Medicine (St Vincent's) - Research Publications

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    Long-term efficacy and tolerability of mycophenolate mofetil therapy in diffuse scleroderma skin disease
    Boulos, D ; Ngian, G-S ; Rajadurai, A ; Elford, K ; Stevens, W ; Proudman, S ; Owen, C ; Roddy, J ; Nikpour, M ; Youssef, P ; Hill, C ; Sahhar, J (WILEY, 2017-04)
    OBJECTIVES: To assess the long-term efficacy and tolerability of mycophenolate mofetil (MMF) in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients enrolled in the Australian Scleroderma Cohort study with dcSSc and baseline modified Rodnan skin score (mRSS) ≥ 12 who were treated for a minimum of 12 months with MMF for the primary indication of skin disease were included and their prospectively collected data retrieved. Change in mRSS, the proportion with a clinically significant improvement (reduction in mRSS ≥ 5 from baseline) and adverse effects due to therapy were determined. RESULTS: Seventy-four participants treated with MMF were identified and of these, 42 met inclusion criteria. The mean age was 53 ± 12 years, with mean disease duration at MMF commencement of 4.8 ± 4.3 years. Twenty-one participants (50%) commenced MMF within 2 years of disease onset and the mean duration of therapy was 2.7 ± 1.7 years. The mean mRSS at baseline was 25.9 ± 9.2 with a reduction of 3.7 ± 7.1 (P = 0.07) after 1 year of therapy, 7.6 ± 8.3 after 2 years (P = 0.01) and 10.5 ± 10.3 after 5 years (P < 0.01). Response to treatment was not affected by disease duration at MMF commencement or baseline skin score. Eighteen participants (43%) demonstrated clinically significant improvement after 1 year, increasing to 92% after 4 years. Two participants (5%) ceased MMF due to adverse effects. CONCLUSION: MMF was associated with a modest improvement in mRSS and was well tolerated in the treatment of dcSSc. Given the natural history of dcSSc where skin involvement can spontaneously improve, randomized, placebo-controlled studies are required to confirm whether improvement can be attributed to MMF therapy.
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    Digital ulcers in systemic sclerosis: their epidemiology, clinical characteristics, and associated clinical and economic burden
    Morrisroe, K ; Stevens, W ; Sahhar, J ; Ngian, G-S ; Ferdowsi, N ; Hill, CL ; Roddy, J ; Walker, J ; Proudman, S ; Nikpour, M (BMC, 2019-12-23)
    BACKGROUND: To determine the frequency and clinical characteristics of systemic sclerosis-related digital ulcers, and associated direct health care costs, quality of life, and survival. METHODS: Digital ulcers (DUs) were defined as an area with a visually discernible depth and a loss of continuity of epithelial coverage. DU severity was calculated based on the physician reported highest number of new DUs at clinical review (mild = 1-5 DUs, moderate 6-10 DUs, severe > 10 DUs). Healthcare use was captured through data linkage, wherein SSc clinical data captured prospectively in a dedicated clinical database were linked with health services databases to capture hospital admissions, emergency department (ED) presentations and ambulatory care (MBS) utilization and cost for the period 2008-2015. Healthcare cost determinants were estimated using logistic regression. RESULTS: Among 1085 SSc patients, 48.6% experienced a DU over a mean follow-up of 5.2 ± 2.5 years. Those who developed DUs were more likely to have diffuse disease subtype (34.9% vs 18.2%, p < 0.001), anti-Scl-70 antibody (18.9% vs 9.3%, p < 0.001), and a younger age at SSc onset (43.6 ± 13.9 vs 48.8 ± 14.0 years, p < 0.001) in addition to reduced health-related quality of life (HRQoL) measured by the SF-36 but without a significant impact on survival. SSc patients with a history of a DU utilized significantly more healthcare resources per annum than those without a DU, including hospitalizations, ED presentation, and ambulatory care services. Total healthcare services, excluding medications, were associated with an annual excess cost per DU patient of AUD$12,474 (8574-25,677), p < 0.001, driven by hospital admission and ED presentation costs. CONCLUSION: DUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.
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    IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis
    Metwally, M ; Thabet, K ; Bayoumi, A ; Nikpour, M ; Stevens, W ; Sahhar, J ; Zochling, J ; Roddy, J ; Tymms, K ; Strickland, G ; Lester, S ; Rischmueller, M ; Ngian, G-S ; Walker, J ; Hissaria, P ; Shaker, O ; Liddle, C ; Manolios, N ; Beretta, L ; Proudman, S ; George, J ; Eslam, M (NATURE PORTFOLIO, 2019-10-16)
    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.
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    The economic burden of systemic sclerosis related pulmonary arterial hypertension in Australia
    Morrisroe, K ; Stevens, W ; Sahhar, J ; Ngian, G-S ; Ferdowsi, N ; Hansen, D ; Patel, S ; Hill, CL ; Roddy, J ; Walker, J ; Proudman, S ; Nikpour, M (BMC, 2019-11-27)
    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.
