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Background: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data., Methods: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes., Results: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual., Conclusions: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus., (© 2024. The Author(s).)

Background: Granulomatosis with polyangiitis and relapsing polychondritis are rare, multisystemic and potentially life-threatening connective tissue diseases. We present two cases of severe endobronchial obstruction in the aforementioned conditions and discuss difficulties with detection and treatment. Despite differing underlying pathophysiologies, endobronchial disease is a less frequently reported but serious complication of both conditions., Case Presentation: Case 1, a 31-year-old South Asian woman with relapsing polychondritis, required partial tracheal resection and reconstruction in combination with immunosuppressive therapy to achieve respiratory recovery following collapse of her right main bronchus and a stricture in her left main bronchus. Case 2, a 22-year-old Caucasian male with granulomatosis with polyangiitis, underwent surgical resection of an endobronchial growth causing occlusion of his right main bronchus. Although his respiratory status was initially stabilised with increased immunosuppression, he continues to have disease progression in spite of this., Conclusions: Our cases highlight the importance of a multidisciplinary approach combining immunosuppression with supportive care and judicious use of surgical interventions in select cases. A further review of the literature shows endobronchial obstruction is potentially under-reported due to overlap in connective tissue disease symptomatology and there is no consensus on best practice., (© 2023. The Author(s).)

Objectives: To describe the clinical phenotype and prognosis of people in the Australian Scleroderma (SSc) Cohort Study with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD)., Methods: Participants meeting ACR/EULAR criteria for SSc were divided into four mutually exclusive groups: those meeting criteria for PAH (PAH-only), ILD (ILD-only), concurrent PAH and ILD (PAH-ILD) or neither PAH nor ILD (SSc-only). Logistic or linear regression analyses were used for associations between clinical features, health-related quality of life (HRQoL) and physical function. Survival analysis was performed using Kaplan-Meier estimates and Cox-regression modelling., Results: Of 1561 participants, 7% fulfilled criteria for PAH-only, 24% ILD-only, 7% PAH-ILD and 62% SSc-only. People with PAH-ILD were more frequently male, with diffuse skin involvement, higher inflammatory markers, older age of SSc onset and higher frequency of extensive ILD than the cohort overall (p < 0.001). People of Asian race more frequently developed PAH-ILD (p < 0.001). People with PAH-ILD or PAH-only had worse WHO functional class and 6-min-walk-distance than ILD-only (p < 0.001). HRQoL scores were worst in those with PAH-ILD (p < 0.001). Survival was reduced in the PAH-only and PAH-ILD groups (p < 0.01). Multivariable hazard modelling demonstrated the worst prognosis in extensive ILD and PAH (HR = 5.65 95% CI 3.50-9.12 p < 0.01), followed by PAH-only (HR = 4.21 95% CI 2.89-6.13 p < 0.01) and PAH with limited ILD (HR = 2.46 95% CI 1.52-3.99 p < 0.01)., Conclusions: The prevalence of concurrent PAH-ILD in the ASCS is 7%, with poorer survival in those patients with PAH-ILD compared to ILD or SSc alone. The presence of PAH confers a poorer overall prognosis than even extensive ILD; however, further data are required to better understand the clinical outcomes of this high-risk patient group., (© 2023. The Author(s).)

Background: Pregnant women with suspected fetal anomalies experience a great deal of stress following prenatal screening tests. The present study aimed to investigate women's worries about prenatal screening tests suspected of fetal anomalies., Methods: Through the use of qualitative content analysis, the reports of women whose prenatal screening tests were suspected of fetal anomalies were analyzed and the results were interpreted. The participants were selected from four public and private maternity care clinics of Babol, Iran, from December 2021 to January 2022, using targeted convenience sampling. Data were collected from 20 women aged 24 to 41 years old, who underwent prenatal screening tests and were suspected of fetal anomalies, using semi-structured face-to-face interviews., Results: The four main themes included the "causes of worries" (with sub-themes of challenge with spouse and relatives, medical diagnosis processes, previous unpleasant experiences, physical and mental problems, financial worries, and misinformation), "anxiety-coping styles" (with cognitive emotion-oriented, behavioral emotion-oriented, and problem-oriented sub-themes), "reactions to a possible diagnosis of anomaly" (with three sub-themes, namely concealment, extreme fear and worry, and denial), and "attribution of the cause of the anomaly" (with sub-themes of consanguine marriage, evil eyes, tendency to have a baby of a particular gender, a history of anomalies in the previous child, the spouse's medical illness, unplanned pregnancy, and high maternal anxiety)., Conclusion: Women with suspected fetal anomalies experience a great deal of stress, the most important reason for which is the "physician's uncertainty". "Sharing worries with relatives" was the most common style of coping with worries. Establishing emotional support and empathetic communication between midwives and physicians with pregnant women suspected of fetal anomalies were important ways to reduce their worries., (© 2023. The Author(s).)

Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2β, gene: TFAP2Β). AP-2β regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2Β has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2β, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2β as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2β as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs., (© 2022. The Author(s).)

