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ObjectiveTo analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjogren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). MethodsFor the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD.ResultsThe results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. ConclusionFor the first time, we suggest that pollution levels could

Objective To analyse how the key components at the time of diagnosis of the Sjogren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. Methods For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. Results After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding

Objective: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. Method(s): The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide polymorphism heterogeneity to determine the number of X chromosomes. For statistical comparisons, we used chi2 analyses with calculation of 95% confidence intervals. Result(s): Three of seventy men with SSc had 47,XXY (P = 0.0001 compared with control men). Among the 435 women with SSc, none had 47,XXX. Among 709 men with polymyositis or dermatomyositis (PM/DM), seven had 47,XXY (P = 0.0016), whereas among the 1783 women with PM/DM, two had 47,XXX. Of 147 men with inclusion body myositis (IBM), six had 47,XXY, and 1 of the 114 women with IBM had 47,XXX. For each of these myositis disease groups, the excess 47,XXY and/or 47,XXX was significantly higher compared with in controls as well as the known birth rate of Klinefelter syndrome or 47,XXX. Conclusion(s): Klinefelter syndrome (47,XXY) is associated with SSc and idiopathic inflammatory myopathies, similar to other autoimmune diseases with type 1 interferon pathogenesis, namely, systemic lupus erythematosus and Sjogren syndrome.Copyright © 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

Objective: To describe the clinical characteristics and outcomes of systemic sclerosis-mixed connective tissue disease (SSc-MCTD) and SSc overlap syndrome. Method(s): 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. Result(s): 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(s): 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.Copyright © 2020, Amer

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(s): 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. Result(s): 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(s): 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.Copyright © 2020 The Author(s) 2020.

Objective: To analyse the prognosis and outcomes of SARS-CoV-2 infection in patients with primary SS. Methods: We searched for patients with primary SS presenting with SARS-CoV-2 infection (defined following and according to the European Centre for Disease Prevention and Control guidelines) among those included in the Big Data Sjögren Registry, an international, multicentre registry of patients diagnosed according to the 2002/2016 classification criteria. Results: A total of 51 patients were included in the study (46 women, mean age at diagnosis of infection of 60 years). According to the number of patients with primary SS evaluated in the Registry (n = 8211), the estimated frequency of SARS-CoV-2 infection was 0.62% (95% CI 0.44, 0.80). All but two presented with symptoms suggestive of COVID-19, including fever (82%), cough (57%), dyspnoea (39%), fatigue/myalgias (27%) and diarrhoea (24%), and the most frequent abnormalities included raised lactate dehydrogenase (LDH) (88%), CRP (81%) and D-dimer (82%) values, and lymphopenia (70%). Infection was managed at home in 26 (51%) cases and 25 (49%) required hospitalization (five required admission to ICU, four died). Compared with patients managed at home, those requiring hospitalization had higher odds of having lymphopenia as laboratory abnormality (adjusted OR 21.22, 95% CI 2.39, 524.09). Patients with comorbidities had an older age (adjusted OR 1.05, 95% CI 1.00, 1.11) and showed a risk for hospital admission six times higher than those without (adjusted OR 6.01, 95% CI 1.72, 23.51) in the multivariate analysis. Conclusion: Baseline comorbidities were a key risk factor for a more complicated COVID-19 in patients with primary SS, with higher rates of hospitalization and poor outcomes in comparison with patients without co

Objective. To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). Methods. By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression. Results. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.

Objective: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjogren's syndrome (pSS) fulfilling the 2002 classification criteria. Methods: The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. Results: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score >= 1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/ SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage

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-lambda3 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-lambda3 serum levels were higher among subjects with PF compared to those unaffected (P<0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.

Objectives: To analyse the frequency and characterise the systemic presentation of primary Sjogren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. Methods: The Big Data Sjogren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. Results: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). Conclusions: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Copyright © 2019, The Author(s).

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.

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.

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. Method(s): 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. Result(s): 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. Conclusion(s): Our study indicates that the PROMIS-29 questionnaire is a valid instrument for measuring healthrelated quality of life in Australian females with lcSSc of long duration.Copyright © 2017 Wichtig International.

