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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.

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).

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 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.

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.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.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.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.

Bronchiectasis has been observed in association with systemic sclerosis (SSc). Theorised aetiology includes aspiration related to oesophageal dysmotility, immunosuppressant medication use and the direct effect of collagen deposition on airway calibre.To detail bronchiectasis prevalence in an SSc population who have had a high-resolution computed tomography (HRCT) of the thorax. We assessed whether oesophageal dysmotility, demographic variables, SSc duration or subclass were associated with bronchiectasis.Participants in the Australian Scleroderma Cohort Study (ASCS) with a HRCT were included. The ASCS provided demographic and clinical data. HRCT studies were reviewed for bronchiectasis, oesophageal dilatation and interstitial lung disease (ILD). Traction bronchiectasis associated with ILD was recorded as a separate entity to bronchiectasis. Oesophageal dysmotility was defined by symptoms and/or oesophageal dilatation.Of the 256 participants, 16.4% (n = 42) had bronchiectasis. Logistic regression analysis revealed no significant association between bronchiectasis and oesophageal dysmotility (observed in 95.7%), any demographic variable, SSc duration or subclass. A negative association between bronchiectasis and ILD was observed (P = 0.009; odds ratio 0.322; 95% confidence intervals 0.137-0.756).Those with SSc appear to have an increased risk for bronchiectasis. Since bronchiectasis was not more frequent in participants with a longer duration of SSc, we hypothesise that its development is not related to immunosuppression alone. Oesophageal dysmotility was almost universal in our population such that its effect on bronchiectasis development could not be concluded. A negative association between bronchiectasis and ILD reflects that bronchiectasis occurring alongside ILD was recorded as a separate entity.

AIM Despite reports of decreased bone mineral density in patients with systemic sclerosis (SSc) in international cohorts, the prevalence of osteoporosis in Australian SSc patients remains unknown. We report rates of dual-energy X-ray absorptiometry (DXA) scanning in an SSc cohort at a tertiary hospital specialized outpatient clinic and the prevalence and associations of osteoporosis in screened patients. METHOD We performed retrospective chart review to determine if patients underwent DXA scanning between 2007 and 2018 and extracted lumbar spine and femoral neck T-scores, fracture history, and osteoporosis therapy. RESULTS Of 244 patients, 104 (42.6%) underwent DXA scanning and among patients in whom T-scores were available (n = 91), 30 (33.0%) had osteoporosis and 48 (52.7%) had osteopenia. Screened patients were more likely to have longer disease duration (19.9 vs 15.2 years, P = 0.002), calcinosis (50.5% vs 36.4%, P = 0.028), myositis (12.6% vs 0.7%, P < 0.001), synovitis (42.7% vs 28.6%, P = 0.022), ever used prednisolone (76.7% vs 47.1%, P < 0.001) or fractures (23.0% vs 0.0%, P < 0.001). Patients with osteoporosis more commonly had a history of nasogastric feeding, percutaneous endoscopic gastrostomy feeding or intravenous total parenteral nutrition (6.9% vs 0.0%, P = 0.038) and, unexpectedly, less commonly ever used prednisolone (58.6% vs 85.2%, P = 0.005) compared with patients with osteopenia or normal bone density. CONCLUSION We identified high rates of osteoporosis among screened Australian SSc patients. Further assessment in larger, prospective studies is needed to establish guidelines for formal osteoporosis screening in SSc patients.

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 p p p Conclusion DUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.

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 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 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.

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 p 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.

