Outcomes of Patients With Diffuse Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation Treated With Conventional Therapy.

OBJECTIVE: The study objective was to determine the event-free survival (EFS) of Australian patients with diffuse cutaneous systemic sclerosis (dcSSc) who met eligibility criteria for autologous stem cell transplant (ASCT) in previously published randomized controlled trials but were not treated with ASCT. METHODS: Patients who met inclusion criteria for the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) and Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trials were identified from the multicenter Australian Scleroderma Cohort Study (ASCS). EFS (survival without cardiac, renal, or pulmonary failure or death) at 4 years was assessed. ASCS patients who had already undergone transplantation were excluded from analysis. RESULTS: Of the 492 patients with dcSSc in the ASCS, 56 met ASTIS inclusion criteria for ASCT (56 of 492 [11.4%]) and 30 met SCOT inclusion criteria (30 of 492 [6.1%]). An additional 11 patients met ASTIS or SCOT inclusion criteria, but they were excluded due to severe organ manifestations. EFS at 4 years in ASCS patients meeting ASTIS inclusion criteria was 83.3% and in ASCS patients meeting SCOT inclusion criteria was 81.2%. EFS at 4 years in ASCS patients who met ASTIS and SCOT inclusion but also exclusion criteria was 46.7% and 45.7%, respectively. CONCLUSION: ASCS patients meeting ASTIS and/or SCOT inclusion criteria who were not treated with ASCT have similar EFS at 4 years as patients receiving ASCT and better EFS than those receiving cyclophosphamide in the ASTIS and SCOT trials. This may reflect confounders unable to be controlled for, including survivor bias, but may also reflect improved standard of care for dcSSc over time.

Evaluation of the European Society of Cardiology Risk Assessment Score in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Patients with pulmonary arterial hypertension (PAH) may be stratified as low, intermediate, or high risk of 1-year mortality. In 2022, the European Society of Cardiology (ESC) updated and simplified its risk stratification tool, based on three variables: World Health Organization functional class, serum N-terminal pro-brain type natriuretic peptide and six-minute walk distance, applied at follow-up visits, intended to guide therapy over time. METHODS: We applied the 2022 ESC risk assessment tool at baseline and follow-up (within 2 years) to a multinational incident cohort of systemic sclerosis-associated PAH (SSc-PAH). Kaplan-Meier curves, Cox hazards regression, and accelerated failure time models were used to evaluate survival by risk score. RESULTS: At baseline (n = 260), the majority of SSc-PAH (72.2%) were graded as intermediate risk of death according to the 2022 tool. At follow-up, according to 2022 tool, half (55.5%) of the cohort were classified as low or intermediate-low risk. The 2022 risk model at follow-up was able to differentiate survival between risk strata. All three individual parameters (World Health Organization functional class, N-terminal pro-brain type natriuretic peptide, six-minute walk distance) were significantly associated with mortality at baseline and/or follow-up. CONCLUSION: The 2022 ESC risk assessment strategy applied at baseline and follow-up predicts survival in SSc-PAH. Treatment decisions for SSc-PAH should include risk assessments, aiming to achieve low-risk status according to the 2022 ESC guidelines.

Multidisciplinary team discussion: the emerging gold standard for management of cardiopulmonary complications of connective tissue disease.

Cardiopulmonary complications of connective tissue diseases (CTDs), particularly pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), are major determinants of morbidity and mortality. Multidisciplinary meetings may improve diagnostic accuracy and optimise treatment. We review the literature regarding multidisciplinary meetings in CTD-ILD and PAH and describe our tertiary centre experience of the role of the multidisciplinary meeting in managing CTD-PAH.

Clinical characteristics and survival of pulmonary arterial hypertension with or without interstitial lung disease in systemic sclerosis.

