1,720,979 research outputs found
Cost savings with a novel algorithm for early detection of systemic sclerosis-related pulmonary arterial hypertension.
No full textPulmonary Arterial Hypertension (PAH) is an important cause of death and disability in Scleroderma (SSc) patients. Yearly screening of all SSc patients with transthoracic echocardiography (TTE) is recommended in international guidelines and currently utilised by the Australian Scleroderma Interest Group (ASIGSTANDARD). Due to the limitations of TTE, the Australian Scleroderma Interest Group (ASIG) developed a new screening algorithm (ASIGPROPOSED) utilizing a serum biomarker, NT-proBNP, in place of TTE, which has been shown to be equally accurate as the current algorithm. The aim of this study was to compare the cost of these two algorithms. The new algorithm resulted in significant yearly cost savings of between AUD84,570 in screening and diagnosis of the ASCS cohort which, if extrapolated to the Australian population, would result in a yearly cost saving of between AUD725,564. There was no scenario in which the proposed algorithm did not result in a cost saving
Immunosuppressive Drugs in Early Systemic Sclerosis and Prevention of Damage Accrual
No full textObjective. Organ damage in patients with systemic sclerosis (SSc) in individual organs such as the lungs may be prevented by receiving immunosuppressive drugs (ISs). A new measure of global organ damage, the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), has allowed us to investigate whether receiving ISs may reduce global organ damage accrual in patients with early SSc. Methods. This was a retrospective study of patients with two or less years of disease duration in Canadian and Australian cohorts with SSc. Patients with either limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc) were observed separately and divided into groups who were either ever or never exposed to ISs. The SCTC-DI was the outcome, and inverse probability of treatment weighting (IPTW) was used to balance the study groups and to fit a marginal structural generalized estimating equation model. Results. In the cohort with lcSSc, there were 210 patients, of whom 34% were exposed to ISs at some time. Exposure to ISs was associated with lower damage scores. In the cohort with dcSSc, there were 192 patients, of whom 76% were exposed to ISs at some time. Exposure to ISs was not associated with damage scores. Conclusion. In this retrospective observational cohort study, using IPTW to adjust for confounders, we found a protective effect of receiving ISs on damage accrual in patients with lcSSc. We were unable to determine such an effect in patients with dcSSc, but unknown confounders may have been present, and prospective studies of patients with dcSSc receiving ISs should include the SCTC-DI to determine the possible effect of ISs on damage accrual.Murray Baron, Mandana Nikpour, Dylan Hansen, Susanna Proudman, and Wendy Stevens, on behalf of the Australian Scleroderma Interest Group and the Canadian Scleroderma Research Group, and Mianbo Wan
Predictive accuracy of the ASIG algorithm in a prospective systemic sclerosis cohort undergoing annual screening for pulmonary arterial hypertension
No full textThe Australian Scleroderma Interest Group (ASIG) algorithm for screening pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) requires only respiratory function tests and serum N-terminal pro-brain natriuretic peptide as first-tier tests, and is recommended in international guidelines. In this communication, we present the findings of the application of the ASIG screening algorithm to a Singaporean cohort undergoing prospective annual screening for PAH, which shows a high negative predictive value. The ASIG algorithm may offer an alternative to more complex and costly SSc-PAH screening algorithms
GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
No full textSystemic 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
Development and Initial Validation of the Novel Scleroderma Clinical Trials Consortium Activity Index
Get PDFOBJECTIVE
Accurate measurement of disease activity in systemic sclerosis (SSc) remains a significant clinical challenge. The Scleroderma Clinical Trials Consortium (SCTC) convened an Activity Index Working Group (WG) to develop a novel measure of disease activity (SCTC-AI).
METHODS
Using consensus methodology, we developed a conceptual definition of disease activity. Literature review and expert consensus generated provisional SCTC-AI items, which were reduced by Delphi survey. Provisional items were weighted against a combined endpoint of morbidity and mortality, using time-dependent Cox proportional hazards regression analysis of the Australian Scleroderma Cohort Study (ASCS) (n=1,254). External validation of the SCTC-AI was performed using data collected from 1,103 Canadian Scleroderma Research Group Study participants.
RESULTS
Disease activity in SSc was defined using consensus methodology as 'aspects of disease that are reversible, or can be arrested, with time and, or effective therapy'. One-hundred and forty-one provisional SCTC-AI items were generated and reduced using 3 rounds of Delphi survey and statistical reduction and weighting, against mortality and quality of life measures, yielding a final 24-item index with a maximum possible score of 140. Survival analysis in an external cohort showed a graded relationship between disease activity scores and survival (p<0.01).