Disease behaviour in interstitial lung disease (ILD) is highly variable and accurate clinical tools to predict prognosis and guide management decisions remain unsatisfactorily elusive. Accurate disease stratification would allow clinicians to better distinguish patients at risk of rapid progression requiring urgent treatment, from those indolent disease where potentially toxic drug therapy could be minimised or avoided. Several serum biomarkers have demonstrated potential utility for diagnosis and prognosis of ILD in small retrospective studies, and the hope is future multicentre prospective trials focussed on the markers with most potential will see translation to clinical practice. Two important and contrasting fibrotic lung diseases with high mortality are idiopathic pulmonary fibrosis (IPF) and systemic sclerosis associated ILD (SSc-ILD). In this era where anti-fibrotics for IPF have proven benefit, there are increasing biologic and non-biologic options for the treatment of connective tissue disease ILD (CTD-ILD), and the incidence of both is increasing, there is an urgent need to improve the diagnostic and prognostic accuracy in these complex patients. This comprehensive literature review will summarise and discuss the current evidence for the major candidate serum biomarkers in IPF and SSc-ILD. Biomarkers will be categorised by the following major mechanistic pathways (1) alveolar epithelial cell damage; (2) aberrant fibrogenesis, fibroproliferation and matrix remodelling; (3) immune dysregulation; and (4) vascular and endothelial damage. The aim is to review the rationale, potential and limitations of current candidate biomarkers and their utility in IPF and SSc-ILD to help direct future research and translation to clinical practice.

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142–2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P

Pulmonary arterial hypertension is an important cause of death and disability in patients with systemic sclerosis (SSc). 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 ). Owing to the limitations of TTE, the ASIG developed a new screening algorithm (ASIGPROPOSED ) utilising 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 using different scenarios. The new algorithm resulted in significant yearly cost savings of between AU$42 913.35 and AU$84 570 in screening and diagnosis of an Australian cohort which, if extrapolated to the Australian population, would result in a yearly cost saving of between AU$367 066 and AU$725 564. There was no scenario in which the proposed algorithm did not result in a cost saving.

Background 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. Methods 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. Results 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

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Background To evaluate the cost‐effectiveness of combination pulmonary arterial hypertension specific therapy in systemic sclerosis–related PAH. Methods and Results Health outcomes and costs were captured through data linkage. Health utility was derived from Medical Outcomes Study Short Form‐36 scores. A probabilistic discrete‐time model was developed to simulate lifetime changes in costs and health utility. Mortality was predicted using a Gompertz parametric survival model. For both treatment arms, the simulations were started using the same cohort of 10 000 patients. Probabilistic sensitivity analysis was performed using the Monte Carlo simulation with 1000 sets of sampled parameter values. Of 143 patients with systemic sclerosis–related pulmonary arterial hypertension, 89 were on monotherapy and 54 on combination therapy. Mean simulated costs per patient per year in monotherapy and combination therapy groups were AU$23 411 (US$16 080) and AU$29 129 (US$19 982), respectively. Mean life years and quality‐adjusted life years from pulmonary arterial hypertension diagnosis to death of patients receiving monotherapy were 7.1 and 3.0, respectively, and of those receiving combination therapy were 9.2 and 3.9, respectively. Incremental costs per life year and quality‐adjusted life year gained of combination therapy compared with monotherapy were AU$47 989 (US$32 920) and AU$113 823 (US$78 082), respectively. At a willingness‐to‐pay threshold of AU$102 000 (US$69 972) per life year gained, and of AU$177 222 (US$121 574) per quality‐adjusted life year gained, the probability of combination therapy being cost‐effective was 0.95. Conclusions The incremental cost per quality‐adjusted life year gained of combination therapy compared with monotherapy was substantial in the base case analysis. Given the fatal prognosis of systemic sclerosis–related pulmonary arterial hypertension and the incremental cost per life year of AU$47 989 (US$32 920), combination therapy could be considered cost‐effective in systemic sclerosis–related pulmonary arterial hypertension.

Assessment of disease activity in systemic sclerosis (SSc) is limited by the absence of a fully validated, multisystem measure of disease activity. The European Scleroderma Trials and Research Group (EUSTAR) SSc activity index (EScSG-AI) was recently revised, and a validation study within the EUSTAR cohort was performed. In this study, we evaluated the performance of the revised EScSG-AI in an external Australian cohort. The association between the EScSG-AI and the physician global assessment of disease activity (PhGA), both collected prospectively at each annual visit over up to 12 years follow-up, was evaluated using Pearson's correlation coefficient and Cohen's kappa coefficient. Generalized linear modelling and time-dependent Cox regression analysis were performed to determine the association of disease activity measured by the EScSG-AI and the summed Medsger Severity Scale (MSS) and death, respectively. There was a moderate correlation between EScSG-AI and PhGA scores (r 0.42, p

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)

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 ≥50% 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.