OBJECTIVES: To describe the clinical phenotype and prognosis of people in the Australian Scleroderma (SSc) Cohort Study with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD). METHODS: Participants meeting ACR/EULAR criteria for SSc were divided into four mutually exclusive groups: those meeting criteria for PAH (PAH-only), ILD (ILD-only), concurrent PAH and ILD (PAH-ILD) or neither PAH nor ILD (SSc-only). Logistic or linear regression analyses were used for associations between clinical features, health-related quality of life (HRQoL) and physical function. Survival analysis was performed using Kaplan-Meier estimates and Cox-regression modelling. RESULTS: Of 1561 participants, 7% fulfilled criteria for PAH-only, 24% ILD-only, 7% PAH-ILD and 62% SSc-only. People with PAH-ILD were more frequently male, with diffuse skin involvement, higher inflammatory markers, older age of SSc onset and higher frequency of extensive ILD than the cohort overall (p < 0.001). People of Asian race more frequently developed PAH-ILD (p < 0.001). People with PAH-ILD or PAH-only had worse WHO functional class and 6-min-walk-distance than ILD-only (p < 0.001). HRQoL scores were worst in those with PAH-ILD (p < 0.001). Survival was reduced in the PAH-only and PAH-ILD groups (p < 0.01). Multivariable hazard modelling demonstrated the worst prognosis in extensive ILD and PAH (HR = 5.65 95% CI 3.50-9.12 p < 0.01), followed by PAH-only (HR = 4.21 95% CI 2.89-6.13 p < 0.01) and PAH with limited ILD (HR = 2.46 95% CI 1.52-3.99 p < 0.01). CONCLUSIONS: The prevalence of concurrent PAH-ILD in the ASCS is 7%, with poorer survival in those patients with PAH-ILD compared to ILD or SSc alone. The presence of PAH confers a poorer overall prognosis than even extensive ILD; however, further data are required to better understand the clinical outcomes of this high-risk patient group.

Evaluation of Patient and Physician Assessments of Gastrointestinal Disease Activity in Systemic Sclerosis.

OBJECTIVE: To assess whether patient and physician global assessment of gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) are associated with a meaningful change in disease status. METHODS: One hundred forty-three participants from the Australian Scleroderma Cohort Study were recruited to this study. Using logistic regression analysis, we evaluated the relationship between patient-reported and physician-assessed GIT disease status and symptoms, measures of health-related quality of life (36-item Short Form Health Survey [SF-36]) and GIT disease severity, measured by the Scleroderma Clinical Trials Consortium UCLA Gastrointestinal Tract 2.0 (GIT 2.0) score. RESULTS: Patient-reported worsening of GIT symptoms in the month preceding assessment was significantly associated with more severe GIT disease (odds ratio [OR] 6.14, P < 0.01) and progressive worsening GIT disease severity as measured by the GIT 2.0 score (OR 45.98, P < 0.01). The new onset of reflux was the only specific symptom associated with patient-reported GIT disease activity (OR 2.98, P = 0.04). Physician-assessed GIT disease activity was not significantly associated with higher GIT 2.0 scores or increasing severity of disease. Patient-reported and physician-assessed GIT activity was not associated with SF-36 scores. CONCLUSION: In the absence of objective measures of GIT disease activity in SSc, patient-reported symptoms of GIT disease could be used to indicate disease activity and should merit consideration for inclusion in a multisystem disease activity index.

Clinical Features of Systemic Sclerosis-Mixed Connective Tissue Disease and Systemic Sclerosis Overlap Syndromes.

OBJECTIVE: To describe the clinical characteristics and outcomes of systemic sclerosis-mixed connective tissue disease (SSc-MCTD) and SSc overlap syndrome. METHODS: We included patients from the Australian Scleroderma Cohort Study who met American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for SSc. Three mutually exclusive groups were created: SSc-MCTD, SSc overlap, and SSc only. Univariate comparison of clinical features was performed by analysis of variance or chi-square test. Survival analysis was performed using Kaplan-Meier (KM) curves and Cox proportional hazards regression models. RESULTS: Of 1,728 patients, 97 (5.6%) had SSc-MCTD, and 126 (7.3%) had SSc overlap. Those with MCTD-SSc were more commonly Asian (18.3% versus 10.1% in SSc overlap, and 3.6% in SSc only; P < 0.0001) and younger at disease onset (38.4 years versus 46.5 or 46.8 years, P < 0.0001). Those with SSc-MCTD or SSc overlap were more likely to have limited cutaneous SSc. All 3 groups had similar frequency of interstitial lung disease (ILD), although pulmonary arterial hypertension (PAH) was less common in SSc overlap. Synovitis and myositis were more common in SSc overlap and SSc-MCTD than in SSc only. KM curves showed better survival in SSc-MCTD than SSc overlap or SSc only (P = 0.011), but this was not significant after adjustment for sex and age at disease onset. SSc-specific antibodies were survival prognostic markers, with antinuclear antibody centromere or anti-RNP conferring better survival than anti-Scl-70 or anti-RNA polymerase III (P = 0.005). Patients with SSc-MCTD and SSc overlap had lower mortality following diagnosis of ILD and PAH than patients with SSc only. CONCLUSION: This study provides insights into the clinical characteristics of patients with SSc-MCTD, SSc overlap, and SSc only and shows that anti-RNP antibodies are associated with better survival than anti-Scl-70 and anti-RNA polymerase III antibodies.