Introduction: We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). Method(s): We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjogren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. Result(s): uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without (p = 0.03), and uBAFF was significantly higher in active renal patients (p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. Conclusion(s): uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.Copyright © The Author(s) 2018.

Introduction: The aim of this study is to compare the clinical features, mortality and causes of death of systemic sclerosis (SSc) patients in four large multicentre registries. Method(s): Patients seen at least once in the Australian Scleroderma Cohort Study (ASCS) (n = 1714), the Canadian Scleroderma Research Group (CSRG) (n = 1628), the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) Network (n = 13,996) and the Systemic Sclerosis Cohort in Singapore (SCORE) (n = 500) before August 2016 were included. Clinical manifestations and survival in cohorts and disease subtypes were compared. Result(s): Among 17,838 SSc patients, most were female (86.1%), Caucasian (84.6%) and had the limited cutaneous subtype (lcSSc) (65.0%). The anti-centromere autoantibody was the most prevalent (37.6%). More patients in SCORE had the diffuse subtype (dcSSc) (49.3%) and Scl-70 autoantibody (38.8%) (p<0.001). Patients with dcSSc were more likely to be younger and male (p<0.001) and have shorter disease duration, more calcinosis, tendon friction rubs and synovitis (all p<0.001). Interstitial lung disease (ILD) occurred more frequently in dcSSc but prevalence of pulmonary arterial hypertension (PAH) was similar in both subtypes. More deaths occurred among SCORE patients who had the shortest median survival (p<0.001). The survival of patients with early disease, males and those with dcSSc was shorter than that of patients with prevalent disease, female gender and lcSSc, respectively. SSc-related complications accounted for more than 50% of deaths, with PAH and ILD being the most common. Conclusion(s): This meta-cohort of SSc patients, the largest reported to date, provides insights into the impact of race and sex on disease manifestations and survival and confirms the early mortality in this disease.Copyright © 2017 Wichtig International

Aim. We examined the clinical relevance of urinary concentrations of B cell-activating factor of the tumor necrosis factor family (BAFF) in systemic lupus erythematosus (SLE). Methods. We quantified urinary BAFF (uBAFF) by ELISA in 85 SLE, 28 primary Sjogren's syndrome (pSS), 40 IgA nephropathy (IgAN) patients and 36 healthy controls (HC). Urinary a proliferation-inducing ligand (APRIL) (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the SLE disease activity index 2000. Results. uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HC, IgAN and pSS subjects. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without (p=0.02), and uBAFF concentrations were significantly higher in active renal patients (p=0.02). In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HC and IgAN patients, both uAPRIL and uMCP-1 were detectable significantly in higher proportions of patients with active renal disease. Conclusion. uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.

Background/Purpose: The clinical associations of anti-Th/To antibodies (Abs) are not fully established, and until recently immunoprecipitation (IP) was the only reliable assay. Using IP, anti-Th/To Abs are mostly detected in SSc but other reported associations include ILD. Our objective was to examine clinical correlates of anti-Th/To Abs targeted against three different proteins associated with the Th/To autoantigen complex in SSc. We used a commercially available hPOP1 immunoblot and a recently described Rpp25 and Rpp38 chemiluminescence assay in a multinational cohort of SSc. Method(s): Cross sectional retrospective study including 1312 patients from the Australian Scleroderma Cohort study (ASCS), Canadian Scleroderma Research Group (CSRG) and the Genetics versus Environment in Scleroderma Outcome Study (GENISOS). Demographic and clinical variables were harmonized and sera tested for anti-Th/To Abs using hPOP1 (EUROLINE, Eurimmun, Lubeck, Germany) and Rpp25/38 (QUANTA Flash Assay, Inova Diagnostics Inc, San Diego, CA). Rpp25/38 was defined as positive if either one or both autoantibodies were present. ILD was determined by high resolution CT chest (HRCT) or a published algorithm [1] which allows diagnosis of ILD by chest X-ray showing increased interstitial markings or fibrosis and/or physician reported "velcro-like crackles" when HRCT is not available. Descriptive statistics summarise baseline demographic and clinical variables and Kaplan Meier analyses were used to assess survival Results: Patients had median (interquartile range) age at disease onset 46.3y (18.6) and disease duration 5.1y (11.4) at recruitment. hPOP1 was positive in 2.4% and Rpp25/38 was positive in 4.5% patients. Notably hPOP1 and Rpp25/38 identified overlapping patient populations (p<0.001). Median age of disease onset for hPOP1 patients was 48.9y (23.3) and for Rpp25/38 patients was 48.8y (17.3). hPOP1 was associated with ILD on HRCT chest (OR:5.16; p=0.02) but not ILD by algorithm (OR:1.19