Introduction Systemic sclerosis (SSc) is characterized by irreversible organ damage rather than fluctuating disease activity. However, there is no validated measure of damage in SSc. We aimed to quantify the accrual of organ damage in patients with early SSc. Methods Patients enrolled in the Australian Scleroderma Cohort Study with less than 2 years of SSc since the onset of the first non-Raynaud's 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 We 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 skin/musculoskeletal (75% vs. 25.2%, pConclusions Substantial accrual of organ damage occurs early in the course of disease, particularly in diffuse SSc. This provides the rationale for the development of a SSc damage index.

Background 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.

Objective To evaluate the association between patient-reported symptoms and changes in disease activity over time in systemic sclerosis (SSc). Methods Using data from 1,636 patients enrolled in the Australian Scleroderma Cohort Study, we used generalized estimating equations to determine the relationship between patient-reported worsening of Raynaud's phenomenon (RP), skin involvement, and breathlessness in the month preceding each study visit and features of disease activity in the corresponding organ systems. The associations between the following parameters were analyzed: patient-reported worsening RP and the presence of new-onset digital pitting and digital ulcers; patient-reported worsening skin involvement and increasing modified Rodnan skin thickness score (MRSS); new areas of skin involvement and new-onset joint contractures; patient-reported worsening breathlessness and deteriorating respiratory functions test (RFT) results, indicated by a 10% decrease in forced vital capacity (FVC) and a 15% decrease in diffusing capacity for carbon monoxide (DLco), new-onset interstitial lung disease (ILD), and new-onset pulmonary arterial hypertension (PAH). Results We found a significant association between patient-reported worsening RP and the presence of digital ulcers (odds ratio [OR] 1.53 [95% confidence interval (95% CI) 0.60-0.93]), patient-reported worsening skin involvement and increasing MRSS (OR 2.10 [95% CI 1.54-2.86]), and worsening patient breathlessness and deteriorating RFTs (FVC OR 2.12 [95% CI 1.70-2.65]; DLco OR 1.97 [95% CI 1.34-2.02]), new-onset ILD (OR 1.91 [95% CI 1.40-2.61]), and new-onset PAH (OR 5.08 [95% CI 3.59-7.19]). Conclusion These results demonstrate that patient-reported symptoms are associated with clinically meaningful changes in disease activity in patients with SSc. This suggests that when objective measures of change in disease status are unavailable, patient-reported symptoms could be used to indicate a change in SSc disease activity.

Purpose Systemic sclerosis (SSc) is a heterogeneous disease that is often divided into subsets to stratify patients and predict prognosis. We hypothesized that individual methods of subsetting would not prognosticate equally well for different outcomes or in patients at different stages of disease. Methods We subsetted subjects with SSc using three approaches: limited versus diffuse cutaneous SSc (lcSSc, dcSSc); grouped by SSc-specific antibodies; and, grouped using unsupervised clustering. We studied patients with Results In this international, multicentered cohort of over 500 SSc subjects with less than four years of disease duration, none of the three methods of subsetting studied was able to predict all of the outcomes of interest. Different subsetting methods predicted different outcomes within and between each disease duration group. In general, subsetting by skin performed somewhat better than the two other methods, but this was not consistent and there was considerable variability in the models. Conclusions Subsetting SSc to consistently predict morbidity and mortality in subjects at different stages of disease remains an important challenge.

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.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.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 (p0.05). Raised CRP was significantly associated with modified Rodnan Skin Score20, FVC80%, DLCO80%, PAH, digital ulcers, BMI, synovitis, tendon friction rub, anaemia, and hypocomplementaemia (p0.05). A significant deterioration in respiratory function tests (RFTs) was associated with a 2-fold increase in both ESR and CRP (p0.05).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.