Background: Healthcare quality for systemic lupus erythematosus (SLE) is a modifiable target for improving patient outcomes. We aimed to assess the quality of care processes in different clinic settings, comparing a subspecialty lupus clinic with hospital-based and private general rheumatology clinics., Methods: Patients with SLE (n = 258) were recruited in 2016 from a subspecialty lupus clinic (n = 147), two hospital general rheumatology clinics (n = 56) and two private rheumatology clinics (n = 55). Data were collected from medical records and patient questionnaires. Quality of care was assessed using 31 validated SLE quality indicators (QI) encompassing diagnostic work-up, disease and comorbidity assessments, drug monitoring, preventative care and reproductive health. Per-QI performance was measured as a percentage of patients that met the QI relative to the number of patients eligible. Per-patient QI performance was calculated as a percentage of QIs met relative to the number of eligible QIs for each patient. Per-QI and per-patient QI performance were compared between the three clinic settings, and multiple regression performed to adjust for sociodemographic, disease and healthcare factors., Results: Per-QI performance was generally high across all clinic settings for diagnostic work-up, comorbidity assessment, lupus nephritis, drug monitoring, prednisolone taper, osteoporosis and pregnancy care. Median [IQR] per-patient performance on eligible QIs was higher in the subspeciality lupus clinic (66.7% [57.1-74.1]) than the hospital general rheumatology (52.7% [47.5-58.1]) and private rheumatology (50.0% [42.9-60.9]) clinics (p <0.001) and the difference remained significant after multivariable adjustment. The subspecialty lupus clinic recorded higher per-QI performance for documentation of disease activity, disease damage, cardiovascular risk factor and drug toxicity assessments, pre-immunosuppression hepatitis and tuberculosis screening, new medication counselling, vaccinations, sun avoidance education and contraception counselling., Conclusions: SLE patients managed in a subspecialty lupus clinic recorded higher per-patient QI performance compared to hospital general rheumatology and private rheumatology clinics, in part related to better documentation on certain QIs., (© 2022. The Author(s).)

Background: To describe the epidemiology, determinants and survival impact of gastric antral vascular ectasia (GAVE) in systemic sclerosis (SSc)., Methods: Consecutive SSc patients prospectively enrolled in the Australian Scleroderma Cohort Study (ASCS) were included. Univariable and multivariable logistic regression were used to determine the associations of GAVE with clinical manifestations and serological parameters. Kaplan-Meier (K-M) survival curves were used to estimate survival., Results: The prevalence of GAVE in this SSc cohort of 2039 SSc patients was 10.6% (n = 216) over a median follow-up period of 4.3(1.7-8.4) years. SSc patients with a history of GAVE compared with those without a history of GAVE were older at SSc onset [49.5 (40.0-58.2) vs 46.7 (36.0-56.7) years, p = 0.05]; more likely to have diffuse disease subtype (dcSSc) (35.3% vs 24.1%, p < 0.001); be negative for Scl-70, U1RNP and Scl/PM antibody (4.0% vs 16.1%, p < 0.001, 3.5% vs 7.4%, p = 0.041, 0.0% vs 2.0%, p = 0.042; and respectively) and positive for RNAP III antibody (24.9% vs 8.3%, p < 0.001). Those with GAVE had a worse HRQoL (p = 0.002). Independent determinants of GAVE included the presence of RNAP III antibody (OR 3.46, p < 0.001), absence of Scl-70 antibody (OR 0.23, p = 0.001), presence of GIT dysmotility (OR 1.64, p = 0.004), and digital ulcers; pits; or digital amputation (OR 1.59, p = 0.014)., Conclusions: GAVE is an underestimated and underappreciated SSc manifestation of SSc, which occurs with a relatively high frequency. Identifying an at-risk GAVE phenotype, as presented herein, is of practical importance as screening may prove advantageous given GAVE can be easily diagnosed and treated., (© 2022. The Author(s).)

Background: Skeletal muscle can be directly affected by systemic sclerosis (SSc); however, a significant burden of SSc-associated myopathy is undetected because clinical parameters such as weakness and creatine kinase (CK) are unreliable biomarkers of muscle involvement. This study presents qualitative and quantitative magnetic resonance imaging (MRI) findings that quantify the prevalence of myopathy and evaluate any association between skeletal and cardiac muscle involvement in SSc., Methods: Thirty-two patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria underwent skeletal muscle MRI in addition to cardiac MRI. Skeletal muscles were independently assessed by two musculoskeletal radiologists for evidence of oedema, fatty infiltration and atrophy. Skeletal muscle T2 mapping times and percentage fat fraction were calculated. Linear regression analysis was used to evaluate the clinical and myocardial associations with skeletal muscle oedema and fatty infiltration. Cardiac MRI was performed using post gadolinium contrast imaging and parametric mapping techniques to assess focal and diffuse myocardial fibrosis., Results: Thirteen participants (40.6%) had MRI evidence of skeletal muscle oedema. Five (15.6%) participants had fatty infiltration. There was no association between skeletal muscle oedema and muscle strength, creatine kinase, inflammatory markers or fibroinflammatory myocardial disease. Patients with skeletal muscle oedema had higher T2-mapping times; there was a significant association between subjective assessments of muscle oedema and T2-mapping time (coef 2.46, p = 0.02) and percentage fat fraction (coef 3.41, p = 0.02). Diffuse myocardial fibrosis was a near-universal finding, and one third of patients had focal myocardial fibrosis. There was no association between skeletal myopathy detected by MRI and burden of myocardial disease., Conclusions: MRI is a sensitive measure of muscle oedema and systematic assessment of SSc patients using MRI shows that myopathy is highly prevalent, even in patients without symptoms or other signs of muscle involvement. Similarly, cardiac fibrosis is highly prevalent but occurs independently of skeletal muscle changes. These results indicate that novel quantitative MRI techniques may be useful for assessing sub-clinical skeletal muscle disease in SSc., (© 2022. The Author(s).)

