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

Objective To 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 &lt; 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.

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Background We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). Methods This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis. Results Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. Conclusions Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. Trial registration EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077