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1.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

2.
Autoimmun Rev ; 18(11): 102394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520797

RESUMO

OBJECTIVES: This study was designed to propose a simple "Fast Track algorithm" for capillaroscopists of any level of experience to differentiate "scleroderma patterns" from "non-scleroderma patterns" on capillaroscopy and to assess its inter-rater reliability. METHODS: Based on existing definitions to categorise capillaroscopic images as "scleroderma patterns" and taking into account the real life variability of capillaroscopic images described standardly according to the European League Against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases, a fast track decision tree, the "Fast Track algorithm" was created by the principal expert (VS) to facilitate swift categorisation of an image as "non-scleroderma pattern (category 1)" or "scleroderma pattern (category 2)". Mean inter-rater reliability between all raters (experts/attendees) of the 8th EULAR course on capillaroscopy in Rheumatic Diseases (Genoa, 2018) and, as external validation, of the 8th European Scleroderma Trials and Research group (EUSTAR) course on systemic sclerosis (SSc) (Nijmegen, 2019) versus the principal expert, as well as reliability between the rater pairs themselves was assessed by mean Cohen's and Light's kappa coefficients. RESULTS: Mean Cohen's kappa was 1/0.96 (95% CI 0.95-0.98) for the 6 experts/135 attendees of the 8th EULAR capillaroscopy course and 1/0.94 (95% CI 0.92-0.96) for the 3 experts/85 attendees of the 8th EUSTAR SSc course. Light's kappa was 1/0.92 at the 8th EULAR capillaroscopy course, and 1/0.87 at the 8th EUSTAR SSc course. CONCLUSION: For the first time, a clinical expert based fast track decision algorithm has been developed to differentiate a "non-scleroderma" from a "scleroderma pattern" on capillaroscopic images, demonstrating excellent reliability when applied by capillaroscopists with varying levels of expertise versus the principal expert and corroborated with external validation.


Assuntos
Algoritmos , Esclerodermia Localizada/diagnóstico , Escleroderma Sistêmico/diagnóstico , Humanos , Angioscopia Microscópica/métodos , Reprodutibilidade dos Testes
3.
Br J Hosp Med (Lond) ; 80(9): 530-536, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31498665

RESUMO

Systemic sclerosis is a complex autoimmune connective tissue disease which carries a significant burden of disease-related morbidity including potentially life-threatening complications. Systemic sclerosis can affect all the major organs and therefore, although the disease is uncommon, many hospital-based specialists are involved in patient care. Vascular disease (e.g. Raynaud's phenomenon) is an almost universal symptom in patients with systemic sclerosis and is often the earliest manifestation of the disease. Systemic sclerosis not uncommonly can overlap with other rheumatological conditions (e.g. rheumatoid arthritis and myositis). During the past few decades there have been major advances in understanding the pathogenesis of systemic sclerosis and these are driving advances in treatment. There are now a number of effective treatments to manage many of the different organ-based complications. Autologous haemopoietic stem cell transplantation is a potential treatment option in highly selected patients. This review updates the clinician about epidemiology, pathogenesis, differential diagnosis, the wide clinical spectrum of disease, and current and emerging treatments for systemic sclerosis.

4.
J Clin Immunol ; 39(6): 620-622, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31367981
6.
Arthritis Res Ther ; 21(1): 147, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200750

RESUMO

OBJECTIVES: To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. METHODS: We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. RESULTS: Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p < 0.0001). There were no differences in mucocutaneous or internal organ involvement between the ISG subgroups. The ISG-positive group had increased frequency of specific autoantibodies and haematological abnormalities which remained significant after adjusting for the SARD subtype. Expression of DDX58, MB21D1 and TLR7 was correlated with the ISG score whilst TLR3, TLR9 and MB21D1 were associated with neutrophil count. CONCLUSION: In SARD patients, IFNα-positivity was associated with specific autoantibodies and haematological parameters but not with other clinical features. The variable NAR expression suggests that different pathways may drive IFNα production in individual patients. The identification of an IFNα-positive subgroup within a mixed SARD cohort supports a pathology-based approach to treatment.

8.
Semin Arthritis Rheum ; 49(2): 279-282, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30981516

RESUMO

INTRODUCTION: Objective outcome measures are needed to facilitate clinical trials of much needed treatments for calcinosis in systemic sclerosis (SSc). Our primary aim was to compare radiography, computed tomography (CT) and magnetic resonance imaging (MRI) to measure calcinotic lesions. Secondary objectives included to examine reproducibility of radiography and MRI, and inter-rater reliability of MRI. MATERIALS AND METHODS: 15 patients with SSc and clinically apparent calcinosis were studied. On one hand, radiography, CT and MRI were performed. The number (all techniques), area (radiography) and volume (CT and MRI) of calcinotic areas were extracted by 'blinded' musculoskeletal radiologists. RESULTS: No significant difference (P = 0.289) in the mean (SD) number of lesions (per hand) was seen between radiography: 5.4 (4.6), CT: 6.3 (6.5) and MRI: 5.2 (3.9). Mean (SD) lesion volumes were systematically higher as measured by CT: 656.7 (1939.9) mm3 compared to MRI: 442 (1083.2) mm3. Radiographic area was highly correlated (P = <0.0001) with volume for both CT and MRI (rho=0.91 and 0.87, respectively). DISCUSSION: It was possible to measure calcinotic lesions by radiography, CT and MRI, with CT volume being higher than MRI volume. Radiographic area was highly correlated with CT and MRI volume, suggesting that low cost radiographs may give comparable information to 3-dimensional imaging. Our findings provide further insight into the development of objective outcome measures to facilitate future calcinosis clinical trials.