Occupational silica exposure in an Australian systemic sclerosis cohort.

OBJECTIVE: To determine the frequency of self-reported occupational exposure to silica in SSc patients enrolled in the Australian Scleroderma Cohort Study, and to compare the disease characteristics of the silica-exposed patients with those of the non-exposed patients. METHOD: Data collected over a 12-year period from 1670 SSc patients were analysed. We compared the demographic and clinical characteristics of those who reported occupational silica exposure with those who did not. A subgroup analysis of male patients was performed, as well as a multivariable analysis of correlates of silica exposure. RESULTS: Overall, 126 (7.5%) of the cohort reported occupational silica exposure. These individuals were more likely to be male (73 of 231, i.e. 31.6% males exposed) and to have worked in mining and construction industries. Those who reported silica exposure were younger at the onset of SSc skin involvement [odds ratio (OR) 0.9, P = 0.02], of male gender (OR 14.9, P < 0.001), have joint contractures (OR 1.8, P = 0.05) and have higher physical disability as defined by scleroderma HAQ (OR 1.4, P = 0.01). CONCLUSION: The highest percentage of silica exposure was found in males. These patients were more likely to have the presence of certain clinical manifestations and Scl-70 antibody, which is known to confer a poor prognosis. These findings support the association between occupational silica exposure and the subsequent development of SSc. Further investigation is required to describe the range of clinical manifestations and disease course, including prognosis and treatment response, in those diagnosed with occupationally induced SSc compared with idiopathic SSc.

Incidence, Risk Factors, and Outcomes of Cancer in Systemic Sclerosis.

OBJECTIVE: To quantify the burden of cancer in systemic sclerosis (SSc). METHODS: Standardized incidence ratios (SIRs) and standardized mortality ratios relative to the general Australian population were derived. Cox proportional hazards regression was used to estimate survival in patients with SSc with cancer compared to patients without. Determinants of cancer were identified using logistic regression. Health care cost was quantified through cross-jurisdictional data linkage. RESULTS: This SSc cohort of 1,727 had a cancer incidence of 1.3% per year and a prevalence of 14.2%, with a SIR of 2.15 (95% confidence interval [95% CI] 1.84-2.49). The most common cancers were breast, melanoma, hematologic, and lung. Anti-RNA polymerase III (RNAP) antibody was associated with an increased risk of cancer (odds ratio [OR] 2.9, P = 0.044), diagnosed within 5 years of SSc disease onset. Calcium channel blockers were associated with a higher risk of overall cancer (OR 1.47, P = 0.016), breast cancer (OR 1.61, P = 0.051), and melanoma (OR 2.01, P = 0.042). Interstitial lung disease (ILD) was associated with lung cancer (OR 2.83, P = 0.031). Incident SSc cancer patients had >2-fold increased mortality compared to patients with SSc without cancer (hazard ratio 2.85 [95% CI 1.51-5.37], P = 0.001). Patients with SSc and cancer utilized more health care than those without cancer, with an excess annual health care cost of $1,496 Australian (P < 0.001). CONCLUSION: SSc carries an increased risk of developing cancer, particularly lung cancer associated with ILD, and breast cancer and melanoma occurring close to SSc disease onset in association with RNAP antibodies. Compared to those patients without cancer, patients with SSc and cancer had higher mortality and an increased health care cost, with an annual excess per patient cost of $1,496 Australian (P < 0.001).

The clinical and economic burden of systemic sclerosis related interstitial lung disease.

