The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently ...used treatment approaches.
This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.
Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.
These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.
NCT02339441.
To determine the frequency and clinical characteristics of systemic sclerosis-related digital ulcers, and associated direct health care costs, quality of life, and survival.
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.
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.
DUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.
Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with ...progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs).
The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV).
66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%.
Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years.
NCT02339441.
Background Abnormalities of left ventricular (LV) structure, filling and long-axis function have all been reported in subjects with systemic sclerosis (SSc) and a normal LV ejection fraction (EF), ...but previous study findings have not been consistent. The aim of this study was to identify factors which could have confounded the analyses in previous studies of SSc, and in particular to consider the variables of body surface area (BSA), sex, age, heart rate, blood pressure (BP), disease duration (DD), disease type (limited versus diffuse) and interstitial lung disease (ILD). Methods Echocardiography was performed on 100 subjects with SSc (79 women; age 56±15 years) with a LVEF greater than or equal to50% and free of pulmonary arterial hypertension, coronary artery disease, more than mild valvular heart disease and atrial fibrillation. Measurements were performed of the LV end-diastolic dimension (LVEDD) and septal wall thickness (SWT), the transmitral Doppler E, A and deceleration time (DT), and the peak systolic (s') and early diastolic (e') LV long-axis velocities. Multivariate analyses were performed to investigate correlations of the above LV variables with BSA, sex, age, heart rate, BP, DD, disease type, and the presence of ILD. Results DD varied between 0.1 and 41.2 years, 25% had diffuse and 75% had limited disease, and 37% had ILD. SWT and LVEDD were positively correlated with BSA, SWT was also positively correlated with age and larger in males, and LVEDD was larger in diffuse disease. Age was positively correlated with A and DT, and inversely correlated with E and E/A, and heart rate was inversely correlated with E and E/A. None of E, A, E/A, or DT were independently associated with DD or disease type. Septal and lateral LV wall s' and e' were all inversely correlated with age, and there was a small independent contribution to the prediction of lateral s' from DD, but no association of either s' or e' with disease type. The presence of ILD was not a predictor of any of the LV variables. Conclusion In SSc there are associations of sex, body size, age and disease type with LV structural variables, of age and heart rate with E/A, and of age with both systolic and early diastolic LV long-axis velocities. Appropriate adjustment for these variables could help to resolve current uncertainties regarding SSc effects on the left ventricle.
To determine the prevalence of coronary heart disease (CHD) and cardiovascular risk factors in a well-characterised cohort of systemic sclerosis (SSc) patients, and to compare this with the general ...population.
A cross-sectional study of the prevalence of CHD and cardiovascular risk factors in participants in the Australian Scleroderma Cohort Study was performed. Controls were drawn from the 2007-8 National Health Survey (NHS) and the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). OR and 95% CI were calculated to determine the prevalence of CHD and cardiovascular risk factors in SSc patients compared with controls.
Data were available for 850 SSc patients (86% female), 15 787 NHS participants (53% female) and 8802 AusDiab participants (56% female). Adjusted for age and gender, the OR of CHD in SSc patients was 1.9 (95% CI 1.4 to 2.4) compared with controls from AusDiab and 2.0 (95% CI 1.5 to 2.5) compared with controls from the NHS. The OR of CHD increased to 3.2 (95% CI 2.3 to 4.5) for SSc patients compared with controls from AusDiab after further adjustment for cardiovascular risk factors. Hypercholesterolaemia, diabetes mellitus and obesity were significantly less prevalent in the SSc cohort than in AusDiab. Within the SSc cohort, the presence of pulmonary arterial hypertension was associated with CHD.
This is the first report of an increased prevalence of CHD in SSc patients. Further studies are required to determine the relative contribution of scleroderma-specific factors such as microvascular disease to the development of CHD.
There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening ...algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines.
We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an 'alternate scenario analysis' in which the prevalence of PAH was set at 10%.
RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%.
In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.
Objective
In patients with systemic sclerosis (SSc), we investigated composite serum biomarker panels for the diagnosis and risk stratification of SSc–associated interstitial lung disease (SSc‐ILD).