11.
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461

RESUMO

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.


Assuntos
Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-30496561

RESUMO

Objectives: To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria in a cohort of incident IIM cases and examine how criteria-assigned IIM subtype correlates with expert opinion. Methods: Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust were identified over a 10 year period. A retrospective review of all putative cases was performed and those fulfilling a consensus expert opinion diagnosis of IIM were included. Clinical, serological and histological data were collected and each case was assigned a single IIM subtype. The EULAR/ACR classification criteria were then applied and sensitivity, specificity and positive and negative predictive values were calculated, presented with 95% CIs. Results: A total of 1637 cases were screened, with 255 consensus expert opinion IIM cases ultimately identified. Applying the EULAR/ACR classification criteria, the sensitivity to diagnose an IIM was 99.6% (95% CI 97.2, 100) and 80.9% (95% CI 76.0, 85.8) for the criteria cut-points of probable and definite diagnoses, respectively. In 94/255 cases the IIM subtype differed between consensus expert opinion and classification criteria, most strikingly in the group subtyped as PM by the EULAR/ACR criteria, where there was discrepancy in the majority (i.e. in 87/161). Conclusion: The EULAR/ACR criteria performed with high sensitivity in identifying IIM in this external cohort of incident IIM. However, substantial disagreements arose between consensus expert opinion and the criteria regarding IIM subtype assignments, resulting in a large proportion of criteria-assigned cases of PM having heterogeneous features. These results may have important implications for future use of these criteria in subsequent research.

13.
Physiotherapy ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30318128

RESUMO

OBJECTIVE: The musculoskeletal features of systemic sclerosis (SSc) are a major cause of disability, causing limitations to movement and function. The study aim was to compare the effects of daily hand exercises with or without daily home wax bath hand treatment in patients with SSc. DESIGN: Assessor-blinded randomised controlled trial of parallel group design. SETTING: Single participating centre, undertaken in secondary care and in participants homes. PARTICIPANTS: 36 participants with hand skin tightening of SSc, two participants lost to follow up. INTERVENTIONS: Participants were randomised into wax bath versus no wax bath groups. Both groups in addition performed regular hand exercises as part of standard care. The study period was 9weeks, with further measures of outcome undertaken at 18weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the Hand Mobility in Scleroderma test (HAMIS). Secondary outcomes measures were the Scleroderma Health Assessment Questionnaire, grip and pinch strength and the Cochin Hand Function Scale. RESULTS: Between group comparisons of HAMIS scores showed no evidence of effectiveness of the wax bath treatment at 9-week follow up (adjusted difference in means (95% CI) experimental-control -1.47 (-3.55 to 0.61), P=0.16) or at 18-week follow up (adjusted difference in means (95% CI) experimental-control 1.94 (-1.07 to 4.95), P=0.20). Analysis of secondary outcomes also showed no evidence for effectiveness of the wax bath treatment at either 9 or 18weeks. CONCLUSION: Our findings suggest that the addition of regular wax bath treatment confers no additional beneficial effect to standard care with daily home exercises. TRIAL REGISTRATION: ISRCTN registry (http://www.isrctn.com) ISRCTN 66736089.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30247696

RESUMO

Objectives: Nailfold capillaroscopy is being increasingly used by rheumatologists in the diagnosis of SSc. However, assessment of all nailfolds can be time-consuming in a busy outpatient clinic. Our aim was to answer the question as to how many (and which) fingers a clinician should routinely assess to capture accurately the true state. Methods: A total of 2994 assessments (by an international panel of expert observers) of 1600 images from 173 participants (101 with SSc, 22 with primary RP and 50 healthy controls) were included in this analysis. Seven single-finger or finger combinations (derived from the middle and ring fingers) were then tested for sensitivity for the presence of two markers of capillary abnormality [presence of giant capillaries and an SSc grade (early, active or late)] compared with assessment of all eight fingers. Results: For the eight-finger gold standard, sensitivity against the diagnostic criteria was 74.6% (53.0% for the presence of giants alone and 73.1% for image grade alone). Examining only one finger gave low sensitivity (ranging from right middle 31.7% to left ring 46.6%). Examining both ring fingers gave a sensitivity of 59.8%, whereas examining the four-finger combination of both ring and both middle fingers gave a sensitivity of 66.7%. Conclusion: During routine capillaroscopic examination, ideally all eight nailbeds (excluding thumbs) should be examined, otherwise some abnormalities will be missed. Examining only four fingers reduces capillaroscopy sensitivity.

