53 research outputs found
Damage Trajectories in Systemic Sclerosis Using Group-Based Trajectory Modeling
No full textFirst published: 28 February 2022Objective. Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive organ damage, which can be measured using the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). We aimed to identify whether distinct trajectories of damage accrual exist and to determine which variables are associated with different trajectory groups. Methods. Incident cases of SSc (<2 years) were identified in the Australian Scleroderma Interest Group and Canadian Scleroderma Research Group prospective registries. Group-based trajectory modeling was used to identify SCTC-DI trajectories over the cohort’s first 5 annual visits. Baseline variables associated with trajectory membership in a univariate analysis were examined in multivariable models. Results. A total of 410 patients were included. Three trajectory groups were identified: low (54.6%), medium (36.2%), and high (10.3%) damage. Patients with faster damage accrual had higher baseline SCTC-DI scores. Older age (odds ratio [OR] 1.57 [95% confidence interval (95% CI) 1.18–2.10]), male sex (OR 2.55 [95% CI 1.10–5.88]), diffuse disease (OR 6.7 [95% CI 2.57–17.48]), tendon friction rubs (OR 5.4 [95% CI 1.86–15.66]), and elevated C-reactive protein level (OR 1.98 [95% CI 1.49–2.63]) increased the odds of being in the high-damage group versus the reference (low damage), whereas White ethnicity (OR 0.31 [95% CI 0.12–0.75]) and anticentromere antibodies (OR 0.24 [95% CI 0.07–0.77]) decreased the odds. Conclusion. We identified 3 trajectories of damage accrual in a combined incident SSc cohort. Several characteristics increased the odds of belonging to worse trajectories. These findings may be helpful in recognizing patients in whom early aggressive treatment is necessary.Ariane Barbacki, Murray Baron, Mianbo Wang, Yuqing Zhang, Wendy Stevens, Joanne Sahhar, Susanna Proudman, Mandana Nikpour, and Ada Man, on behalf of the Australian Scleroderma Interest Group and the Canadian Scleroderma Research Grou
Anti-phospholipid antibodies in systemic sclerosis: prevalence and clinical correlations
No full textScientific abstract FRI0261K.B. Morrisroe, W.M. Stevens, J. Byron, V. Thakkar, O. Moore, S. Proudman, M. Nikpour, and Australian Scleroderma Interest Grou
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
Development and Initial Validation of the Novel Scleroderma Clinical Trials Consortium Activity Index
No full textOBJECTIVE
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
Identifying and quantifying prognostic factors in systemic sclerosis-related interstitial lung disease using a time-varying covariate survival model
No full textScientific abstract THU0235O.A. Moore, N. Goh, T. Corte, H. Rouse, O. Hennessy, V. Thakkar, J. Byron, J. Sahhar, J. Roddy, P. Youssef, P. Nash, J. Zochling, S.M. Proudman, W. Stevens, M. Nikpour, and Australian Scleroderma Interest Grou
Extent of disease on high-resolution CT lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease
No full textScientific abstract FRI0243O.A. Moore, N. Goh, T. Corte, H. Rouse, O. Hennessy, V. Thakkar, J. Byron, J. Sahhar, J. Roddy, P. Youssef, P. Nash, J. Zochling, S.M. Proudman, W. Stevens, M. Nikpour, and Australian Scleroderma Interest Grou
N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis
No full textScientific abstract THU0258V. Thakkar, W. Stevens, D. Prior, O. Moore, J. Byron, K. Patterson, P. Hissaria, J. Roddy, J. Zochling, J. Sahhar, P. Nash, K. Tymms, D. Celermajer, E. Gabbay, P. Youssef, S. Proudman, M. Nikpour, and Australian Scleroderma Interest Grou
An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3
No full textINTRODUCTION The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population. METHODS We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls. RESULTS A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10(-10)) in anti-centromere antibody (ACA) positive cases. CONCLUSIONS This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.The Wellcome Trust Case Control Consortium, Australian Scleroderma Interest Group, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, Pfizer, NHMRC Program Grant 569938 and the Australian Cancer Research Foundation - Tasmanian Inherited Cancer Centre Computing Facility. MB was supported by an NHMRC Senior Principal Research Fellowship APP1024879
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
- …
