESULTS: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. CONCLUSION: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

5.
Nat Rev Dis Primers ; 5(1): 45, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273209

RESUMO

Sarcoidosis is an inflammatory disorder of unknown cause that is characterized by granuloma formation in affected organs, most often in the lungs. Patients frequently suffer from cough, shortness of breath, chest pain and pronounced fatigue and are at risk of developing lung fibrosis or irreversible damage to other organs. The disease develops in genetically predisposed individuals with exposure to an as-yet unknown antigen. Genetic factors affect not only the risk of developing sarcoidosis but also the disease course, which is highly variable and difficult to predict. The typical T cell accumulation, local T cell immune response and granuloma formation in the lungs indicate that the inflammatory response in sarcoidosis is induced by specific antigens, possibly including self-antigens, which is consistent with an autoimmune involvement. Diagnosis can be challenging for clinicians because of the potential for almost any organ to be affected. As the aetiology of sarcoidosis is unknown, no specific treatment and no pathognomic markers exist. Thus, improved biomarkers to determine disease activity and to identify patients at risk of developing fibrosis are needed. Corticosteroids still constitute the first-line treatment, but new treatment strategies, including those targeting quality-of-life issues, are being evaluated and should yield appropriate, personalized and more effective treatments.

6.
Nat Rev Dis Primers ; 5(1): 49, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311930

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
Respir Med ; 150: 131-135, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30961939

RESUMO

BACKGROUND: Pulmonary hypertension (PH) often presents with non-specific symptoms making early diagnosis difficult. Red cell distribution width (RDW) is a parameter routinely reported on an automated complete blood cell count that has been associated with numerous disease states. The purpose of this study was to further evaluate RDW as a biomarker for PH in at-risk populations. METHODS: In a retrospective, cross-sectional analysis of patients seen at a PH center over 1 year, we examined both patients with PH and patients at risk for but without PH (e.g. systemic sclerosis, [SSc]). We also studied a group of age-and sex-matched, non-diseased controls. Relevant characteristics were compared among the 3 groups using one-way ANOVA. Similar comparisons were made across World Health Organization (WHO) PH groups 1-4. RESULTS: RDW was highest in the PH patients (n = 181), intermediate in the at-risk for PH patients (n = 52), and lowest in matched controls (n = 100) (15.9 ±â€¯2.8 vs 14.8 ±â€¯2.8 vs 14.2 ±â€¯1.1%, respectively; p < 0.0001). There were no significant differences in RDW across WHO PH groups (p = 0.50). SSc patients with PH had significantly higher RDW values compared to SSc patients without PH (16.0 ±â€¯2.2 vs 14.4 ±â€¯1.9%, respectively; p = 0.03). CONCLUSIONS: RDW is significantly higher in PH patients, without regard to disease etiology, when compared to age- and sex-matched non-diseased controls. Importantly, RDW is also higher in PH patients compared to at-risk patients, particularly in the SSc cohort. The ease of obtaining RDW as a biomarker may help detect incident PH at earlier stages among patients who are at high risk for development of PH.

9.
Ann Rheum Dis ; 78(7): 979-987, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30967395

RESUMO

OBJECTIVE: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. METHODS: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. RESULTS: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). CONCLUSION: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

10.
Respirology ; 24(7): 675-683, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30747487

RESUMO

BACKGROUND AND OBJECTIVE: Endothelial microparticles (EMP) are submicron vesicles released from endothelial cells. We aimed to determine the utility of EMP as biomarkers of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients and the pathogenic role of microparticles (MP) in vascular inflammation. METHODS: Levels of EMP (CD144+, CD31+, CD62E+ and CD143+) were compared between three groups (10 SSc patients with PAH, 10 SSc patients without pulmonary hypertension (no-PH) and 10 healthy age- and sex-matched controls). Human pulmonary artery endothelial cells (HPAEC) were exposed in vitro to MP obtained from SSc patients or healthy controls, and levels of cytokines and inflammatory adhesion molecules were compared. RESULTS: CD144+ EMP were significantly higher in the SSc-PAH group compared to either the SSc-no PH or healthy controls (diagnostic accuracy 80%, P = 0.02). Compared to controls, SSc patients had higher CD31+/CD62E+ ratios, indicating larger contributions of apoptosis to EMP release (P = 0.04). Patients with limited SSc had significantly higher levels of CD143+ EMP compared to those with diffuse subtype (P = 0.008). When HPAEC were exposed to MP from SSc patients, there was a significant increase in inflammatory cytokines and adhesion molecules. Interestingly, exposure to healthy control MP caused a reduction in inflammatory markers. CONCLUSION: EMP (particularly CD144+) are promising biomarkers of PAH in SSc but require further study. MP isolated from SSc patients induced an increase in endothelial cell inflammation and may be an important pathogenic factor in SSc.

