Clinical Features of Systemic Sclerosis-Mixed Connective Tissue Disease and Systemic Sclerosis Overlap Syndromes.

OBJECTIVE: To describe the clinical characteristics and outcomes of systemic sclerosis-mixed connective tissue disease (SSc-MCTD) and SSc overlap syndrome. METHODS: We included patients from the Australian Scleroderma Cohort Study who met American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for SSc. Three mutually exclusive groups were created: SSc-MCTD, SSc overlap, and SSc only. Univariate comparison of clinical features was performed by analysis of variance or chi-square test. Survival analysis was performed using Kaplan-Meier (KM) curves and Cox proportional hazards regression models. RESULTS: Of 1,728 patients, 97 (5.6%) had SSc-MCTD, and 126 (7.3%) had SSc overlap. Those with MCTD-SSc were more commonly Asian (18.3% versus 10.1% in SSc overlap, and 3.6% in SSc only; P < 0.0001) and younger at disease onset (38.4 years versus 46.5 or 46.8 years, P < 0.0001). Those with SSc-MCTD or SSc overlap were more likely to have limited cutaneous SSc. All 3 groups had similar frequency of interstitial lung disease (ILD), although pulmonary arterial hypertension (PAH) was less common in SSc overlap. Synovitis and myositis were more common in SSc overlap and SSc-MCTD than in SSc only. KM curves showed better survival in SSc-MCTD than SSc overlap or SSc only (P = 0.011), but this was not significant after adjustment for sex and age at disease onset. SSc-specific antibodies were survival prognostic markers, with antinuclear antibody centromere or anti-RNP conferring better survival than anti-Scl-70 or anti-RNA polymerase III (P = 0.005). Patients with SSc-MCTD and SSc overlap had lower mortality following diagnosis of ILD and PAH than patients with SSc only. CONCLUSION: This study provides insights into the clinical characteristics of patients with SSc-MCTD, SSc overlap, and SSc only and shows that anti-RNP antibodies are associated with better survival than anti-Scl-70 and anti-RNA polymerase III antibodies.

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.

Performance of the 2017 EUSTAR activity index in an scleroderma cohort.

Assessment of disease activity in systemic sclerosis (SSc) is limited by the absence of a fully validated, multisystem measure of disease activity. The European Scleroderma Trials and Research Group (EUSTAR) SSc activity index (EScSG-AI) was recently revised, and a validation study within the EUSTAR cohort was performed. In this study, we evaluated the performance of the revised EScSG-AI in an external Australian cohort. The association between the EScSG-AI and the physician global assessment of disease activity (PhGA), both collected prospectively at each annual visit over up to 12 years follow-up, was evaluated using Pearson's correlation coefficient and Cohen's kappa coefficient. Generalized linear modelling and time-dependent Cox regression analysis were performed to determine the association of disease activity measured by the EScSG-AI and the summed Medsger Severity Scale (MSS) and death, respectively. There was a moderate correlation between EScSG-AI and PhGA scores (r 0.42, p < 0.001) and moderate association between rising EScSG-AI and summed MSS (r 0.60, p < 0.001). High disease activity, measured by the EScSG-AI at any time during follow-up, was associated with a hazard ratio of 2.07 (95% CI 1.51-2.79) for mortality. The EScSG-AI has a moderate correlation with physician-assessed SSc disease activity. This suggests that the criterion and construct validity of the EScSG-AI are yet to be demonstrated in an external cohort of SSc patients. Key Points •There remains no gold standard measure of SSc disease activity. •The revised 2017 EUSTAR SSc disease activity index shows moderate correlation with physician-rated global disease activity. •Significant work remains to develop a validated multisystem measure of disease activity in SSc.

Can Patient-Reported Symptoms Be Used to Measure Disease Activity in Systemic Sclerosis?

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

IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis.

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

Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis.

BACKGROUND: Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality. METHODS: Clinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models. RESULTS: Of 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p < 0.001), anti-MPO positive vs anti-MPO negative (38.5% vs 13.6%, p = 0.006) and anti-PR3 positive vs anti-PR3 negative patients (44.4% vs 13.4%, p < 0.001). A higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%, p < 0.001) and the anti-PR3 positive groups (50.0% vs 23.4%, p = 0.009). In multivariable analysis, ANCA-positive status remained associated with ILD after adjusting for anti-Scl-70 antibodies. Pulmonary embolism (PE) was more common in ANCA-positive patients (8.6% vs 3.0%, p = 0.002) and anti-PR3-positive patients (16.7% vs 3.3%, p = 0.022). ANCA-positive status remained associated with PE in a multivariable analysis adjusting for anti-phospholipid antibodies. Kaplan-Meier analysis revealed increased mortality in ANCA-positive patients (p = 0.006). In Cox regression analysis, ANCA was associated with increased mortality, after adjusting for age and sex. CONCLUSIONS: ANCA is associated with increased prevalence of ILD and PE in SSc. ANCA should be tested in SSc, as it identifies individuals with worse prognosis who require close monitoring for adverse outcomes.

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.

Mortality in systemic sclerosis-a single centre study from the UK.