15.
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
16.
J Scleroderma Relat Disord ; 3(2): 170-174, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29876526

RESUMO

Introduction: The reliability of clinician grading of systemic sclerosis-related digital ulcers has been reported to be poor to moderate at best, which has important implications for clinical trial design. The aim of this study was to examine the reliability of new proposed UK Scleroderma Study Group digital ulcer definitions among UK clinicians with an interest in systemic sclerosis. Methods: Raters graded (through a custom-built interface) 90 images (80 unique and 10 repeat) of a range of digital lesions collected from patients with systemic sclerosis. Lesions were graded on an ordinal scale of severity: 'no ulcer', 'healed ulcer' or 'digital ulcer'. Results: A total of 23 clinicians - 18 rheumatologists, 3 dermatologists, 1 hand surgeon and 1 specialist rheumatology nurse - completed the study. A total of 2070 (1840 unique + 230 repeat) image gradings were obtained. For intra-rater reliability, across all images, the overall weighted kappa coefficient was high (0.71) and was moderate (0.55) when averaged across individual raters. Overall inter-rater reliability was poor (0.15). Conclusion: Although our proposed digital ulcer definitions had high intra-rater reliability, the overall inter-rater reliability was poor. Our study highlights the challenges of digital ulcer assessment by clinicians with an interest in systemic sclerosis and provides a number of useful insights for future clinical trial design. Further research is warranted to improve the reliability of digital ulcer definition/rating as an outcome measure in clinical trials, including examining the role for objective measurement techniques, and the development of digital ulcer patient-reported outcome measures.

17.
Med Hypotheses ; 116: 101-104, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29857890

RESUMO

Digital ulcers (DU) are a common manifestation of systemic sclerosis (SSc) and occur at a variety of locations including the fingertips and over the extensor aspects of the hands. However, most recent clinical trials have included only fingertip DUs as these are believed to be ischaemic in aetiology, and therefore likely to benefit from treatment with vasoactive drug therapies. There is an emerging evidence base to suggest that all DUs in SSc could share an ischaemic component which is potentially responsive to vascular therapy. Our hypothesis is that is that DUs occurring at sites other than the fingertips, in particular, those overlying the extensor aspect of the hands, may also have a potentially reversible ischaemic component. We review the evidence under the headings: 'microvascular imaging', 'structural microvascular' and, 'functional vascular disease', 'macrovascular involvement' and 'vascular associates'. Based upon the current evidence, we would encourage the expert SSc community to reconsider the rationale for including only fingertip DUs in future SSc clinical trials, and suggest an agenda for future research.


Assuntos
Dedos/patologia , Escleroderma Sistêmico/terapia , Úlcera Cutânea/terapia , Doenças Vasculares/terapia , Calcinose/terapia , Ensaios Clínicos como Assunto , Humanos , Isquemia/fisiopatologia , Isquemia/terapia , Microcirculação , Modelos Teóricos
18.
Microvasc Res ; 118: 173-177, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29605552

RESUMO

OBJECTIVES: Despite increasing interest in nailfold capillaroscopy, objective measures of capillary structure and blood flow have been little studied. We aimed to test the hypothesis that structural measurements, capillary flow, and a combined measure have the predictive power to separate patients with systemic sclerosis (SSc) from those with primary Raynaud's phenomenon (PRP) and healthy controls (HC). METHODS: 50 patients with SSc, 12 with PRP, and 50 HC were imaged using a novel capillaroscopy system that generates high-quality nailfold images and provides fully-automated measurements of capillary structure and blood flow (capillary density, mean width, maximum width, shape score, derangement and mean flow velocity). Population statistics summarise the differences between the three groups. Areas under ROC curves (AZ) were used to measure classification accuracy when assigning individuals to SSc and HC/PRP groups. RESULTS: Statistically significant differences in group means were found between patients with SSc and both HC and patients with PRP, for all measurements, e.g. mean width (µm) ±â€¯SE: 15.0 ±â€¯0.71, 12.7 ±â€¯0.74 and 11.8 ±â€¯0.23 for SSc, PRP and HC respectively. Combining the five structural measurements gave better classification (AZ = 0.919 ±â€¯0.026) than the best single measurement (mean width, AZ = 0.874 ±â€¯0.043), whilst adding flow further improved classification (AZ = 0.930 ±â€¯0.024). CONCLUSIONS: Structural and blood flow measurements are both able to distinguish patients with SSc from those with PRP/HC. Importantly, these hold promise as clinical trial outcome measures for treatments aimed at improving finger blood flow or microvascular remodelling.

20.
Arthritis Rheumatol ; 70(6): 974, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29513930
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