11.
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.

12.
Rheumatology (Oxford) ; 58(1): 18-26, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29538754

RESUMO

RP is the most common manifestation of SSc and a major cause of disease-related morbidity. This review provides a detailed appraisal of the patient experience of SSc-RP and potential implications for disease classification, patient-reported outcome instrument development and SSc-RP clinical trial design. The review explores the clinical features of SSc-RP, the severity and burden of SSc-RP symptoms and the impact of SSc-RP on function, work and social participation, body image dissatisfaction and health-related quality of life in SSc. Where management of SSc-RP is concerned, the review focuses on the 'patient experience' of interventions for SSc-RP, examining geographic variation in clinical practice and potential barriers to the adoption of treatment recommendations concerning best-practice management of SSc-RP. Knowledge gaps are highlighted that could form the focus of future research. A more thorough understanding of the patient experience could support the development of novel reported outcome instruments for assessing SSc-RP.


Assuntos
Doença de Raynaud/psicologia , Escleroderma Sistêmico/complicações , Adulto , Imagem Corporal/psicologia , Feminino , Humanos , Masculino , Qualidade de Vida , Doença de Raynaud/etiologia , Participação Social/psicologia
13.
RMD Open ; 4(1): e000533, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018796

RESUMO

Three randomised controlled trials of haematopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) demonstrated long-term survival benefits, induction of clinically meaningful, sustained improvement of forced vital capacity with improvements in skin thickening, vasculopathy and health-related quality of life, in contrast to a clinical decline in standard of care control groups. These benefits, however, must be weighed against the increased risk of transplant-related mortality. Further, with disease progression, severe extensive internal organ involvement and damage ensues, constituting an exclusion criterion for safety reasons, leaving a limited window whereby patients with SSc are eligible for HSCT. Although autologous HSCT offers the possibility of drug-free remission, relapse can occur, requiring re-initiation of disease modifying antirheumatic drugs. HSCT is also associated with secondary autoimmune diseases and gonadal failure. HSCT should be proposed for carefully selected patients with early rapidly progressive diffuse SSc whose clinical picture portends a poor prognosis for survival, but yet lacks advanced organ involvement.

14.
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
15.
ERJ Open Res ; 4(2)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29750143

RESUMO

A modified mindfulness-based exercise intervention has beneficial impact on people living with sarcoidosis http://ow.ly/XYTO30jtmms.

16.
Rheum Dis Clin North Am ; 44(2): 267-284, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29622294

RESUMO

This article provides an overview of the basis, usefulness, and validity of qualitative methods in research. It is aimed to enhance the understanding of a broad spectrum of readers, ranging from those mystified by such approaches, to those wanting a better critical knowledge to apply to literature review, and for health care providers considering developing an interest in the field. Qualitative research is crucial in augmentation of disease knowledge as well as the development of incremental care strategies and operational aspects of care that improves health outcomes.


Assuntos
Pesquisa Qualitativa , Doenças Reumáticas , Humanos , Assistência ao Paciente , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/terapia
18.
ERJ Open Res ; 4(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29577043

RESUMO

Pulmonary hypertension is a potentially fatal disease. Despite pharmacological advances in pulmonary hypertension, fatigue remains common in patients with pulmonary hypertension. A convenience sample of 120 participants at an international patient conference completed the Multidimensional Fatigue Inventory (MFI)-20 scale. Data on New York Heart Association Functional Class, body mass index, oxygen use and medication type/use were also collected. There was a high prevalence of "severe" to "very severe" fatigue for each dimension: General Fatigue (60%), Physical Fatigue (55.8%), Reduced Activity (41.7%), Reduced Motivation (32.5%) and Mental Fatigue (27.5%). The mean±sd overall MFI-20 score was 58±5.1. Dimensions with the highest averaged levels were General Fatigue (13.40±3.61), Physical Fatigue (13.23±3.67) and Reduced Activity (11.33±4.16). Body mass index correlated with higher fatigue scores. Phosphodiesterase inhibitor plus endothelin receptor antagonist combination negatively predicted General Fatigue, Physical Fatigue, Reduced Motivation and Reduced Activity. Triple therapy was a significant predictor of General Fatigue, Physical Fatigue and Reduced Activity. There were no significant predictors of Mental Fatigue. Multidimensional fatigue is common and severe in patients with pulmonary hypertension. Phosphodiesterase inhibitor plus endothelin receptor antagonist combination resulted in lower scores in most fatigue dimensions. Comprehensive assessment of fatigue should be considered in the clinical care of patients with pulmonary hypertension and clinical research to develop formal interventions that target this disabling symptom.

19.
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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