Objective. To evaluate the construct validity of the Workers Productivity and Impairment Activity Index: Specific Health Problem (WPAI:SHP) in Australian systemic sclerosis (SSc) patients. Methods. 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 (rho), was used to test the validity of WPAI:SHP and ability to distinguish between different health states. Results. 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 (rho=0.34-0.39, p=0.001), physical function (rho=0.55-0.62, p=0.001), disease severity(rho=0.55-0.62, p=0.001), fatigue (rho= 0.62-0.63, p=0.001), pain (rho=0.68-0.71, p=0.001), and breathlessness (rho=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. Conclusion. 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.Copyright © Clinical and Experimental Rheumatology 2017.

Aim: To determine autoantibody (AA) associations in SSc. Method(s): 505 patients enrolled in the Australian Scleroderma Interest Group (ASIG), underwent line immunoassay (EUROLINE, Euroimmun, Germany) which tests for AA to CENP A and B, RNA polymerase III (11&155 epitopes), NOR-90, fibrillarin,Th/To, PMScl-75 and PMScl-100, Ku, topoisomerase-1 (Scl-70), TRIM21/Ro52 and PDGF-Receptor. Results were analysed for associations with clinical data. Result(s): 89% of subjects were positive for at least one autoantibody by immunoblot. Heatmap visualisation of AA scores demonstrated, as expected, strong, mutually exclusive relationships between CENP, RNA Polymerase III (RNAP) and Scl-70. Patients were objectively classified into AA subgroups by hierarchical clustering of the first two dimensions of a principal components analysis of all AA scores. This identified 5 major subgroups (CENP, RNAP strong, RNAP weak, Scl-70 and 'other'), which were subsequently analysed for clinical associations. Statistical separation for RNAP lies predominantly with the risk of GAVE (RNAP strong increased) and oesophageal dysmotility (RNAP strong protective) and is of uncertain clinical significance. Otherwise, clinical associations were very similar between the two groups. CENP was associated with clinical features of limited SSc while RNAP and Scl-70 were associated with features of diffuse SSc as expected. The final cluster was strongly associated with the presence of positive ANA by immunofluorescence, Th/To (immunoblot), male sex, Raynauds, joint contractures and a history of malignancy. 20/21 patients with mixed connective tissue disease mapped to the 'other' cluster. Greater homogeneity of cohorts was achieved by cluster analysis of antibodies compared with ACR criteria. Conclusion(s): Cluster analysis of extended autoantibody profiles in SSc identifies 5 major AA cohorts, with specific clinical and serological associations. Among the ASIG cohort tested, greater homogeneity within patient

Aim: To determine autoantibody HLA-DRB1 allele associations with anticentromere (CENP), RNA polymerase III (RNAP) and topoisomerase 1 (Topo1) autoantibodies in Australian patients with systemic sclerosis (SSc). Method(s): SSc patients were ascertained from the Australian Scleroderma Interest Group (ASIG) clinical database and sample repository. Autoantibody testing was performed by a line blot assay (EUROBlotMaster, Euroimmun AG, Luebeck, Germany) which tests for autoantibodies to CENP A and B, RNA polymerase III (11 and 155 epitopes), NOR-90, fibrillarin, Th/To, PMScl-75 and PMScl-100, Ku, topoisomerase-1, TRIM21/Ro52 and PDGF-Receptor. HLA-DRB1 alleles were imputed from Immunochip (Illumina) genotyping data. The study included 404 SSc patients (75% limited disease, 86% female and mean age of onset 47 years) and HLA-DRB1 data for 4457 ethnically matched controls. Patients were divided into 4 subgroups prior to analysis (i) CENP, n = 172 (43%) ii) RNAP, n = 49 (12%) iii) Topo1, n = 68 (17%) and iv) 'Other', n = 115 (28%), of whom 69/115 (60%) were positive for other line blot antibodies. The most frequent individual autoantibodies in the 'Other' subgroup were Ro52 (33%), PMScl (19%) and Th/To (9%). Result(s): Multiple DRB1 associations were observed, with both susceptibility and protective alleles identified. DRB1*11:04 was increased in frequency in all four autoantibody subgroups, but was most strikingly associated with Topo1 (p < 10-14). Topo1 was also associated with DRB1*15:01 (p = 0.002), which was protective for CENP (p = 0.009). DRB1*08:01 was associated with both CENP and RNAP, with DRB1:07:01 being protective; however CENP was also associated with DRB1*01:04 (p = 0.017). DRB1*03:01 was protective for CENP, but was increased in the 'Other' patient subgroup (p = 0.035), which may reflect a previously identified association with anti-Ro52. Conclusion(s): HLA class II influences both susceptibility to SSc, and SSc autoantibody specificity. However the pattern o