Background: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes., Methods: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI)., Results: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients., Conclusion: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality., (© 2022. The Author(s).)

Background: The accuracy of subjective risk perception is a matter of concern in breast cancer development. The objective of this study was to evaluate the accuracy of self-perceived risk assessment of breast cancer development and compared to actual risk in Iranian women., Methods: The demographic, clinical, and reproductive characteristics of 800 women aged 35-85 years were collected with an in-person interview. The self-perceived risk and the actual risk were assessed using the visual analog scale (VAS) and he Gail model respectively. Gail's cutoff of 1.66% risk was used to categorize the estimated 5-year actual risk as low/average risk (< 1.66%) and high risk (≥ 1.66). In low/average risk, if the self-perceived risk > actual risk, then individuals were considered as overestimating. Similarly, in high-risk women, if the perceived risk < actual risk, then, the subjects were labeled as under-estimate; otherwise, it was labeled as accurate. The Kappa statistics were used to determine the agreement between self-perceived risk and actual risk. ROC analysis was applied to determine the accuracy of self-perceived risk in the prediction of actual risk., Results: The perceived risk was significantly higher than actual risk (p = 0.001, 0.01 for 5-year and lifetime risk respectively). Both in low and high-risk groups about half of the women over-estimate and underestimate the risk by subjective risk perception. For a 5-year risk assessment, there was no agreement between perceived risk and actual risk (Kappa = 0.00, p = 0.98) but a very low agreement between them in lifetime risk assessment (Kappa = 0.09, p = 0.005). The performance of accuracy of risk perception versus actual risk was very low (AUC = 0.53, 95% CI 0.44-0.61 and AUC = 0.58, 95% CI 0.54-0.62 for the 5-year risk and lifetime risk respectively)., Conclusion: The clinical performance of risk perception based on VAS is very poor. Thus, the efforts of the public health education program should focus on the correct perception of breast cancer risk among Iranian women.

Background: There is no standard and comprehensive questionnaire for reproductive health assessment among women shift workers. This study aimed at the development and psychometric evaluation of the Women Shift Workers' Reproductive Health Questionnaire., Methods: This sequential exploratory mixed-method study was conducted in a qualitative (item generation) and a quantitative (psychometric evaluation) phase. In the qualitative phase, the primary item pool of the questionnaire was generated based on the findings of the qualitative content analysis of 21 interviews held with 21 women shift workers as well as the findings of a literature review. In the quantitative phase, the face, content, construct, convergent, and discriminant validity and the reliability of the questionnaire were assessed. For construct validity assessment through exploratory and confirmatory factor analyses, 620 women shift workers were conveniently selected to fill out the questionnaire. Reliability assessment was done through assessing internal consistency, stability, and composite reliability., Results: The primary item pool contained 88 items. During face and content validity, item number was reduced to 55. Construct validity assessment through factor analysis revealed that 56.50% of the total variance was explained by five factors with 34 items. The factors were named motherhood, general health, sexual relationships, menstruation, and delivery. Confirmatory factor analysis confirmed the fit of the five-factor model. The Cronbach's alpha and the composite reliability value of the questionnaire were more than 0.7., Conclusion: The Women Shift Workers' Reproductive Health Questionnaire is a valid and reliable instrument and can be used for reproductive health assessment among women shift workers.

Background: Valid and reliable instruments are needed to assess such beliefs, attitudes, and knowledge. This study aimed to translate Breast Cancer Screening Beliefs Questionnaire into Persian and evaluate its psychometric properties among Iranian women., Methods: In this methodological study, the twelve-item Breast Cancer Screening Beliefs Questionnaire was translated into Persian and filled out by 1256 Iranian women. Face, content, convergent, and discriminant validity were evaluated and exploratory and confirmatory factor analyses were performed for construct validity evaluation. Reliability was also evaluated through calculating Cronbach's alpha, McDonald's omega, Average inter-item correlation, and test-retest intraclass correlation coefficient and finally, composite reliability was estimated., Results: Three factors were extracted in factor analysis which included screening attitude, screening knowledge and perception, and screening practice. These factors explained 55.71% of the total variance of breast cancer screening beliefs. This three-factor model was confirmed in confirmatory factor analysis based on model fit indices (PCFI = 0.703, PNFI = 0.697, CMIN/DF = 2.127, RMSEA = 0.30, GFI = 0.980, AGFI = 0.998, and CFI = 0.991). Convergent and discriminant validity were also confirmed. Composite reliability and test-retest intraclass correlation coefficient were more than 0.7., Conclusion: With a three-factor structure, the Persian Breast Cancer Screening Beliefs Questionnaire has acceptable validity and reliability and hence, can be used to evaluate Iranian women's breast cancer screening beliefs.