Background Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, the pathogenesis of which remains unknown. Recent evidence suggests dysregulation of the innate immune system, particularly interleukin-(IL)−1 family cytokines. Given the emerging role of macrophage migration inhibitory factor (MIF) in pathways of IL-1 family cytokine secretion, the role of MIF, IL-1α, IL-1β and IL-18 in SSc is of interest. Objectives To examine associations between MIF and IL-1 cytokines (IL-1α, IL-1β, IL-18), in SSc, and associations with clinical features. Methods 115 SSc patients (2013 ACR/EULAR criteria) attending Monash Scleroderma Clinic and 52 healthy controls were recruited between August 2015 and August 2017. Serum MIF, IL-1α, IL-1β and IL-18 levels were quantified using ELISA and analysed alongside concurrent clinical and laboratory data from the Australian Scleroderma Cohort Study database Results Compared to controls, SSc patients had significantly elevated serum MIF and IL-18 (figure 1). A weak positive correlation was observed between MIF and SScHAQ score (R=0.2107, p=0.0437) which was stronger in the diffuse cutaneous (dcSSc) subgroup (R=0.457, p=0.0373). Patients with elevated IL-18 levels were more likely to have active disease (EUSTAR score ≥3) however IL-18 was lower in patients with pulp atrophy and sclerodactyly. IL-1β was elevated in dcSSc patients with pulmonary fibrosis and correlated with mRSS (R=0.213, p=0.0254) in all SSc patients. IL-1α was elevated in patients with joint contractures and pulp atrophy. Positive correlations were found between concentrations of MIF and both IL-1α and IL-1β. However, there was no significant correlation between MIF and IL-18. Conclusions MIF and IL-18 were significantly elevated in SSc compared to health controls, and IL-1 family cytokines were variably associated with clinical manifestations of SSc. A relationship between MIF and IL-1β was confirmed. Further investigation into the roles of MIF and IL-1 family cytokines in SSc is justified. References [1] Zhang L, Yan JW, Wang YJ, Wan YN, Wang BX, Tao JH, et al. Association of interleukin 1 family with systemic sclerosis. Inflammation2014;37(4):1213–20. [2] van Bon L, Cossu M, Radstake TR. An update on an immune system that goes awry in systemic sclerosis. Curr Opin Rheumatol2011;23(6):505–10. Disclosure of Interest None declared

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (S.D.) HAQ-DI 1.1 (0.83)], with ‘grip’ and ‘activity’ being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = −0.53, P < 0.0001).Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Objective To determine the relationships between systemic sclerosis (SSc)–related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. Methods Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif–containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. Results A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. Conclusion Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Background: Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is now standard care in this disease. The existing Australian Scleroderma Interest Group algorithm (ASIG STANDARD ) is based on transthoracic echocardiography (TTE) and pulmonary function tests (PFT). Recently, ASIG has derived and validated a new screening algorithm (ASIG PROPOSED ) that incorporates N-terminal pro-B-type natriuretic peptide level together with PFT in order to decrease reliance on TTE, which has some limitations. Right heart catheterisation (RHC) remains the gold standard for the diagnosis of PAH in patients who screen ‘positive’. Aim: To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms. Methods: We applied both ASIG STANDARD and ASIG PROPOSED algorithms to 643 screen-naive SSc patients from the Australian Scleroderma Cohort Study (ASCS), assuming a PAH prevalence of 10%. We compared the costs of screening, the number of TTE required and both the total number of RHC required and the number of RHC needed to diagnose one case of PAH, and costs, according to each algorithm. We then extrapolated the costs to the estimated total Australian SSc population. Results: In screen-naive patients from the ASCS, ASIG PROPOSED resulted in 64% fewer TTE and 10% fewer RHC compared with ASIG STANDARD , with $1936 (15%) saved for each case of PAH diagnosed. When the costs were extrapolated to the entire Australian SSc population, there was an estimated screening cost saving of $946 000 per annum with ASIG PROPOSED , with a cost saving of $851 400 in each subsequent year of screening. Conclusions: ASIG PROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIG STANDARD .