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    Clinical Features of Systemic Sclerosis-Mixed Connective Tissue Disease and Systemic Sclerosis Overlap Syndromes
    Fairley, JL ; Hansen, D ; Proudman, S ; Sahhar, J ; Ngian, G-S ; Walker, J ; Strickland, G ; Wilson, M ; Morrisroe, K ; Ferdowsi, N ; Major, G ; Roddy, J ; Stevens, W ; Nikpour, M (WILEY, 2021-05)
    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.
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    Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis
    Moxey, J ; Huq, M ; Proudman, S ; Sahhar, J ; Ngian, G-S ; Walker, J ; Strickland, G ; Wilson, M ; Ross, L ; Major, G ; Roddy, J ; Stevens, W ; Nikpour, M (BMC, 2019-02-14)
    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.
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    Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study
    Ngian, GS ; Stevens, W ; Prior, D ; Gabbay, E ; Roddy, J ; Tran, A ; Minson, R ; Hill, C ; Chow, K ; Sahhar, J ; Proudman, S ; Nikpour, M (BioMed Central, 2012)
    Introduction Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy. Methods Patients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data. Results Among 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective. Conclusions In this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials.
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    Survival and quality of life in incident systemic sclerosis-related pulmonary arterial hypertension
    Morrisroe, K ; Stevens, W ; Huq, M ; Prior, D ; Sahhar, J ; Ngian, G-S ; Celermajer, D ; Zochling, J ; Proudman, S ; Nikpour, M (BMC, 2017-06-02)
    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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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    Potential role of the lectin pathway of complement in the pathogenesis and disease manifestations of systemic sclerosis: a case-control and cohort study
    Osthoff, M ; Ngian, G-S ; Dean, MM ; Nikpour, M ; Stevens, W ; Proudman, S ; Eisen, DP ; Sahhar, J (BMC, 2014)
    INTRODUCTION: Repetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis. The complement system is a key mediator of tissue damage after I/R, primarily by activation of the lectin pathway. This study investigated whether serum levels and polymorphisms of mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway, are associated with the predisposition to and clinical features of SSc. METHODS: A case-control study was undertaken involving 90 patients with SSc from a single SSc outpatient clinic and 90 age- and sex-matched blood donors. MBL and FCN2 levels and polymorphisms were measured in both groups, and in cases correlated with clinical data. RESULTS: MBL levels and genotypes were equally distributed in cases and controls while there were some significant differences in FCN2 polymorphisms. Median MBL levels were higher in SSc cases with diffuse disease compared with controls (2.6 versus 1.0 μg/ml, P <0.001). CONCLUSIONS: Overall, predisposition to SSc was not influenced by the lectin pathway of complement in our matched case-control study. However, our preliminary data suggest that MBL, and to a lesser extent FCN2, may modulate disease manifestations of SSc, particularly in diffuse cutaneous disease.
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    Quantifying the direct public health care cost of systemic sclerosis A comprehensive data linkage study
    Morrisroe, K ; Stevens, W ; Sahhar, J ; Ngian, G-S ; Rabusa, C ; Ferdowsi, N ; Hill, C ; Proudman, S ; Nikpour, M (LIPPINCOTT WILLIAMS & WILKINS, 2017-12)
    To quantify the direct healthcare cost of systemic sclerosis (SSc) and identify its determinants. Healthcare use was captured through data linkage, wherein clinical and medication data for SSc patients from the state of Victoria enrolled in the Australian Scleroderma Cohort Study were linked with the Victorian hospital admissions and emergency presentations data sets, and the Medicare Benefits Schedule which contains all government subsidized ambulatory care services, for the period 2011-2015. Medication cost was determined from the Pharmaceutical Benefits Scheme. Costs were extrapolated to all Australian SSc patients based on SSc prevalence of 21.1 per 100,000 and an Australian population of 24,304,682 in 2015. Determinants of healthcare cost were estimated using logistic regression. Total healthcare utilization cost to the Australian government extrapolated to all Australian SSc patients from 2011 to 2015 was Australian Dollar (AUD)$297,663,404.77, which is an average annual cost of AUD$59,532,680.95 (US Dollar [USD]$43,816,040.08) and annual cost per patient of AUD$11,607.07 (USD$8,542.80). Hospital costs, including inpatient hospitalization and emergency department presentations, accounted for the majority of these costs (44.4% of total), followed by medication cost (31.2%) and ambulatory care cost (24.4%). Pulmonary arterial hypertension (PAH) and gastrointestinal (GIT) involvement were the major determinants of healthcare cost (OR 2.3 and 1.8, P = .01 for hospitalizations; OR 2.8 and 2.0, P = .01 for ambulatory care; OR 7.8 and 1.6, P < .001 and P = .03 for medication cost, respectively). SSc is associated with substantial healthcare utilization and direct economic burden. The most costly aspects of SSc are PAH and GIT involvement.