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Objective: The aim of this study was to determine the impact of season, temperature and humidity on the severity of Raynaud phenomenon (RP) in systemic sclerosis. Methods: Data from the Australian Scleroderma Cohort Study were used to assess associations of patient‐reported worsened RP in the month preceding each study visit. Mean monthly weather data were obtained from the closest weather station to the patient's address. We evaluated the relationship between worsened RP and health‐related quality of life (HRQoL) measured using the Short Form 36 instrument. Results: Among 1,972 patients with systemic sclerosis, RP was a near‐universal finding, and worsened RP in the preceding month was reported in 26.7% of 9,175 visits. "Worsened RP" showed significant environmental variability. On multivariable analysis, worsened RP was associated with low mean maximum temperatures (odds ratio [OR] 0.91, 95% confidence interval [95% CI] 0.90–0.92, P < 0.001), high relative humidity (OR 1.05, 95% CI 1.04–1.05, P < 0.001) and lower mean daily evaporation (OR 0.77, 95% CI 0.73–0.81, P < 0.001). Worsened RP was strongly associated with telangiectasia, calcinosis, and digital ulceration, as well as demonstrating an association with anticentromere antibody and gastroesophageal reflux disease and a negative correlation with diffuse disease. Worsened RP was also strongly associated with worse HRQoL. Conclusion: Lower environmental temperature and higher relative humidity had significant associations with worsened RP in this systemic sclerosis cohort, suggesting an important role for dry warmth in managing this condition. [ABSTRACT FROM AUTHOR]

Objective: The gastrointestinal tract (GIT) is the most commonly affected internal organ in systemic sclerosis (SSc). We sought to determine the prevalence and impact of GIT symptoms on survival and patient‐reported outcomes. Methods: A total of 907 consecutive patients from the Australian Scleroderma Cohort Study who had prospectively completed the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 Questionnaire (UCLA GIT) between 2015 and 2021 were included. The associations between UCLA GIT scores and physical function (Scleroderma Health Assessment Questionnaire), quality of life (QoL; Short Form 36), mood (Patient‐Reported Outcomes Measurement Information System [PROMIS] anxiety and depression domains), fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue score), and employment were investigated using multivariable population‐averaged panel models using generalized estimating equations (GEEs). Kaplan‐Meier curves and multivariable Cox proportional hazard regression models were used to evaluate survival according to total UCLA GIT scores. Results: GIT symptoms were reported in 87% of participants, with 46% to 52% reporting moderate to very severe symptoms of reflux, distension, diarrhea, and constipation. Higher total UCLA GIT scores were associated with worse QoL, physical function, fatigue, anxiety, and depression (P < 0.001). In the multivariable GEE analysis, moderate and severe to very severe total scores, reflux scores, and distension scores were associated with worse physical function, QoL, fatigue, anxiety, and depression compared to mild scores (P < 0.05). Patients with severe total scores and diarrhea scores were more likely to be unemployed compared to those with mild scores (P < 0.05). UCLA GIT total scores were not independently associated with death in our cohort. Conclusion: GIT manifestations are common in SSc and negatively impact QoL, physical function, and employment but are not directly associated with increased death. [ABSTRACT FROM AUTHOR]

Objective To define the frequency and associations of opioid use in SSc. Methods Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc were included. Current or previous opioid use was recorded at each visit, with long-term use defined as use on two or more consecutive visits. Groups were compared using two-sample t -test, Wilcoxon rank sum test or chi-squared test. Generalised estimating equations were used to model longitudinal data. Results Of 1951 participants with a mean age of 46.7 years (s. d. 14.4), 88% were female and 12% had ever received any opioids since SSc onset. Of these, 46% recorded opioid use across multiple consecutive study visits. Digital ulcers (63% vs 52%), synovitis (57% vs 38%), interstitial lung disease (37% vs 27%), gastrointestinal (GI) symptoms (upper 97% vs 88%, lower 90% vs 80%) and immunosuppression (59% vs 46%) were all more frequent in opioid-exposed groups (P  < 0.05). In multivariable modelling, current opioid use at each study visit was associated with digital ulcers [odds ratio (OR) 1.5 (95% CI 1.1, 2.0), P  = 0.01], synovitis [OR 1.5 (95% CI 1.1, 2.1), P  = 0.02], lower GI symptoms [OR 1.8 (95% CI 1.3, 2.6), P  < 0.01] and poorer physical [OR 1.8 (95% CI 1.3, 2.4), P  < 0.01] and mental [OR 1.8 (95% CI 1.1, 3.0), P  = 0.02] quality of life (QoL). Current opioid use was associated with worse fatigue [regression coefficient (RC) 3.0 units (95% CI 1.2, 4.8), P  < 0.01], functional disability [RC 0.2 (95% CI 0.2, 0.3), P  < 0.01], dyspnoea [RC 2.0 (95% CI 0.8, 3.1), P  < 0.01], depression [RC 2.5 (95% CI 0.9, 4.0), P  < 0.01] and anxiety [RC 2.5 (95% CI 0.9, 4.0), P  < 0.01]. Conclusions Opioid use in SSc was associated with musculoskeletal, GI and lung involvement. Opioid prescription was associated with poorer QoL and physical function. [ABSTRACT FROM AUTHOR]

Objectives To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups. Methods Participants with sera, high-resolution CT and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. Twenty-seven of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc. Results A total of 407 participants were identified, 252 (61.9%) with SSc-ILD. The median (interquartile range) follow-up after biomarker measurement was 6.31 (3.11–9.22) years. Sixteen biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality [hazard ratio (HR) 3.55; 95% CI 2.37–5.33; P <  0.001]. Five additional biomarkers had an HR >2: SP-D (2.28, 1.57–3.31; P <  0.001), E-selectin (2.19, 1.53–3.14; P <  0.001), IL-6 (2.15, 1.50–3.09; P <  0.001), MMP-3 (2.05, 1.42–2.95; P <  0.001) and ET-1 (2.03, 1.40–2.92; P <  0.001). Eleven biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at 1-year follow-up: CXCL4 (odds ratio 2.67, 1.46–4.88; P  = 0.001), MMP-1 (2.56, 1.43–4.59; P =  0.002) and ET-1 (2.18, 1.24–3.83; P =  0.007). Conclusion Multiple biomarkers, especially VCAM-1, E-selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc. [ABSTRACT FROM AUTHOR]

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

Objective To describe the frequency of progressive pulmonary fibrosis (PPF) in an incident cohort of systemic sclerosis (SSc)-related interstitial lung disease (ILD) and its impact on survival. Methods Incident ILD was defined as the new development of characteristic fibrotic changes on chest HRCT scan. PPF was defined as per the 2022 American Thoracic Society. Determinants of PPF were identified using generalised estimating equations. Impact on survival was analysed using accelerated failure time regression modelling. Results Of our incident SSc-ILD cases, 38.8% (n  = 180) experienced PPF within a 12-month period after ILD diagnosis. Determinants of PPF included older age (OR 1.02, 95%CI 1.00–1.03, P  = 0.011), dcSSc (OR 1.54, 95% CI 1.06–2.25, P  = 0.024) and SSc-specific antibodies (anticentomere antibody OR 0.51, 95%CI 0.29–0.91, P  = 0.021 and anti-Scl-70 antibody OR 1.46, 95%CI 1.01–2.09, P  = 0.043). Raised CRP was numerically associated with PPF but did not reach statistical significance (OR 1.29, 95%CI 0.99–1.68, P  = 0.064) nor did GORD or dysphagia (OR 1.18, 95%CI 0.57–2.42, P  = 0.658 and OR 1.17, 95%CI 0.57–2.40, P  = 0.664, respectively). The presence of PPF significantly impacted survival in SSc-ILD (hazard ratio 2.66, 95%CI 1.59–4.41, P  < 0.001). Conclusions PPF occurred in a third of our incident SSc-ILD cohort; however, its occurrence was significantly associated with mortality indicating an at-risk group who may be suitable for earlier introduction of immunosuppressive and/or antifibrotic therapy. [ABSTRACT FROM AUTHOR]

Objectives Damage accrual in SSc can be tracked using the Scleroderma Clinical Trials Consortium Damage Index (DI). Our goal was to develop a prediction model for damage accrual in SSc patients with early disease. Methods Using patients with <2 years disease duration from Canada and Australia as a derivation cohort, and from the Netherlands as a validation cohort, we used group-based trajectory modelling (GBTM) to determine 'good' and 'bad' latent damage trajectories. We developed a prediction model from this analysis and applied it to patients from derivation and validation cohorts. We plotted the actual DI trajectories of the patients predicted to be in 'good' or 'bad' groups. Results We found that the actual trajectories of damage accumulation for lcSSc and dcSSc were very different, so we studied each subset separately. GBTM found two distinct trajectories in lcSSc and three in dcSSc. We collapsed the two worse trajectories in the dcSSc into one group and developed a prediction model for inclusion in either 'good' or 'bad' trajectories. The performance of models using only baseline DI and sex was excellent with ROC AUC of 0.9313 for lcSSc and 0.9027 for dcSSc. Using this model, we determined whether patients would fall into 'good' or 'bad' trajectory groups and then plotted their actual trajectories which showed clear differences between the predicted 'good' and 'bad' cases in both derivation and validation cohorts. Conclusions A simple model using only cutaneous subset, baseline DI and sex can predict damage accumulation in early SSc. [ABSTRACT FROM AUTHOR]

Objective: In patients with systemic sclerosis (SSc), we investigated composite serum biomarker panels for the diagnosis and risk stratification of SSc–associated interstitial lung disease (SSc‐ILD). Methods: We analyzed 28 biomarkers in 640 participants: 259 patients with SSc‐ILD and 179 SSc patients without ILD (Australian Scleroderma Cohort Study), 172 patients with idiopathic pulmonary fibrosis (IPF‐controls) (Australian IPF Registry), and 30 healthy controls. A composite index was developed from biomarkers associated with ILD in multivariable analysis derived at empirical thresholds. We evaluated the performance of the index to identify ILD, and specifically SSc‐ILD, and its association with lung function, disease extent on radiography, and patient health–related quality of life in derivation and validation cohorts. Biomarkers to distinguish SSc‐ILD from IPF‐controls were identified. Results: A composite biomarker index, comprising surfactant protein D (SP‐D), Ca15‐3, and intercellular adhesion molecule 1 (ICAM‐1), was strongly associated with SSc‐ILD diagnosis, independent of age, sex, smoking history, and lung function (for biomarker index score 3, pooled adjusted odds ratio was 12.72 (95% confidence interval 4.59–35.21) (P < 0.001). The composite index strengthened the performance of individual biomarkers for SSc‐ILD identification. In SSc patients, a higher index was associated with worse baseline disease severity (for biomarker index score 3 relative to biomarker index score 0, the adjusted absolute change in forced vital capacity percent predicted was −17.84% and the diffusing capacity for carbon monoxide percent predicted was −20.16%; both P < 0.001). Conclusion: A composite serum biomarker index, comprising SP‐D, Ca15‐3, and ICAM‐1, may improve the identification and risk stratification of ILD in SSc patients at baseline. [ABSTRACT FROM AUTHOR]

Background: 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. Aims: 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. Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. Methods: 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 χ2 analyses with calculation of 95% confidence intervals. Results: 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: 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 Sjögren syndrome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]