This study aims to determine the cause and predictors of mortality in a cohort of patients with systemic sclerosis (SSc) and assess whether the mortality rate differs significantly from the general population. Patients enrolled onto the Royal National Hospital for Rheumatic Diseases Connective Tissue Disease database between 1999 and 2010 were included in this study. The NHS Strategic Tracing Service and UK Registry of Births, Marriages and Deaths were used to establish date and cause of deaths. A retrospective case note review collected information on clinical phenotype and serology. A standardised mortality ratio (SMR) was calculated and survival was determined using Kaplan-Meier estimates. Univariate and multivariate predictors of survival were assessed using proportional hazards regression modelling. Amongst this cohort of 204 patients (25 males, 40 diffuse SSc), the mean age at diagnosis was 51.6 years (SD13.7) and the mean duration of follow-up was 12.5 years (SD 8.8 years). In the deceased group (53 patients), the mean age of death was 72.0 years (SD 12.3 years). The mean disease duration at death was 14.2 years (SD 8.5 years). The overall SMR was 1.34 (95 % confidence interval (CI) 1.00-1.75). The SMR was higher in males (1.54 [95 % CI 0.67-3.04] vs. 1.30 [95 % CI 0.95-1.74]). The leading causes of death in this cohort were infection, respiratory disease and malignancy. The most common cause of SSc-related mortality was pulmonary complications. Factors adversely affecting survival were older age at diagnosis, male gender, interstitial lung disease (ILD) and anti-RNA polymerase III antibody. The mortality rate of our cohort, who had predominantly limited disease, was higher than that of the general population; although not as high as reported in previous retrospective studies.

Predictors of health-related quality of life and fatigue in systemic sclerosis: evaluation of the EuroQol-5D and FACIT-F assessment tools.

This study evaluates predictors of health-related quality of life (HRQoL) and fatigue in systemic sclerosis (SSc) using two novel self-report indices. A cross-sectional study of patients with SSc was undertaken using a postal questionnaire including the EuroQol-5Domain health questionnaire (EQ-5D™), Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F) and the Scleroderma Health Assessment Questionnaire (SHAQ). The EQ-5D assesses five domains of health quality and is quantified as a time trade-off (TTO) value and patient global assessment (0-100 visual analogue scale [VAS]). The FACIT-F is a 13-item questionnaire (0-52 scale). Higher scores for both the EQ-5D and FACIT-F indicate better health. Case notes were scrutinised for patient demographics, disease duration, serology and clinical phenotype. Sixty-eight patients (60 females, mean age 62.6 years) completed the questionnaires. Fatigue correlated closely with HRQoL (r (s) = 0.78 and 0.77 for FACIT-F vs. EQ-5D VAS and TTO respectively, p < 0.01) and disability (r (s) = -0.74 for FACIT-F vs. HAQ-DI, p < 0.01). Pain was the most frequently reported health problem (80 %) in the EQ-5D. HRQoL also correlated closely with disability (r (s) = 0.83 for EQ-5D vs. HAQ-DI, p < 0.01). SHAQ-VAS scores correlated well with the FACIT-F, EQ-5D and HAQ-DI scores (p < 0.05 for all comparisons). Of the patient demographics and clinical disease associations, only the absence of upper gastrointestinal complications was associated with better levels of fatigue, HRQoL and function. There is a strong correlation between disability, fatigue and HRQoL measured using self-reports, possibly reflecting similarly perceived health beliefs amongst patients across outcomes. There was little association between self-report indices and patient demographics and/or clinical phenotype.

Retinal vascular calibre is altered in patients with rheumatoid arthritis: a biomarker of disease activity and cardiovascular risk?

OBJECTIVES: Alterations in retinal vascular calibre, particularly wider venular calibre, have been independently associated with elevated markers of inflammation and cardiovascular risk in the general population. We hypothesized that retinal vascular calibre would be altered in patients with RA, who are known to have both elevated cardiovascular risk and chronic, systemic inflammation. METHODS: Retinal vascular calibre was measured from digital retinal photographs using computerized methods in 51 RA patients and 51 age- and gender-matched controls. Retinal vascular calibre was compared between RA and control patients with adjustment for relevant variables including cardiovascular risk factors and companion vessel calibre. The relationship between retinal venular calibre and inflammation was assessed by comparing controls and RA patients with high and lower disease activity. RESULTS: Retinal venular calibre [mean (s.d.)] was significantly wider in RA patients than in controls [235.9 (24.6) vs. 211.6 (21.0) µm, P < 0.001]. After adjustment for all relevant variables, mean venular calibre remained 20.3 µm (95% CI 10.4, 30.3) wider in RA patients compared with controls. Retinal venular calibre [mean (s.d.)] also increased with increasing levels of systemic inflammation: 211.6 (21.0) µm in controls, 232.3 (22.4) µm in RA patients with moderate or lower disease activity and 255.5 (28.3) µm in RA patients with high disease activity (P for trend < 0.0001). CONCLUSIONS: This study demonstrates that RA patients have dilated retinal venular calibre, reflecting systemic inflammation and possibly increased cardiovascular risk. Longitudinal studies correlating retinal vascular calibre with subsequent cardiovascular events will clarify the clinical utility of this test in patients with RA.