Background: Fertility, in addition to the biomedical aspect, is phenomena of social, economic and demographic changes. Social network were considered for understanding fertility behaviors and changes in the levels of fertility. This study was conducted to investigate the relationship between social capital and childbirth behaviors in Iranian women employees., Methods: This cross-sectional study was conducted in 2017 on 536 women health care workers who randomly selected from health care setting Babol/Iran. Data were collected using demographic, childbearing behavior and social capital questionnaires. The SPSS-21 software was employed to analysis the data at a significant level of 0.05., Results: The results of the study showed that, there was significant relationship between number of pregnancy and social capital (P = 0.039). Furthermore, social capital has a significant relationship with the time of pregnancy (P = 0.043), the time of pregnancy in women with high social capital was observed to be relatively 30% shorter compare the women with low social capital., Conclusion: Social capital, as one of the important factors influencing childbirth behaviors, should be considered in population planning and policy making.

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.

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.

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.

Background: The psychosocial environment of the workplace has received less attention in terms of occupational health. Trust, social network and social cohesion at the workplace (that is, factors related to social capital) may have effects on employee health. Thus, the objective of this study was to examine the association between workplace social capital and mental health among Iranian workers., Methods: In this cross-sectional study, data were obtained from 5 factories in Babol, Northern Iran, in 2016, where 280 workers responded to a survey on social capital at work and psychosocial distress., Results: Approximately 23.6% of the workers had psychological distress, and 23.4% had low social capital in the workplace. There was a significant relationship between mental health and individual workplace social capital (p = 0.025) and aggregated workplace social capital (p = 0.027). After controlling for each individual's characteristics, the prevalence ratio of psychological distress was 2.11 (95% CI: 1.43-3.17) times higher among workers with low individual social capital, and low aggregated workplace social capital was associated with 2.64 (95% CI: 1.28-5.45) times higher odds of psychological distress., Conclusion: Higher social capital is associated with a reduced risk of psychological distress. The promotion of social capital can be considered as a means to increase workplace mental health among workers.

Background: Fertility rate in Iran has decreased by more than 70% in the last three decades. Continuous decrease in fertility rate will create socioeconomic crises for the country in a near future. A significant factor behind fertility behaviors is women's attitudes towards maternal and spousal roles. Such attitudes are mainly determined by social capital. This study aims to determine and explore of relationship between social capital and fertility behavior among female healthcare workers., Methods: This sequential explanatory mixed methods study will be conducted using the follow-up explanations model in two phases. In the first phase, a population-based cross-sectional survey will be conducted on 500 female workers recruited through multistage cluster sampling from healthcare settings located in Babol, Iran, and the relationship of social capital with fertility behaviors will be assessed. In the second phase, a qualitative study will be done to explain the findings of the first phase. Finally, the findings of the first phase will be explained using the findings of the second phase., Discussion: Understanding the relationship of social capital with fertility behaviors is essential to effective planning for the management of population decline. The findings of the present study will provide population policy-makers with helpful information.

Background: Although shift works is a certain treat for female reproductive health, but currently, there is no standardized instrument for measuring reproductive health among female shift workers. This study aims to develop and evaluate the psychometric properties of a Women Shift Workers' Reproductive Health Questionnaire (WSW-RHQ)., Methods: This is a sequential exploratory mixed-method study with a qualitative and a quantitative phase. In the qualitative phase, semi-structured interviews will be held with female shift workers who live in Mazandaran Province, Iran, additionally, the literature review will be performed by searching electronic databases. Sampling will be done in different workplaces and with maximum variation respecting female shift workers' age and job and educational and different economic situation. Interview data will be analyzed using conventional content analysis and then, the primary item pool for the questionnaire will be developed. In the quantitative phase, we will evaluate the psychometric properties of the questionnaire, i.e. its face, content, construct as well as reliability via the internal consistency, stability. Finally, a scoring system will be developed for the questionnaire., Discussion: The development of WSW-RHQ will facilitate the promotion and implementation of reproductive health interventions and assessment of their effectiveness. Other scholars can cross-culturally adapt and use the questionnaire according to their immediate contexts.

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.

Background: Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). Recently, meeting a definition of a lupus low disease activity state (LLDAS), analogous to low disease activity in rheumatoid arthritis, was preliminarily validated as associated with protection from damage accrual. The LLDAS definition has not been previously evaluated for association with patient-reported outcomes. The objective of this study was to determine whether LLDAS is associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of patients with SLE., Methods: HR-QoL was measured using the Medical Outcomes Study 36-item short form health survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using the SLE disease activity index (SLEDAI-2 K), physician global assessment (PGA) and LLDAS., Results: Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level and damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p < 0.001), a higher level of education (p < 0.001), younger age (p < 0.001) and shorter disease duration (p < 0.01) remained significantly associated with better physical component scores (PCS). Musculoskeletal disease activity (p < 0.001) was negatively associated with PCS, and cutaneous activity (p = 0.04) was negatively associated with mental component scores (MCS). Patients in LLDAS had better PCS (p < 0.001) and MCS (p < 0.001) scores and significantly better scores in multiple individual SF-36 domain scores. Disease damage was associated with worse PCS (p < 0.001), but not MCS scores., Conclusions: Ethnicity, education, disease damage and specific organ involvement impacts HR-QoL in SLE. Attainment of LLDAS is associated with better HR-QoL.

Background: Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc). Annual screening with echocardiogram (ECHO) is recommended. We present the methodological aspects of a PAH screening programme in a large Australian SSc cohort, the epidemiology of SSc-PAH in this cohort, and an evaluation of factors influencing physician adherence to PAH screening guidelines., Methods: Patient characteristics and results of PAH screening were determined in all patients enrolled in a SSc longitudinal cohort study. Adherence to PAH screening guidelines was assessed by a survey of Australian rheumatologists. Summary statistics, chi-square tests, univariate and multivariable logistic regression were used to determine the associations of risk factors with PAH., Results: Among 1636 patients with SSc, 194 (11.9%) had PAH proven by right-heart catheter. Of these, 160 were detected by screening. The annual incidence of PAH was 1.4%. Patients with PAH diagnosed on subsequent screens, compared with patients in whom PAH was diagnosed on first screen, were more likely to have diffuse SSc (p = 0.03), be in a better World Health Organisation (WHO) Functional Class at PAH diagnosis (p = 0.01) and have less advanced PAH evidenced by higher mean six-minute walk distance (p = 0.03), lower mean pulmonary arterial pressure (p = 0.009), lower mean pulmonary vascular resistance (p = 0.006) and fewer non-trivial pericardial effusions (p = 0.03). Adherence to annual PAH screening using an ECHO-based algorithm was poor among Australian rheumatologists, with less than half screening their patients with SSc of more than ten years disease duration., Conclusion: PAH is a common complication of SSc. Physician adherence to PAH screening recommendations remains poor. Identifying modifiable barriers to screening may improve adherence and ultimately patient outcomes.

Background: Systemic lupus erythematosus (SLE) is a chronic heterogeneous disease with considerable burden from disease activity and damage. A novel clinical treatment target in the form of the lupus low disease activity state (LLDAS) has been recently reported, with retrospective validation showing that time spent in LLDAS translates to reduced damage accrual. The objectives of this study were to describe the frequency and identify the predictors of attaining LLDAS in a large multinational cohort of patients with SLE., Methods: Data were collected at the recruitment visit in patients with SLE enrolled in a longitudinal study in nine countries. Data were analysed cross-sectionally against the recently published definition of LLDAS, and the frequency and characteristics associated with presence of LLDAS were determined. Stepwise multivariable logistic regression was used to determine predictors of LLDAS., Results: Of the 1846 patients assessed, criteria for LLDAS were met by 44 %. Patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95 % CI 0.19-0.49, p < 0.001). Likewise, patients with a history of discoid rash (OR 0.66, 95 % CI 0.49-0.89, p = 0.006), renal disease (OR 0.60, 95 % CI 0.48-0.75, p < 0.001), elevated double stranded DNA (OR 0.65, 95 % CI 0.53-0.81, p < 0.001) or hypocomplementaemia (OR 0.52, 95 % CI 0.40-0.67, p < 0.001) were less likely to be in LLDAS. When countries were compared, higher national social wealth (OR 1.57, 95 % CI 1.25-1.98, p < 0.001) as measured by the gross domestic product per capita was positively associated with LLDAS, but ethnicity was not., Conclusion: The lupus low disease activity state is observed in less than half of patients with SLE at a single point in time. Disease duration and phenotype, and national social wealth, are predictive of LLDAS.

Background: In some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement ('hypocomplementaemia') is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc., Methods: The study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively., Results: At least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti-ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti-Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity., Conclusions: While hypocomplementaemia is not associated with disease activity in patients with non-overlap SSc, it is associated with some features of increased SSc disease activity in patients with overlap disease features.

Background: Pulmonary arterial hypertension (PAH) is the leading cause of mortality in patients with systemic sclerosis (SSc). We sought to determine the incidence, prevalence and risk factors for PAH development in a large Australian SSc cohort., Methods: PAH was diagnosed on right heart catheterisation (mPAP >25 and PAWP <15 mmHg at rest). Patients with PH secondary to interstitial lung disease (ILD; defined as abnormal HRCT scan and FVC < 60 %) were excluded. Summary statistics, chi-square tests, univariate and multivariable logistic regression along with post-estimation diagnostics were used to determine the associations of different combinations of risk factors with PAH., Results: Among 1579 SSc patients, 8.4 % (132 patients) were diagnosed with PAH over a mean (±SD) follow-up of 3.2 (±2.5) years. The incidence of PAH in this cohort was 0.7 % per annum. Of these, 68.9 % had limited disease subtype (lcSSc). In multivariable regression analysis, the presence of anti-centromere antibody (ACA) (OR 1.6, 95 % CI 1.1-2.5, p = 0.03), oesphageal stricture (OR 2.0, 95 % CI 1.2-3.3, p = 0.006), calcinosis (OR 1.9, 95 % CI 1.2-2.9, p = 0.003), sicca symptoms (OR 1.6, 95 % CI 1.1-2.5, p = 0.03), mild ILD (OR 2.3, 95 % CI 1.5-3.7, p < 0.001) and digital ulcers (OR 1.6, 95 % CI 1.0-2.4, p = 0.03) were predictive of PAH. This model had an area under the curve of 0.7 and concordance of 91.8 %. When analysed by disease subtype, the presence of calcinosis (OR 2.2, 95 % CI 1.4-3.7, p = 0.01), sicca symptoms (OR 2.6, 95 % CI 1.5-4.6, p = 0.001), mild ILD (OR 2.3, 95 % CI 1.4-3.8, p = 0.001) and digital ulcers (OR 1.9, 95 % CI 1.2-3.7, p = 0.01) were predictive of PAH in lcSSc; and oesophageal stricture (OR 4.4, 95 % CI 1.9-10.5, p = 0.001), mild ILD (OR 2.8, 95 % CI 1.2-6.8, p = 0.02) and ACA (OR 5.2, 95 % CI 1.8-14.8, p = 0.002) were predictive of PAH in dcSSc., Conclusions: The incidence and prevalence of PAH in this cohort are 0.7 % per annum and 8.4 %, respectively. The clinical-serologic risk factors for PAH differ based on disease subtype. In both subtypes, mild ILD is associated with PAH, suggesting the possibility of common pathogenic mechanisms underlying both of these disease manifestations. This model identifies a subset of patients at an appreciably higher risk of developing PAH, who should be screened and would in future, benefit from preventative therapies.

Background: Osteoarthritis (OA) is a leading cause of disability in developed nations. Total knee arthroplasty (TKA) is a clinically effective treatment for people with end-stage knee OA, and represents one of the highest volume medical interventions globally. However, up to one in three patients remain dissatisfied following TKA. Research indicates that the strongest predictor of patient dissatisfaction following TKA is unmet expectations. This study will use a discrete choice experiment (DCE) provided to patients to improve knowledge of the expected outcomes of TKA. This increased knowledge is based on actual outcome data and is hypothesised to optimise patient expectations of TKA outcomes, thereby increasing their satisfaction and self-reported health outcomes., Methods/design: One hundred and thirty-two people with end-stage OA on the waiting list for TKA will be recruited and randomly allocated to one of two groups using computer-generated block randomisation. A randomised controlled trial (RCT) adhering to SPIRIT and CONSORT guidelines will evaluate the effect of administering a DCE prior to surgery on patient-reported pain and function and satisfaction following TKA. Patients in the intervention arm will complete a survey containing the DCE, compared to the control group who will complete a modified survey that does not contain the DCE activity. The DCE contains information on actual risks of postoperative complications, as well as health status after TKA. The DCE encourages patients to actively make trade-offs between risks and health outcomes to elicit their preferences. Participants in both groups will be required to complete the survey after consenting to have the procedure, but prior to surgery during their routine preadmission appointment at St. Vincent's Hospital, Melbourne, Australia (SVHM). Patients in both the intervention and control groups will also be required to complete a brief patient expectation survey 1 week prior to scheduled TKA. In addition, orthopaedic surgeons will complete a brief expectations survey for each patient consented for TKA to compare matched surgeon and patient expectations for recovery following TKA. Primary outcomes will be evaluated by a blinded examiner at 12 months post surgery using a validated self-reported pain and physical function scale, and a validated patient satisfaction scale. Secondary outcomes will include a range of validated measures of health and psychological wellbeing. All analyses will be conducted on an intention-to-treat basis using linear regression models., Discussion: This study is the first of its kind to use a DCE to provide information to patients to optimise their expectations of the outcomes of surgery. Reducing the rate of patient dissatisfaction commonly seen in patients following TKA will help to reduce the burden associated with poor outcomes on the health system., Trial Registration: Australian New Zealand Clinical Trials Registry ( ACTRN12615001226594p ). Version 1; registered on 9 November 2015.

Introduction: There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines., Methods: We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an 'alternate scenario analysis' in which the prevalence of PAH was set at 10%., Results: RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%., Conclusions: In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.

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.

Background: We sought to determine whether socio-economic status (SES) is an independent predictor of outcome following total knee (TKR) and hip (THR) replacement in Australians., Methods: In this prospective cohort study, we included patients undergoing TKR and THR in a public hospital in whom baseline and 12-month follow-up data were available. SES was determined using the Australian Bureau of Statistics 'Index of Relative Advantage and Disadvantage'. Other independent variables included patients' demographics, comorbidities and procedure-related variables. Outcome measures were the International Knee Society Score and Harris Hip Score pain and function subscales, and the Short Form Health Survey (SF-12) physical and mental component scores., Results: Among 1,016 patients undergoing TKR and 835 patients undergoing THR, in multiple regression analysis, SES score was not independently associated with pain and functional outcomes. Female sex, older age, being a non-English speaker, higher body mass index and presence of comorbidities were associated with greater post-operative pain and poorer functional outcomes following arthroplasty. Better baseline function, physical and mental health, and lower baseline level of pain were associated with better outcomes at 12 months. In univariate analysis, for TKR, the improvement in SF-12 mental health score post arthroplasty was greater in patients of lower SES (3.8 ± 12.9 versus 1.5 ± 12.2, p=0.008), with a statistically significant inverse association between SES score and post-operative SF-12 mental health score in linear regression analysis (coefficient-0.28, 95% CI: -0.52 to -0.04, p=0.02)., Conclusions: When adjustments are made for other covariates, SES is not an independent predictor of pain and functional outcome following large joint arthroplasty in Australian patients. However, relative to baseline, patients in lower socioeconomic groups are likely to have greater mental health benefits with TKR than more privileged patients. Large joint arthroplasty should be made accessible to patients of all SES.

Background: The incidence and characteristics of tuberculosis (TB) in remote areas of Papua New Guinea (PNG) are largely unknown. The purpose of our study was to determine the incidence of TB in the Gulf Province of PNG and describe disease characteristics, co-morbidities and drug resistance profiles that could impact on disease outcomes and transmission., Methods: Between March 2012 and June 2012, we prospectively collected data on 274 patients presenting to Kikori Hospital with a presumptive diagnosis of TB, and on hospital inpatients receiving TB treatment during the study period. Sputum was collected for microscopy, GeneXpert analysis, culture and genotyping of isolates., Results: We estimate the incidence of TB in Kikori to be 1290 per 100,000 people (95% CI 1140 to 1460) in 2012. The proportion of TB patients co-infected with HIV was 1.9%. Three of 32 TB cases tested were rifampicin resistant. Typing of nine isolates demonstrated allelic diversity and most were related to Beijing strains., Conclusions: The incidence of TB in Kikori is one of the highest in the world and it is not driven by HIV co-infection. The high incidence and the presence of rifampicin resistant warrant urgent attention to mitigate substantial morbidity in the region.

Introduction: Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH., Methods: We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)., Results: Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively., Conclusions: The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.

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.

Introduction: Pulmonary arterial hypertension is a major cause of mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) has emerged as a candidate biomarker that may enable the early detection of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The objective of our study was to incorporate NT-proBNP into a screening algorithm for SSc-PAH that could potentially replace transthoracic echocardiography (TTE) as a more convenient and less costly "first tier" test., Methods: NT-proBNP levels were measured in patients from four clinical groups: a group with right heart catheter (RHC)-diagnosed SSc-PAH before commencement of therapy for PAH; a group at high risk of SSc-PAH based on TTE; a group with interstitial lung disease; and systemic sclerosis (SSc) controls with no cardiopulmonary complications. NT-proBNP levels were compared by using ANOVA and correlated with other clinical variables by using simple and multiple linear regression. ROC curve analyses were performed to determine the optimal cut point for NT-proBNP and other clinical variables in prediction of PAH., Results: NT-proBNP was highest in the PAH group compared with other groups (P < 0.0001), and higher in the risk group compared with controls (P < 0.0001). NT-proBNP was positively correlated with systolic pulmonary artery pressure (PAP) on TTE (P < 0.0001), and mean PAP (P = 0.013), pulmonary vascular resistance (P = 0.005), and mean right atrial pressure (P = 0.006) on RHC. A composite model wherein patients screened positive if NT-proBNP was ≥ 209.8 pg/ml, and/or DLCOcorr was < 70.3% with FVC/DLCOcorr ≥ 1.82, had a sensitivity of 100% and specificity of 77.8% for SSc-PAH., Conclusion: We have proposed a screening algorithm for SSc-PAH, incorporating NT-proBNP level and PFTs. This model has high sensitivity and specificity for SSc-PAH and, if positive, should lead to TTE and confirmatory testing for PAH. This screening algorithm must be validated prospectively.

Introduction: The prevalence of antibodies to RNA polymerase III (anti-RNAP) differs among systemic sclerosis (SSc) cohorts worldwide. Previously reported associations of anti-RNAP include diffuse cutaneous disease, tendon friction rubs and renal crisis, with recent reports suggesting a close temporal association between malignancy and SSc disease onset among patients with anti-RNAP., Methods: Patients with SSc were tested for the presence of anti-RNAP at recruitment into the Australian Scleroderma Cohort Study. We used univariate and multivariable methods to identify and quantify clinical and laboratory correlates of anti-RNAP in SSc. Diagnostic testing procedures were used to determine the usefulness of these antibodies in estimating the likelihood of clinically important outcomes., Results: There were 451 patients with mean ± standard deviation age and disease duration at recruitment of 58.1 ± 12.4 and 11.6 ± 10.0 years, respectively; 151 (33.5%) patients were recruited within 5 years of diagnosis of SSc. Overall, 69 (15.3%) patients had anti-RNAP. Univariate associations of anti-RNAP were diffuse disease (75.4% vs. 20.9%, P < 0.0001), joint contractures (73.9% vs. 30.1%, P < 0.0001), greater highest-recorded modified Rodnan skin score (20.6 ± 12.4 vs. 10.1 ± 7.9, P < 0.0001), synovitis (31.9% vs. 19.9%, P = 0.03), myositis (2.9% vs. 0.5%, P = 0.05), systemic hypertension (59.4% vs. 39.7%, P = 0.002), renal crisis (24.6% vs. 1.8%, P < 0.0001) and malignancy diagnosed within 5 years of onset of SSc skin disease (13.3% vs. 3.9%, P = 0.01). In multiple regression analysis, after adjustment for other covariates, anti-RNAP were independently associated with renal crisis (odds ratio (OR) 3.8, 95% confidence interval (CI) 1.2 to 11.5, P = 0.02; positive predictive value (PPV) 24.6%, negative predictive value (NPV) 98.2%), diffuse disease (OR 6.4, 95% CI 2.9 to 13.8, P < 0.0001; PPV 75.4%, NPV 20.9%), joint contractures (OR 2.5, 95% CI 1.2 to 5.3, P = 0.02; PPV 73.9%, NPV 69.9%) and malignancy diagnosed within 5 years of onset of SSc skin disease (OR 4.2, 95% CI 1.3 to 13.4, P = 0.01; PPV 13.3%, NPV 96.1%)., Conclusions: Anti-RNAP status is a clinically useful prognostic marker in SSc and enables clinicians to identify patients at high risk of developing renal crisis, synovitis, myositis and joint contractures. Patients with anti-RNAP also have an increased risk of malignancy within a 5-year timeframe before or after onset of SSc skin changes.

Introduction: Previous studies have shown that traditional risk factors such as hypercholesterolemia and hypertension account for only a small proportion of the dramatically increased risk of atherosclerotic coronary artery disease (CAD) in systemic lupus erythematosus (SLE). However, in these studies, exposure to risk factors was measured only at baseline. In this study, our objective was to compare measures of cumulative exposure with remote and recent values for each of total cholesterol (TC), systolic (SBP), and diastolic (DBP) blood pressure in terms of ability to quantify risk of atherosclerotic CAD in patients with SLE., Methods: Patients in the Toronto lupus cohort had TC and BP measured at each clinic visit and were followed up prospectively for the occurrence of CAD. For each patient, arithmetic mean, time-adjusted mean (AM) and area-under-the-curve (AUC) were calculated for serial TC, SBP, and DBP measurements. Proportional hazards regression models were used to compare these summary measures with recent and first-available ("remote") measurements in terms of ability to quantify risk of CAD events, defined as myocardial infarction, angina, or sudden cardiac death., Results: The 991 patients had a mean ± SD of 19 ± 19 TC measurements per patient. Over a follow-up of 6.7 ± 6.4 years, 86 CAD events occurred; although remote TC was not significantly predictive of CAD, mean and AM TC were more strongly predictive (hazard ratio (HR) 2.07; P = 0.003) than recent TC (HR 1.86, P = 0.001). AUC TC was not predictive of CAD. A similar pattern was seen for DBP and SBP. Older age, male sex, higher baseline and recent disease activity score, and corticosteroid use also increased CAD risk, whereas antimalarials were protective., Conclusions: In contrast to the population-based Framingham model, first-available TC and BP are not predictive of CAD among patients with SLE, in whom measures reflecting cumulative exposure over time are better able to quantify CAD risk. This is an important consideration in future studies of dynamic risk factors for CAD in a chronic relapsing-remitting disease such as SLE. Our findings also underpin the importance of adequate control of SLE disease activity while minimizing corticosteroid use, and highlight the cardioprotective effect of antimalarials.

Introduction: Total cholesterol (TC) and blood pressure (BP) are likely to take a dynamic course over time in patients with systemic lupus erythematosus (SLE). This would have important implications in terms of using single-point-in-time measurements of these variables to assess coronary artery disease (CAD) risk. The objective of this study was to describe and quantify variability over time of TC and BP among patients with SLE and to determine their correlates., Methods: Patients in the Toronto lupus cohort who had two or more serial measurements of TC and systolic and diastolic BP (SBP and DBP) were included in the analysis. Variability over time was described in terms of the proportion of patients whose TC and BP profile fluctuated between normal and elevated (TC>5.2 mmol/L; SBP>or=140 mm Hg or DBP>or=90 mm Hg), and also in terms of within- and between-patient variance quantified by using analysis of variance modeling. Generalized estimating equations (GEEs) were used to determine independent correlates of each of TC, SBP, and DBP, treated as continuous outcome variables., Results: In total, 1,260 patients, comprising 26,267 measurements of each of TC, SBP, and DBP, were included. Mean+/-SD number of measurements per patient was 20.8+/-20. Mean+/-SD time interval between measurements was 5.4+/-9.7 months. Mean+/-SD time interval from the start to the end of the study was 9.3+/-8.5 years. Over time, 64.7% of patients varied between having normal and elevated cholesterol levels, whereas the status of 46.4% of patients varied between normotensive and hypertensive. By using analysis of variance (ANOVA), the within-patient percentage of total variance for each of TC, SBP, and DBP was 48.2%, 51.2%, and 63.9%, respectively. By using GEE, independent correlates of TC and BP included age, disease activity, and corticosteroids; antimalarial use was negatively correlated with TC (all P values<0.0001)., Conclusions: TC and BP vary markedly over time in patients with SLE. This variability is due not only to lipid-lowering and antihypertensive medications, but also to disease- and treatment-related factors such as disease activity, corticosteroids, and antimalarials. The dynamic nature of TC and BP in SLE makes a compelling case for deriving summary measures that better capture cumulative exposure to these risk factors.