Medicine (St Vincent's) - Theses
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ItemDevelopment of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis( 2018)Objective: Systemic Sclerosis (SSc) is a multi-organ connective tissue disease resulting in fibrosis of the skin and internal organs. We sought to develop the first damage index (DI) in systemic sclerosis (SSc). Methods: Following systematic review of the literature focusing on methodology used to develop damage indices in other rheumatological conditions, the following methods were used to develop the SCTC-DI. The conceptual definition of organ damage in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic review of the literature and consultation with three experienced patient partners and 7 non-rheumatologist experts produced a list of potential items for inclusion in the DI. The following steps were used to reduce the items; (1) Expert members of the SCTC (n=331) were invited by email to rate the appropriateness of each item for inclusion in the DI using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1,568 patients followed for a mean of 4.8 years, the univariable relationships between the remaining items and the end points of mortality and morbidity (physical component summary score of the Short Form 36) were analysed, and items with p value < 0.10 were retained; (3) using multivariable regression analysis against the above endpoints, coefficients were used to determine a weighted score for each item; (4) internal and external retrospective validation was performed to demonstrate construct and criterion validity. Results: Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items. One further item was forced into the multivariable model by experts, due to clinical importance, to create a 23-item weighted SCTC Damage Index (SCTC-DI). Conclusions: Through the combined use of consensus and data driven methods, a 23-item SCTC-DI was developed. Future prospective validation is planned.
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ItemQuantifying organ damage in systemic sclerosis: rationale, methodology and item generation( 2018)Purpose: The overall purpose of this thesis is to form a rationale for the development of a disease damage index in systemic sclerosis and to inform item generation for inclusion in this index through: (1) appraisal of existing measures of disease status in systemic sclerosis (SSc); and (2) quantifying the accrual of organ damage in patients with early SSc using ad hoc criteria. Methods: (1) A systematic review of Medline (1966–2015), EMBASE (1974–2015), and Cochrane Library (inception–2015) was undertaken to identify indices of disease status in SSc. The study focused on objective measures and excluded non-English articles. Measures were reviewed for content, whether they measured activity, damage and/or severity and if they were validated according to the OMERACT filter; (2) Patients in the Australian Scleroderma Cohort Study enrolled within two years of onset of the first non-Raynaud’s SSc symptom were included. Organ damage was defined by a group of six experts as substantial and permanent loss of organ function due to SSc. Results: (1) Of the 4558 articles retrieved through the search, 58 articles were identified for review. A further 44 articles were found through a search of the bibliography of relevant articles. The systematic review identified the following 10 “composite” (multi-organ) indices: two disease activity indices, six disease severity scales, and two combined response indices. There was no disease ‘damage index’ for SSc. The Valentini disease activity index has face validity, partial validity for content and criterion validity, and sensitivity to change, but not for reliability. The Medsger disease severity scale has face, content and criterion validity but not construct validity, sensitivity to change and reliability. (2) The study identified 278 patients with early SSc. Among these, 38% had diffuse SSc. Damage was more common in the diffuse than in the limited disease subtype in the kin/musculoskeletal (75% vs. 25.2%, p<0.001) and lung (31.4% vs. 19.9%, p = 0.035) domains at year seven of follow-up. The rates of damage accrual were highest in the kin/musculoskeletal, gastrointestinal and respiratory systems at year two (29.1%, 18.7%, 14.4%), increasing at year five (41.4%, 30.6%, 21.2%) and declining thereafter to year seven (43.9%, 32.7%, 23.0%). In particular, there was early accrual of damage due to joint contracture (22.3%), gastrointestinal dysmotility (11.5%) and pulmonary fibrosis with forced vital capacity <70% predicted (9.7%) at year two. The highest accrual rate of organ-specific damage from years two to seven was seen in faecal incontinence followed by proximal muscle weakness and pulmonary fibrosis. Conclusions: (1) The study identified a number of composite and organ-specific indices in SSc, incorporating mostly objective measures, developed to quantify disease activity, severity, and response in clinical trials. However, none of the indices was developed to exclusively quantify organ damage. Most of the existing indices require further validation according to the OMERACT filter; (2) Substantial accrual of organ damage occurs early in the course of disease, particularly in diffuse SSc. This provides a strong rationale for the development and validation of a SSc damage index.