...Methods
We analyzed 28 biomarkers in 640 participants: 259 patients with SSc‐ILD and 179 SSc patients without ILD (Australian Scleroderma Cohort Study), 172 patients with idiopathic pulmonary fibrosis (IPF‐controls) (Australian IPF Registry), and 30 healthy controls. A composite index was developed from biomarkers associated with ILD in multivariable analysis derived at empirical thresholds. We evaluated the performance of the index to identify ILD, and specifically SSc‐ILD, and its association with lung function, disease extent on radiography, and patient health–related quality of life in derivation and validation cohorts. Biomarkers to distinguish SSc‐ILD from IPF‐controls were identified.
Results
A composite biomarker index, comprising surfactant protein D (SP‐D), Ca15‐3, and intercellular adhesion molecule 1 (ICAM‐1), was strongly associated with SSc‐ILD diagnosis, independent of age, sex, smoking history, and lung function (for biomarker index score 3, pooled adjusted odds ratio was 12.72 (95% confidence interval 4.59–35.21) (P < 0.001). The composite index strengthened the performance of individual biomarkers for SSc‐ILD identification. In SSc patients, a higher index was associated with worse baseline disease severity (for biomarker index score 3 relative to biomarker index score 0, the adjusted absolute change in forced vital capacity percent predicted was −17.84% and the diffusing capacity for carbon monoxide percent predicted was −20.16%; both P < 0.001).
Conclusion
A composite serum biomarker index, comprising SP‐D, Ca15‐3, and ICAM‐1, may improve the identification and risk stratification of ILD in SSc patients at baseline.
Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and ...the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality.
Clinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models.
Of 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p < 0.001), anti-MPO positive vs anti-MPO negative (38.5% vs 13.6%, p = 0.006) and anti-PR3 positive vs anti-PR3 negative patients (44.4% vs 13.4%, p < 0.001). A higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%, p < 0.001) and the anti-PR3 positive groups (50.0% vs 23.4%, p = 0.009). In multivariable analysis, ANCA-positive status remained associated with ILD after adjusting for anti-Scl-70 antibodies. Pulmonary embolism (PE) was more common in ANCA-positive patients (8.6% vs 3.0%, p = 0.002) and anti-PR3-positive patients (16.7% vs 3.3%, p = 0.022). ANCA-positive status remained associated with PE in a multivariable analysis adjusting for anti-phospholipid antibodies. Kaplan-Meier analysis revealed increased mortality in ANCA-positive patients (p = 0.006). In Cox regression analysis, ANCA was associated with increased mortality, after adjusting for age and sex.
ANCA is associated with increased prevalence of ILD and PE in SSc. ANCA should be tested in SSc, as it identifies individuals with worse prognosis who require close monitoring for adverse outcomes.
To describe the epidemiology, determinants and survival impact of gastric antral vascular ectasia (GAVE) in systemic sclerosis (SSc).
Consecutive SSc patients prospectively enrolled in the Australian ...Scleroderma Cohort Study (ASCS) were included. Univariable and multivariable logistic regression were used to determine the associations of GAVE with clinical manifestations and serological parameters. Kaplan-Meier (K-M) survival curves were used to estimate survival.
The prevalence of GAVE in this SSc cohort of 2039 SSc patients was 10.6% (n = 216) over a median follow-up period of 4.3(1.7-8.4) years. SSc patients with a history of GAVE compared with those without a history of GAVE were older at SSc onset 49.5 (40.0-58.2) vs 46.7 (36.0-56.7) years, p = 0.05; more likely to have diffuse disease subtype (dcSSc) (35.3% vs 24.1%, p < 0.001); be negative for Scl-70, U1RNP and Scl/PM antibody (4.0% vs 16.1%, p < 0.001, 3.5% vs 7.4%, p = 0.041, 0.0% vs 2.0%, p = 0.042; and respectively) and positive for RNAP III antibody (24.9% vs 8.3%, p < 0.001). Those with GAVE had a worse HRQoL (p = 0.002). Independent determinants of GAVE included the presence of RNAP III antibody (OR 3.46, p < 0.001), absence of Scl-70 antibody (OR 0.23, p = 0.001), presence of GIT dysmotility (OR 1.64, p = 0.004), and digital ulcers; pits; or digital amputation (OR 1.59, p = 0.014).
GAVE is an underestimated and underappreciated SSc manifestation of SSc, which occurs with a relatively high frequency. Identifying an at-risk GAVE phenotype, as presented herein, is of practical importance as screening may prove advantageous given GAVE can be easily diagnosed and treated.
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).
...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.
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).
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.
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