Background: Pulmonary arterial hypertension (PAH) is a leading cause of mortality in systemic sclerosis (SSc). We sought to determine survival, predictors of mortality, and health-related quality of life (HRQoL) related to PAH in a large SSc cohort with PAH. Method(s): We studied consecutive SSc patients with newly diagnosed (incident) World Health Organization (WHO) Group 1 PAH enrolled in a prospective cohort between 2009 and 2015. Survival methods were used to determine age and sex-adjusted standardised mortality ratio (SMR) and years of life lost (YLL), and to identify predictors of mortality. HRQoL was measured using the Short form 36 (SF-36) instrument. Result(s): Among 132 SSc-PAH patients (112 female (85%); mean age 62 +/- 11 years), 60 (45.5%) died, with a median (+/-IQR) survival time from PAH diagnosis of 4.0 (2.2-6.2) years. Median (+/-IQR) follow up from study enrolment was 3.8 (1.6-5.8) years. The SMR for patients with SSc-PAH was 5.8 (95% CI 4.3-7.8), with YLL of 15.2 years (95% CI 12.3-18.1). Combination PAH therapy had a survival advantage (p < 0.001) compared with monotherapy, as did anticoagulation compared with no anticoagulation (p < 0.003). Furthermore, combination PAH therapy together with anticoagulation had a survival benefit compared with monotherapy with or without anticoagulation and combination therapy without anticoagulation (hazard ratio 0.28, 95% CI 0.1-0.7). Older age at PAH diagnosis (p = 0.03), mild co-existent interstitial lung disease (ILD) (p = 0.01), worse WHO functional class (p = 0.03) and higher mean pulmonary arterial pressure at PAH diagnosis (p = 0.001), and digital ulcers (p = 0.01) were independent predictors of mortality. Conclusion(s): Despite the significant benefits conferred by advanced PAH therapies suggested in this study, the median survival in SSc PAH remains short at only 4 years.Copyright © 2017 The Author(s).

Aim: 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 / Respiratory Society (ESC/ERS 2009) guidelines. Method(s): We included 73 consecutive SSc patients with suspected PAH undergoing RHC. The predictive accuracy of the models was presented as sensitivity, specificity, positive (PPV) and negative predictive values (NPV). These properties were also evaluated in an 'alternate scenario analysis' where the prevalence of PAH was set at 10%. Result(s): RHC revealed PAH (WHO group 1 PH) in 27 (36.9%) patients and non-PH in 34 patients, while 12 patients hadWHO group 2 or 3 PH and were excluded from further analyses. TR jet was undetectable in 3 patients to whom the ESC/ERS guidelines could not be applied; none had PAH on RHC. Both 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 91%, missing one case of PAH. The ASIG algorithm had the highest specificity (54.5%) and PPV (60%). The DETECT algorithm and ESC/ERS guidelines had similar specificity (35.3% vs 32.3%) and PPV (55.1% vs 55.3%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%. Conclusion(s): In this cohort, the DETECT and ASIG algorithms outperform the ESC/ERS guidelines, detecting all patients with PAH. The specificity of all models is low, as expected in a screening test. The ESC/ERS guidelines have limitations in the absence of TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.