CONCLUSION
We present a novel instrument to quantify the burden of disease activity in SSc. We have employed a rigorous consensus-based process in combination with data-driven methods, to develop an instrument that has face, content and criterion validity. Further work is required to fully validate and confirm the construct and discriminative validity of the SCTC-AI
Validity of the Workers Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) in patients with systemic sclerosis
No full textTo evaluate the construct validity of the Workers Productivity and Impairment Activity Index: Specific Health Problem (WPAI:SHP) in Australian systemic sclerosis (SSc) patients.SSc patients, identified through the Australian Scleroderma Cohort Study database, completed the WPAI:SHP and a quality of life instrument (PROMIS-29) cross-sectionally. The construct validity of the WPAI:SHP was assessed by the correlations between the WPAI:SHP and a range of SSc health states. Non-parametric correlation, including Spearman's correlation (ρ), was used to test the validity of WPAI:SHP and ability to distinguish between different health states.A total of 476 completed questionnaires was returned, equating to a response rate of 63.7%. Among those under 65 years of age, 155 patients (55.2%) were in paid employment. Employed patients had a mean (± SD) age of 56.5 (9.8) years and were predominantly female (87.3%) with limited disease subtype (75.6%). The WPAI:SHP showed construct validity based on moderate to strong correlations with health status as assessed by a range of health outcome measures including disease activity (ρ=0.34-0.39, p=0.001), physical function (ρ=0.55-0.62, p=0.001), disease severity(ρ=0.55-0.62, p=0.001), fatigue (ρ= 0.62-0.63, p=0.001), pain (ρ=0.68-0.71, p=0.001), and breathlessness (ρ=0.39-0.46, p=0.001). Furthermore, according to the effect size, the WPAI:SHP scores have a large discriminative ability (d=1.26-1.47) for distinguishing SSc patients with different health outcomes.The WPAI is a valid questionnaire for assessing impairments in paid employment and social activities in SSc patients, and for measuring the relative differences between SSc patients with varying health states.K. Morrisroe, W. Stevens, M. Huq, J. Sahhar, G. Ngian, J. Zochling, J. Roddy, S. Proudman, M. Nikpour, the Australian Scleroderma Interest Group, (ASIG
Validity of the PROMIS-29 in a large Australian cohort of patients with systemic sclerosis
No full textBackground: We aimed to evaluate the construct validity of the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) in Australian systemic sclerosis (SSc) patients. Methods: SSc patients, identified through the Australian Scleroderma Cohort Study database, completed two quality-of-life instruments concurrently, the PROMIS-29 and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). The construct validity of the PROMIS-29 was assessed by the correlations between the PROMIS-29 and the SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI). Cronbach’s alpha was used to test the internal reliability of all instruments in Australian SSc patients and non-parametric correlation, including Spearman’s correlation, was used to test the construct validity of PROMIS-29 against the SF-36 and HAQ-DI. Results: A total of 477 completed questionnaires were returned, equating to a response rate of 59.6%. The mean (±SD) age of respondents at the time of the survey was 64.1 (±11.1) years. They were predominantly female (87.4%), with limited disease subtype (lcSSc) (77.8%) and long disease duration from onset of first non-Raynaud’s phenomenon symptom at the time of survey (10.9 ± 11.1 years). For the correlation analysis between the PROMIS-29 and the legacy instruments, all Spearman correlation coefficients were in the logical direction and highly significant suggesting that the PROMIS-29 is a good alternative to other validated measures of disease burden. Conclusions: Our study indicates that the PROMIS-29 questionnaire is a valid instrument for measuring health related quality of life in Australian females with lcSSc of long duration.Kathleen Morrisroe, Wendy Stevens, Molla Huq, Joanne Sahhar, Gene-Siew Ngian, Jane Zochling, Janet Roddy, the Australian Scleroderma Interest Group, ASIG, Susanna Proudman, Mandana Nikpou
Generation of a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology
No full textBackground: Scleroderma Renal Crisis (SRC) is characterized by malignant hypertension and acute kidney injury. The absence of a gold standard or classification criteria for SRC has hindered research in this field. The Scleroderma Clinical Trials Consortium (SCTC) SRC Working Group was created to develop consensus and data-driven classification criteria for SRC. This project was undertaken to generate a core set of items using consensus methodology to be considered in the development of classification criteria for SRC.
Methods: A survey using items identified by a scoping review was developed (REDCap platform, Vanderbilt University, Nashville, Tennessee). An international, multidisciplinary panel of experts from the SCTC, European Scleroderma Trials and Research Group (EUSTAR), Canadian Scleroderma Research Group (CSRG), and Australian Scleroderma Interest Group (ASIG) were invited to participate in a 3-round Delphi exercise. 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 1-9 (1= very invalid/unfeasible, 5 = uncertain, 9 = very valid/feasible), and to provide comments. In Round 3, participants reviewed the results and comments of Round 2, and were asked to provide final ratings. Items rated as highly valid and feasible (both median scores ≥7) in Round 3 were selected as the provisional core set of items. A nominal group discussion meeting followed the Delphi exercise to achieve final consensus on the core set of items.
Results: Overall, 216 experts were invited and 99 from 16 countries agreed to participate in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13 items pertaining to hypertension, renal insufficiency, proteinuria and hemolysis. Eleven experts took part in the nominal group discussion, where consensus was achieved for 5 domains: blood pressure, kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and histopathology.
Conclusions: A core set of items defining SRC was identified using consensus methodology. Future data-driven phases of the project are planned to develop classification criteria for SRC
Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
No full textCopy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals. © 2022, The Author(s)
GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
No full textSystemic 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. © 2019, The Author(s)
- …