The diagnosis of interstitial lung disease (ILD) requires meticulous evaluation for an underlying connective tissue disease (CTD), with major implications for prognosis and management. CTD associated ILD (CTD-ILD) occurs most commonly in the context of an established CTD, but can be the first and/or only manifestation of an occult CTD or occur in patients who have features suggestive of an autoimmune process, but not meeting diagnostic criteria for a defined CTD—recently defined as “interstitial pneumonia with autoimmune features” (IPAF). The detection of specific autoantibodies serves a critical role in the diagnosis of CTD-ILD, but there remains a lack of data to guide clinical practice including which autoantibodies should be tested on initial assessment and when or in whom serial testing should be performed. The implications of detecting autoantibodies in patients with IPAF on disease behaviour and management remain unknown. The evaluation of CTD-ILD is challenging due to the heterogeneity of presentations and types of CTD and ILD that may be encountered, and thus it is imperative that immunologic tests are interpreted in conjunction with a detailed rheumatologic history and examination and multidisciplinary collaboration between respiratory physicians, rheumatologists, immunologists, radiologists and pathologists.

Objective: To evaluate work productivity and its economic burden in SSc patients. Methods: Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study were mailed questionnaires assessing employment (Workers' Productivity and Activity Impairment Questionnaire and a custom-made questionnaire) and health-related quality of life (HRQoL) (36-item Short Form Health Survey and Patient-Reported Outcomes Measurement Information System 29). Linear regression methods were used to determine factors associated with work productivity. Results: Among 476 patients submitting responses, 55.2%

To 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.

Introduction Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30–40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals. Trial registration number ACTRN12614000418673, Pre-results.

Background Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc). Annual screening with echocardiogram (ECHO) is recommended. We present the methodological aspects of a PAH screening programme in a large Australian SSc cohort, the epidemiology of SSc-PAH in this cohort, and an evaluation of factors influencing physician adherence to PAH screening guidelines. Methods Patient characteristics and results of PAH screening were determined in all patients enrolled in a SSc longitudinal cohort study. Adherence to PAH screening guidelines was assessed by a survey of Australian rheumatologists. Summary statistics, chi-square tests, univariate and multivariable logistic regression were used to determine the associations of risk factors with PAH. Results Among 1636 patients with SSc, 194 (11.9%) had PAH proven by right-heart catheter. Of these, 160 were detected by screening. The annual incidence of PAH was 1.4%. Patients with PAH diagnosed on subsequent screens, compared with patients in whom PAH was diagnosed on first screen, were more likely to have diffuse SSc (p = 0.03), be in a better World Health Organisation (WHO) Functional Class at PAH diagnosis (p = 0.01) and have less advanced PAH evidenced by higher mean six-minute walk distance (p = 0.03), lower mean pulmonary arterial pressure (p = 0.009), lower mean pulmonary vascular resistance (p = 0.006) and fewer non-trivial pericardial effusions (p = 0.03). Adherence to annual PAH screening using an ECHO-based algorithm was poor among Australian rheumatologists, with less than half screening their patients with SSc of more than ten years disease duration. Conclusion PAH is a common complication of SSc. Physician adherence to PAH screening recommendations remains poor. Identifying modifiable barriers to screening may improve adherence and ultimately patient outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1250-z) contains supplementary material, which is available to authorized users.