OBJECTIVE: To quantify the burden of interstitial lung disease (ILD) in SSc. METHODS: Clinical data for SSc patients enrolled in the Australian Scleroderma Cohort Study were linked with healthcare databases for the period 2008-2015. ILD was defined by characteristic fibrotic changes on high-resolution CT (HRCT) lung, while severity was defined by the extent lung involvement on HRCT (mild <10%, moderate 10-30%, severe >30%). Determinants of healthcare cost were estimated using logistic regression. RESULTS: SSc-ILD patients utilized more healthcare resources, including hospitalization, emergency department presentation and ambulatory care services, than those without ILD with a total cost per patient of AUD$48 368 (26 230-93 615) vs AUD$33 657 (15 144-66 905), P<0.001) between 2008-2015. Healthcare utilization was associated with an annual median (25th-75th) excess cost per SSc-ILD patient compared with those without ILD of AUD$1192 (807-1212), P<0.001. Increasing ILD severity was associated with significantly more healthcare utilization and costs with an annual excess cost per patient with severe ILD compared with mild ILD of AUD$2321 (645-1846), P<0.001. ILD severity and the presence of coexistent PAH were the main determinants of overall healthcare cost above median for this SSc-ILD cohort (OR 5.1, P<0.001, and OR 2.6, P=0.01, respectively). Furthermore, SSc-ILD patients reported worse physical HRQoL compared with those without ILD [34.3 (10.5) vs 39.1 (10.8), P<0.001], with a progressive decline with increasing ILD severity (P=0.002). CONCLUSION: SSc-ILD places a large burden on the healthcare system and the patient through poor HRQoL in addition to incremental healthcare resource utilization and associated direct cost.

Digital ulcers in systemic sclerosis: their epidemiology, clinical characteristics, and associated clinical and economic burden.

BACKGROUND: To determine the frequency and clinical characteristics of systemic sclerosis-related digital ulcers, and associated direct health care costs, quality of life, and survival. METHODS: Digital ulcers (DUs) were defined as an area with a visually discernible depth and a loss of continuity of epithelial coverage. DU severity was calculated based on the physician reported highest number of new DUs at clinical review (mild = 1-5 DUs, moderate 6-10 DUs, severe > 10 DUs). Healthcare use was captured through data linkage, wherein SSc clinical data captured prospectively in a dedicated clinical database were linked with health services databases to capture hospital admissions, emergency department (ED) presentations and ambulatory care (MBS) utilization and cost for the period 2008-2015. Healthcare cost determinants were estimated using logistic regression. RESULTS: Among 1085 SSc patients, 48.6% experienced a DU over a mean follow-up of 5.2 ± 2.5 years. Those who developed DUs were more likely to have diffuse disease subtype (34.9% vs 18.2%, p < 0.001), anti-Scl-70 antibody (18.9% vs 9.3%, p < 0.001), and a younger age at SSc onset (43.6 ± 13.9 vs 48.8 ± 14.0 years, p < 0.001) in addition to reduced health-related quality of life (HRQoL) measured by the SF-36 but without a significant impact on survival. SSc patients with a history of a DU utilized significantly more healthcare resources per annum than those without a DU, including hospitalizations, ED presentation, and ambulatory care services. Total healthcare services, excluding medications, were associated with an annual excess cost per DU patient of AUD$12,474 (8574-25,677), p < 0.001, driven by hospital admission and ED presentation costs. CONCLUSION: DUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.

The economic burden of systemic sclerosis related pulmonary arterial hypertension in Australia.

BACKGROUND: To quantify the financial cost of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc). METHODS: Healthcare use was captured through data linkage, wherein clinical data for SSc patients enrolled in the Australian Scleroderma Cohort Study were linked with hospital, emergency department (ED) and ambulatory care databases (MBS) for the period 2008-2015. PAH was diagnosed on right heart catheter according to international criteria. Determinants of healthcare cost were estimated using logistic regression. RESULTS: Total median (25th-75th) healthcare cost per patient (including hospital, ED and MBS cost but excluding medication cost) for our cohort during 2008-2015 was AUD$37,685 (18,144-78,811) with an annual per patient healthcare cost of AUD$7506 (5273-10,654). Total healthcare cost was higher for SSc-PAH patients compared with those without PAH with a total cost per patient of AUD$70,034 (37,222-110,814) vs AUD$34,325 (16,093 - 69,957), p < 0.001 respectively with an annual excess healthcare cost per PAH patient of AUD$2463 (1973-1885), p < 0.001. The cost of SSc-PAH occurs early post PAH diagnosis with 89.4% utilizing a healthcare service within the first 12 months post PAH diagnosis with an associated cost per patient of AUD$4125 (0-15,666). PAH severity was the main significant determinant of increased healthcare cost (OR 2.5, p = 0.03) in our PAH cohort. CONCLUSIONS: Despite SSc-PAH being a low prevalence disease, it is associated with significant healthcare resource utilization and associated economic burden, predominantly driven by the severity of PAH.

Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis.

OBJECTIVE: We sought to develop the first Damage Index (DI) in systemic sclerosis (SSc). METHODS: The conceptual definition of 'damage' in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort. 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, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort. CONCLUSIONS: Through the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups.

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.

The role of inflammatory markers in assessment of disease activity in systemic sclerosis.

OBJECTIVES: The role of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the assessment of disease activity in systemic sclerosis (SSc) remains controversial. We sought to evaluate the relationship between clinical features of SSc and raised inflammatory markers and to determine if changes in ESR and CRP reflect changes in other disease features over time. METHODS: One thousand, five hundred and forty-five patients enrolled in the Australian Scleroderma Cohort Study were observed over a mean 3.52±2.91 years and assessed at 6,119 study visits. Generalised estimating equations were used to determine the relationship between ESR≥20mm/hr and CRP≥5mg/L and features of disease. The associations between change in inflammatory markers and change in skin scores and respiratory function tests were analysed. RESULTS: Overall, there was a significant association between raised ESR and forced vital capacity (FVC)<80% predicted, diffusing capacity of the lung (DLCO)<80% predicted, pulmonary arterial hypertension (PAH), body mass index (BMI), proximal muscle strength, anaemia, and hypocomplementaemia (p<0.05). Raised CRP was significantly associated with modified Rodnan Skin Score>20, FVC<80%, DLCO<80%, PAH, digital ulcers, BMI, synovitis, tendon friction rub, anaemia, and hypocomplementaemia (p<0.05). A significant deterioration in respiratory function tests (RFTs) was associated with a 2-fold increase in both ESR and CRP (p<0.05). CONCLUSIONS: Raised inflammatory markers are associated with pulmonary, cutaneous and musculoskeletal manifestations of SSc. Rising inflammatory markers are correlated with declining respiratory function tests. This suggests inflammatory markers have a role in the assessment of SSc disease activity.

Quantifying the direct public health care cost of systemic sclerosis: A comprehensive data linkage study.

To quantify the direct healthcare cost of systemic sclerosis (SSc) and identify its determinants. Healthcare use was captured through data linkage, wherein clinical and medication data for SSc patients from the state of Victoria enrolled in the Australian Scleroderma Cohort Study were linked with the Victorian hospital admissions and emergency presentations data sets, and the Medicare Benefits Schedule which contains all government subsidized ambulatory care services, for the period 2011-2015. Medication cost was determined from the Pharmaceutical Benefits Scheme. Costs were extrapolated to all Australian SSc patients based on SSc prevalence of 21.1 per 100,000 and an Australian population of 24,304,682 in 2015. Determinants of healthcare cost were estimated using logistic regression. Total healthcare utilization cost to the Australian government extrapolated to all Australian SSc patients from 2011 to 2015 was Australian Dollar (AUD)$297,663,404.77, which is an average annual cost of AUD$59,532,680.95 (US Dollar [USD]$43,816,040.08) and annual cost per patient of AUD$11,607.07 (USD$8,542.80). Hospital costs, including inpatient hospitalization and emergency department presentations, accounted for the majority of these costs (44.4% of total), followed by medication cost (31.2%) and ambulatory care cost (24.4%). Pulmonary arterial hypertension (PAH) and gastrointestinal (GIT) involvement were the major determinants of healthcare cost (OR 2.3 and 1.8, P = .01 for hospitalizations; OR 2.8 and 2.0, P = .01 for ambulatory care; OR 7.8 and 1.6, P < .001 and P = .03 for medication cost, respectively). SSc is associated with substantial healthcare utilization and direct economic burden. The most costly aspects of SSc are PAH and GIT involvement.

Measures of disease status in systemic sclerosis: A systematic review.

OBJECTIVES: To identify and appraise measures of disease status in systemic sclerosis (SSc). METHODS: 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. We focused on objective measures and excluded non-English articles. Measures were reviewed for content, whether they measured activity, damage and/or severity and whether they were validated according to the OMERACT filter. RESULTS: Of the 4558 articles retrieved through the search, we identified 58 articles for review. We found a further 44 articles through a search of the bibliography of relevant articles. We 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. CONCLUSIONS: We 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. There is a need to develop and validate a disease damage index in SSc.