Predictors and prognosis of pulmonary hypertension complicating interstitial lung disease in systemic sclerosis.

OBJECTIVE: To identify those with concurrent pulmonary hypertension (PH) and interstitial lung disease (ILD) in systemic sclerosis (SSc) and determine their disease severity, therapeutic approach, and survival. METHODS: Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study (ASCS) who were diagnosed on right heart catherisation with pulmonary hypertension were included. Logistic regression was used to determine the associations of ILD with PH hemodynamic parameters and therapeutic approach. Kaplan-Meier survival curves were used to estimate survival. RESULTS: Of 1,883 SSc patients, 164 (8.7%) developed incident PH over a median follow up of 4.3 (1.7-7.9) years. Of these, 43.9% had concurrent ILD at PH diagnosis (PH-ILD) and 56.1% had Group 1 PAH. Extensive ILD was present at PH diagnosis in 40.3%. Despite these distinct PH cohorts, a similar frequency of each PH cohort was treated with vasodilatory therapy at PH diagnosis, regardless of the presence or severity of ILD. The majority (87.5%) of those with extensive ILD and PH received upfront vasodilatory therapy at PH diagnosis with no difference in its tolerability or therapy cessation compared with Group 1 PAH. Although vasodilator therapy was not associated with a survival advantage in those with extensive ILD, its use was associated with an improvement in symptoms, physical function, and quality of life (QoL). CONCLUSION: Despite vasodilator therapy, survival in SSc-PH is poor, with the presence of concurrent ILD associated with worse survival. Although vasodilator therapy commenced at PH diagnosis does not portray an improved survival in PH with extensive ILD, it appears well tolerated and may improve symptoms, physical function, and QoL.

Multiple serum biomarkers associate with mortality and interstitial lung disease progression in systemic sclerosis.

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 computed tomography, and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. 27 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: 407 participants were identified, 252 (61.9%) with SSc-ILD. The median follow up after biomarker measurement was 6.31 (3.11-9.22) years. 16 biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality (HR 3.55; 95%CI 2.37-5.33; p< 0.001). Five additional biomarkers had a 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), MMP3 (1.42-2.95; p< 0.001) and ET-1 (2.03, 1.40-2.92; p< 0.001). 11 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 one year follow up: CXCL4 (OR 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.

Frequency and implications of malnutrition in systemic sclerosis.

OBJECTIVES: To quantify the frequency and impact of malnutrition in systemic sclerosis (SSc), as diagnosed by the Global Leadership Initiative on Malnutrition (GLIM) criteria, based on weight loss, body mass index (BMI) and muscle atrophy. METHODS: Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc with ≥1 concurrent weight and height measurement were included. Chi-squared tests, two-sample t-tests or Wilcoxon rank-sum tests were used for between-group comparison as appropriate. Multivariable logistic regression models were used to establish the determinants of malnutrition diagnosis. Kaplan-Meier and Cox proportional hazard models were used for survival analyses, based on malnutrition diagnosis, and individual GLIM criteria (% weight loss, BMI thresholds and presence of muscle atrophy). RESULTS: In this study of 1903 participants, 43% were diagnosed with malnutrition according to GLIM criteria, of whom 33% had severe malnutrition. Participants diagnosed with malnutrition were older, and more likely to have dcSSc, higher SSc severity scores and RNA polymerase-3 positivity. Gastrointestinal (GI) involvement, multimorbidity, cardiopulmonary disease, raised inflammatory markers, hypoalbuminaemia and anaemia were more common in malnourished participants (p< 0.01). Multimorbidity (OR1.6, 95%CI1.2-2.0, p< 0.01), pulmonary arterial hypertension (OR2.1, 95%CI1.4-2.0, p< 0.01) and upper GI symptoms (OR1.6, 95%CI1.3-2.0, p< 0.01) were all associated with malnutrition.Health-related quality-of-life (HRQoL) and physical function were poorer in malnourished participants. Survival was worse in those with malnutrition after adjusting for age, sex and dcSSc (HR 1.4, 95%CI1.1-1.7, p< 0.01). CONCLUSIONS: Malnutrition is common in SSc and confers poorer survival, HRQoL and physical function.

Progressive pulmonary fibrosis and its impact on survival in systemic sclerosis related interstitial lung disease.

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.

Prediction of damage trajectories in systemic sclerosis using group-based trajectory modelling.

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.

The emerging association between bronchiectasis and systemic sclerosis: assessing prevalence and potential causality.

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.

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

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

Occupational silica exposure in an Australian systemic sclerosis cohort.

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

Cost savings with a novel algorithm for early detection of systemic sclerosis-related pulmonary arterial hypertension: alternative scenario analyses.

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.

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

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

Work productivity in systemic sclerosis, its economic burden and association with health-related quality of life.

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% <65 years of age were employed. Unemployed patients were older at the time of survey completion (57.1 vs 53.7 years; P < 0.001) and had longer disease duration from first SSc clinical manifestation (16.2 vs 14.9 years; P = 0.01) than employed patients. The mean age at unemployment onset was 13.2 years below the average Australian retirement age. Of those working in the week prior to completing the survey, 16.0% reported missing work (absenteeism) due to their SSc, accounting for 32.9% of their working week. Reduced productivity while at work (presenteeism) accounted for 22% of their working week. Annual costs per patient as a consequence of unemployment and reduced productivity equated to a total of AUD$67 595.40. Factors independently associated with reduced work productivity were presence of synovitis and sicca symptoms, while tertiary education protected against work impairment. Patients with low HRQoL scores also had low work productivity. Conclusion: SSc is associated with considerable unemployment and reduced productivity, which in turn is associated with a substantial economic burden and poor HRQoL. Raising awareness and identifying modifiable factors are possible ways of reducing this burden.

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

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

Validity of the Workers Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) in patients with systemic sclerosis.

OBJECTIVES: 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 (ρ), 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 (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. CONCLUSIONS: 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.

Mycophenolate mofetil is an effective and safe option for the management of systemic sclerosis-associated interstitial lung disease: results from the Australian Scleroderma Cohort Study.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The role of asymmetric dimethylarginine alone and in combination with N-terminal pro-B-type natriuretic peptide as a screening biomarker for systemic sclerosis-related pulmonary arterial hypertension: a case control study.

OBJECTIVES: 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). METHODS: 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. RESULTS: The PAH group had significantly higher mean ADMA levels than the control group (0.76±0.14 µM versus 0.59±0.07 µM; p<0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p<0.01). 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. CONCLUSIONS: 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.

Quantifying change in pulmonary function as a prognostic marker in systemic sclerosis-related interstitial lung disease.

OBJECTIVES: Clinically meaningful change in systemic sclerosis (SSc) related interstitial lung (SSc-ILD) disease is unknown. The aim of this study was to quantify change in pulmonary function as a predictor of outcome in SSc-ILD. METHODS: All patients had SSc-ILD defined by HRCT chest. All PFTs during follow-up, including FVC (L), DLCO (ml/min/mmHg) and KCO (DLCO/alveolar volume ratio; DLCO/VA) (ml/min/mmHg/L) were retrieved. The rate of change over the first four years, and percentage change in the first year of follow-up were used in ROC curve analysis to determine the best cut-off points to predict adverse outcome (home oxygen, lung transplantation, or death). RESULTS: Among 264 patients, there were 49 events (38 deaths, 10 supplemental oxygen, one lung transplant) over a mean (±SD) follow-up of 3.0 (±1.7) years. The rates of decline over time and percentage change over one year in each of FVC, DLCO and KCO were predictive of adverse outcome. Stable PFTs over four years gave the optimal negative predictive values (NPVs) of 88-96%. The best sensitivity-specificity trade-off was a decline in FVC of 10% and in DLCO and KCO of 15% with NPVs of 92-93%. CONCLUSIONS: The course that SSc-ILD takes is evident within the first 1-4 years of follow up. Patients who have no decline in PFTs over 4 years have better outcomes. A decline within one year in DLCO or KCO of 15% or more is a poor prognostic factor, and identifies patients who should be monitored more closely and considered for therapy.

The effect of calcium channel blockers on digital ulcers in systemic sclerosis: data from a prospective cohort study.

Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p < 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p < 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p < 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU.

Inflammatory Arthritis in Systemic Sclerosis: Its Epidemiology, Associations, and Morbidity.

OBJECTIVE: To describe the epidemiology, associations, and impact of inflammatory arthritis (IA) in systemic sclerosis (SSc). METHODS: Patients with SSc prospectively enrolled in the Australian Scleroderma Cohort Study were included. IA was defined clinically as the presence of synovitis on examination. Logistic regression was used to determine the associations of IA with SSc manifestations and serological parameters. Patient-reported outcome measures were used to capture physical function and health-related quality of life (HRQoL). RESULTS: IA was a common SSc manifestation affecting one-third (33.3%) of patients over a median follow-up of 4.3 (1.7-8.4) years. Associations of IA included diffuse SSc (odds ratio [OR] 1.33, 95% confidence interval [95% CI] 1.01-1.74, P = 0.042), concurrent musculoskeletal manifestations (joint contractures and tendon friction rubs, OR 1.70, 95% CI 1.34-2.15, P < 0.001); myositis (OR 2.11, 95% CI 1.39-3.20, P < 0.001), and sicca symptoms (OR 1.57, 95% CI 1.14-2.16, P = 0.006), whereas IA was negatively associated with pulmonary arterial hypertension (OR 0.52, 95% CI 0.35-0.78, P = 0.002). Neither the presence of rheumatoid factor nor U1 small nuclear RNP were associated with IA (OR 1.13, 95% CI 0.88-1.44, P = 0.331, OR 1.46, 95% CI 0.89-2.39, P = 0.129 respectively). Positive anticyclic citrullinated protein antibodies, although at low frequency, were more common in those with IA compared with those without IA (7.5% vs 1.5%, P < 0.001). IA was associated with significantly lower HRQoL score (P < 0.001) and more physical disability than in those without IA (P < 0.001). CONCLUSION: IA is a common disease manifestation that is more frquently seen in diffuse disease. IA is associated with poor HRQoL and physical disability. Further research is needed into the effective management of IA in SSc.

Impact of the COVID-19 Pandemic on Health Care Access and Diagnosis of Pulmonary Arterial Hypertension Among Patients With Systemic Sclerosis.

OBJECTIVE: Regular clinical assessment for complications of systemic sclerosis (SSc) such as pulmonary arterial hypertension (PAH) is essential for early institution of therapy and improved outcomes. The objective of this study was to determine the impact of COVID-19 pandemic-related restrictions on health care access of patients with SSc, including screening for PAH. METHODS: South Australian and Victorian patients enrolled in the Australian Scleroderma Cohort Study were surveyed about their perceptions of the impact of the pandemic on mental well-being, access to medications, investigations, and management of SSc. Frequency of annual rheumatology assessments, pulmonary function tests (PFT), and transthoracic echocardiography (TTE) to screen for PAH were compared with rates from before the pandemic. RESULTS: A total of 312 of 810 patients with SSc responded (38.5% response); 273 were female (87.5%), the median age was 64.7 years, 77.2% had limited disease, the median illness duration was 15.6 years, 15.7% were immunosuppressed, 32.1% had interstitial lung disease, and 6.4% had PAH. A total of 65.7% of consultations were by telehealth, of which 81.2% were by telephone. Compared with respondents in South Australia (n = 109), Victorian respondents (n = 203) experiencing prolonged lockdown, reported reduced access to their rheumatologist (49.3% vs 27.9%; P = 0.004), greater use of consultation by video (17.3% vs 2.1%; P = 0.008), greater health care disruption (49.0% vs 23.2%; P < 0.001), and worse mental health (P = 0.002). Respondents reported reduced access to PFT and TTE (31.7% and 22.5%, respectively). Annual visits, PFT, TTE, and new diagnoses of PAH were reduced in 2020 to 2022 compared with 2011 to 2019. CONCLUSION: The COVID-19 pandemic-related disruption to health care for patients with SSc was associated with worse mental health and reduced screening and diagnosis of PAH, which may impact long-term outcomes.

Quantifying the Need for Specialist Palliative Care Management in Patients With Systemic Sclerosis.

OBJECTIVE: The importance of early integration of palliative care in the management of complex multisystem diseases has been recognized. In this study, we aimed to quantify the need for specialist palliative care in patients with systemic sclerosis (SSc). METHODS: Using data from 875 patients enrolled in the Australian Scleroderma Cohort Study, we defined the need for palliative care as a high symptom burden at two or more consecutive study visits, at ≥50% of overall study visits, or at the study visit immediately before death. Symptoms of interest included breathlessness, fatigue, pain, depression, anxiety, constipation, and diarrhea. Logistic regression analyses evaluated the association between individual symptoms and SSc manifestations. Linear regression analysis evaluated the relationship between palliative care needs and quality of life (QoL) and function. RESULTS: Almost three-quarters of patients (72.69%) met the threshold for specialist palliative care needs. Severe fatigue (54.17%) was most common, followed by breathlessness (23.66%) and severe constipation (21.14%). Concurrent severe symptoms were frequently observed. Severe breathlessness (coefficient [coef] -7.95, P < 0.01) and pain (coef -7.70, P < 0.01) were associated with the largest reductions in physical QoL. Severe mood symptoms were associated with the greatest reduction in mental QoL (coef -12.91, P < 0.01). Severe pain (coef 0.56, P < 0.01), breathlessness (coef 0.49, P < 0.01), and mood symptoms (coef 0.40, P < 0.01) had a significant impact on function. CONCLUSION: SSc is frequently associated with multiple severe symptoms that may be amenable to palliative care intervention. Given the strong association between symptom burden and impaired QoL targeted, effective symptom management in parallel with standard-of-care treatments may improve overall patient outcomes.