In a multi-centre study, we sought to determine whether extent of disease on high-resolution CT (HRCT) lung, reported using a simple grading system, is predictive of decline and mortality in SSc-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables.SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All HRCTs and PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease:20%: extensive;20%: limited; unclear: indeterminate. Indeterminate HRCTs were converted to limited or extensive using a forced vital capacity threshold of 70%. The composite outcome variable was deterioration (need for home oxygen or lung transplantation), or death.Among 172 patients followed for mean (s.d.) of 3.5 (2.9) years, there were 30 outcome events. In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) = 3.0, 95% CI 1.2, 7.5 and P = 0.02. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in 172 patients), serial diffusing capacity of the lung for carbon monoxide by alveolar volume ratio (ml/min/mmHg/l) (aHR = 0.4; 95% CI 0.3, 0.7; P = 0.001) and forced vital capacity (dl) (aHR = 0.9; 95% CI 0.8, 0.97; P = 0.008), were also strongly predictive of outcome.Extensive disease (20%) on HRCT at baseline, reported using a semi-quantitative grading system, is associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited disease. Serial PFTs are informative in follow-up of patients.

Objectives 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. Methods 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. Results 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. Conclusions 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.

Objectives Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis, vascular dysfunction and immune dysregulation. The pathogenesis of SSc remains poorly understood, although studies have indicated a role for the innate immune response. Methods Here, we measured serum interleukin (IL)‐1α, IL‐1β and IL‐18 levels in 105 SSc patients and 47 healthy controls (HC) and analysed them with respect to multiple clinical parameters. Results Serum IL‐18 concentrations were significantly higher in SSc patients than in HC, while no significant differences in concentrations of IL‐1α and IL‐1β were observed between SSc and HC. In both SSc and HC serum, IL‐1α and IL‐1β were positively correlated, while in SSc, both cytokines negatively correlated with IL‐18. Serum IL‐18 was significantly negatively correlated with both carbon monoxide transfer coefficient (KCO) and diffusing capacity of the lungs for carbon monoxide (DLCO). Serum IL‐1β was positively correlated with the modified Rodnan skin score (mRSS), particularly in patients with limited subtype. DLCO, KCO and tricuspid regurgitation (TR) velocity were significantly higher in patients with high serum IL‐1β. Serum IL‐1α was significantly lower in SSc patients with low KCO and positively correlated with KCO. SSc patients with high serum IL‐1α concentrations were more likely to have digital ulcers. Conclusions Our data suggest that these IL‐1 family cytokines may have different roles in the pathogenesis of SSc fibrotic complications.

To report the efficacy and tolerability of mycophenolate mofetil (MMF) and azathioprine (AZA) in the management of systemic sclerosis-associated interstitial lung disease (SSc-ILD).Patients in the Australian Scleroderma Cohort Study treated with at least 3 months of MMF or AZA for SSc-ILD confirmed on high resolution computed tomography (HRCT) chest were identified and their pulmonary function tests (PFTs) retrieved. Individuals with available results for T-1 (12 months prior to treatment commencement), T0 (date of treatment commencement) and at least one subsequent time point were included in the drug efficacy analysis. The Wilcoxon signed-rank test was used to compare absolute FVC at T1, T0, 12 months (T1), 24 months (T2) and 36 months (T3). Analysis of drug tolerability included all identified patients treated with MMF or AZA.18/22 patients treated with MMF and 29/49 treated with AZA had adequate PFTs for inclusion in the drug efficacy analysis. Median absolute FVC at T1 for MMF treatment was 2.50L, declining to 2.12L at T0 (p=0.02). Following MMF therapy, FVC results were stable at T1 (2.13L, p=0.86), T2 (2.17L, p=0.65) and T3 (2.25L, p=0.78). In the AZA group, a statistically significant decline did not occur prior to treatment, however FVC results remained stable at T1, T2 and T3.Adverse events leading to early discontinuation (12 months treatment) were less common in the MMF group (4/22 vs. 13/49). Gastrointestinal complications were the main cause of discontinuation in both groups.In patients with SSc-ILD with declining pulmonary function, MMF therapy was associated with stability for up to 36 months. Early adverse events leading to discontinuation occurred less frequently in patients treated with MMF than in AZA treated patients.

Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH).ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc-controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc-PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of ≥210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers.The PAH group had significantly higher mean ADMA levels than the control group (0.76±0.14 μM versus 0.59±0.07 μM; p0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p0.01). An ADMA level ≥0.7 μM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP ≥210ng/mL and/ or ADMA ≥0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc-PAH.In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation.