Laboratory investigation results influence Physician's Global Assessment (PGA) of disease activity in SLE.

OBJECTIVE: To evaluate the impact of laboratory results on scoring of the Physician Global Assessment (PGA) of disease activity in systemic lupus erythematosus. METHODS: Fifty clinical vignettes were presented via an online survey to a group of international lupus experts. For each case, respondents scored the PGA pre and post knowledge of laboratory test results (pre-lab and post-lab PGAs). Agreement between individual assessors and relationships between pre-lab and post-lab PGAs, and PGAs and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) were determined. Respondents were also asked about factors they incorporate into their PGA determinations. RESULTS: Sixty surveys were completed. The inter-rater PGA reliability was excellent (pre-lab intraclass correlation coefficient (ICC) 0.98; post-lab ICC 0.99). Post-lab PGAs were higher than pre-lab PGAs: median (IQR) pre-lab PGA 0.5 (1.05), post-lab PGA 1 (1.3) (p<0.001), with a median (IQR) difference of 0.2 (0.45). In general, all abnormal labs including elevated anti-double stranded DNA antibody level (dsDNA) and low complement impacted PGA assessment. Cases with weakest correlations between pre-lab and post-lab PGA were characterised by laboratory results revealing nephritis and/or haematological manifestations. Both pre-lab and post-lab PGAs correlated with SLEDAI-2K. However, a significantly stronger correlation was observed between post-lab PGA and SLEDAI-2K. Multiple factors influenced PGA determinations. Some factors were considered by an overwhelming majority of lupus experts, with less agreement on others. CONCLUSIONS: We found excellent inter-rater reliability for PGAs in a group of international lupus experts. Post-lab PGA scores were higher than pre-lab PGA scores, with a significantly stronger correlation with the SLEDAI-2K. Our findings indicate that PGA scoring should be performed with knowledge of pertinent laboratory results.

Autologous stem cell transplantation in systemic sclerosis: a systematic review.

OBJECTIVES: Haematopoetic autologous stem cell transplantation (ASCT) has emerged as a treatment option for patients with refractory, severe autoimmune disease. This is a systematic review of the current literature on ASCT in adult patients with systemic sclerosis (SSc). METHODS: Original articles published between 2005 and 2016 that evaluated the use of ASCT in patients with SSc were reviewed with respect to the primary outcomes of overall and transplant related mortality (TRM) rates, and secondary outcomes of changes in modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), progression/event free survival (P/EFS) and quality of life measures. We also focussed on patient characteristics, the ASCT conditioning and mobilisation regimens used, and their relationship to patient outcome in each study. RESULTS: Of the 155 articles found, only 9 articles were suitable for review. There were 2 placebo-controlled trials (RCTs), ASTIS and ASSIST, and 7 observational and cohort studies. In general, patients undergoing ASCT had diffuse SSc with mRSS >14, and interstitial lung disease. The 2 RCTs showed a benefit in P/EFS (80-81%), FVC and quality of life measures in ASCT compared to monthly cyclophosphamide. All the studies showed an improvement in mRSS. TRM rates varied among studies, from 0 to 23%, with a trend to higher mortality rates in studies using higher doses of cyclophosphamide or myeloablative conditioning regimens. CONCLUSIONS: We conclude that ASCT is beneficial in some patients with SSc and that patient selection and conditioning regimens are critical determinants of prognosis and mortality post-ASCT.

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

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

The impact of season, environmental temperature and humidity on Raynaud phenomenon in an Australian systemic sclerosis cohort.

OBJECTIVE: The aim of this study was to determine the impact of season, temperature and humidity on the severity of Raynaud phenomenon in systemic sclerosis. METHODS: Data from the Australian Scleroderma Cohort Study were utilised to assess associations of patient-reported worsened RP in the month preceding each study visit. Mean monthly weather data were obtained from the closest weather station to the patient's address. We evaluated the relationship between worsened RP and health-related quality of life (HRQoL) measured using the SF-36 instrument. RESULTS: Among 1972 systemic sclerosis patients, RP was a near universal finding, and worsened RP in the preceding month was reported in 26.7% of 9175 visits. 'Worsened RP' showed significant environmental variability. On multivariable analysis, worsened RP was associated with low mean maximum temperatures (OR 0.91, 95% CI 0.90-0.92, p<0.001), high relative humidity (OR 1.05, 95% CI 1.04-1.05, p<0.001 and lower mean daily evaporation (OR 0.77, 95% CI 0.73-0.81, p<0.001). Worsened RP was strongly associated with telangiectasia, calcinosis and digital ulceration (DU), as well as demonstrating an association with anti-centromere antibody and gastro-oesophageal reflux disease (GORD) and a negative correlation with diffuse disease. Worsened RP was also strongly associated with worse HRQoL. CONCLUSION: Lower environmental temperature and higher relative humidity had significant associations with worsened RP in this systemic sclerosis cohort, suggesting an important role for dry warmth in managing this condition.

Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

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.

p38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model.

UNLABELLED: The aim of this study was to determine the degree of p38 mitogen-activated protein kinase (p38 MAPK) activation in rat heart and lungs after experimentally induced brain death and to test whether SD-282, a synthetic and selective small molecule inhibitor of p38 MAPK, abrogates p38 MAPK activation invoked by this brain death model. METHODS: Adult male Sprague Dawley rats were treated with vehicle (control, n=7) or SD-282 (40mg/kg, n=6), for 15min prior to the induction of brain death and maintained with ventilatory support for 3h. IL-6 and TNFalpha were measured in plasma, heart and lungs using ELISA, and p38 MAPK via Western blot assay. RESULTS: p38 MAPK inhibition was demonstrated by lower p38 MAPK activity in lungs from SD-282-treated donors compared to control (Median [inter-quartile range]: 13.6[4.0-19.0]% vs 20.2[14.7-31.5]% activity, p=0.06). Although levels varied, significant inhibition of p38 MAPK by SD-282 was not observed in the heart. SD-282 significantly lowered IL-6 and TNFalpha values compared to control in plasma (64[51-81]pg/ml vs 352[200-755]pg/ml, p=0.003 and 4.3[1.5-9.0]pg/ml vs 21.1[10.5-31.5]pg/ml, p=0.015, respectively) and lungs (0.14[0.12-0.62] vs 5.8[3.6-6.0]pg/mg protein, p=0.03 and 0.41[0.33-0.45] vs 2.1[1.4-2.7]pg/mg protein, p=0.0027, respectively), however SD-282 did not significantly affect cardiac cytokine levels. CONCLUSIONS: p38 MAPK inhibition with SD-282 decreases the pro-inflammatory response as represented by lower IL-6 and TNFalpha in plasma and lungs following brain death. However, although in heart this response was variable, no significant effect could be demonstrated under the present conditions.

Does expert opinion match the operational definition of the Lupus Low Disease Activity State (LLDAS)? A case-based construct validity study.

OBJECTIVE: To evaluate the construct validity of the Lupus Low Disease Activity State (LLDAS), a treatment target in systemic lupus erythematosus (SLE). METHODS: Fifty SLE case summaries based on real patients were prepared and assessed independently for meeting the operational definition of LLDAS. Fifty international rheumatologists with expertise in SLE, but with no prior involvement in the LLDAS project, responded to a survey in which they were asked to categorize the disease activity state of each case as remission, low, moderate, or high. Agreement between expert opinion and LLDAS was assessed using Cohen's kappa. RESULTS: Overall agreement between expert opinion and the operational definition of LLDAS was 77.96% (95% CI: 76.34-79.58%), with a Cohen's kappa of 0.57 (95% CI: 0.55-0.61). Of the cases (22 of 50) that fulfilled the operational definition of LLDAS, only 5.34% (59 of 22 × 50) of responses classified the cases as moderate/high activity. Of the cases that did not fulfill the operational definition of LLDAS (28 of 50), 35.14% (492 of 28 × 50) of responses classified the cases as remission/low activity. Common reasons for discordance were assignment to remission/low activity of cases with higher corticosteroid doses than defined in LLDAS (prednisolone ≤ 7.5mg) or with SLEDAI-2K >4 due to serological activity (high anti-dsDNA antibody and/or low complement). CONCLUSIONS: LLDAS has good construct validity with high overall agreement between the operational definition of LLDAS and expert opinion. Discordance of results suggests that the operational definition of LLDAS is more stringent than expert opinion at defining a low disease activity state.

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol.

INTRODUCTION: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. METHODS AND ANALYSIS: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. ETHICS AND DISSEMINATION: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals. TRIAL REGISTRATION NUMBER: ACTRN12614000418673, Pre-results.

A multicenter, randomized trial of a nurse-led, home-based intervention for optimal secondary cardiac prevention suggests some benefits for men but not for women: the Young at Heart study.

BACKGROUND: We examined the impact of a prolonged secondary prevention program on recurrent hospitalization in cardiac patients with private health insurance. METHODS AND RESULTS: The Young at Heart multicenter, randomized, controlled trial compared usual postdischarge care (UC) with nurse-led, home-based intervention (HBI). The primary end point was rate of all-cause hospital stay (31.5±7.5 months follow-up). In total, 602 patients (aged 70±10 years, 72% men) were randomized to UC (n=296) or HBI (n=306, 96% received ≥1 home visit). Overall, 42 patients (7.0%) died, and 492 patients (82%) accumulated 2397 all-cause hospitalizations associated with 10,258 hospital days costing >$17 million. There were minimal group differences (HBI versus UC) in the primary end point of all-cause hospital stay (5405 versus 4853 days; median [interquartile range], 0.08 [0.03-0.17] versus 0.07 [0.03-0.13]/patient per month). There were similar trends with respect to all hospitalizations (1197 versus 1200; P=0.802) and associated costs ($8.66 versus $8.58 million; P=0.375). At 2 years, however, more HBI versus UC (39% versus 27%; odds ratio, 1.67; 95% confidence interval, 1.15-2.41; P=0.007) patients were assessed as stable and optimally managed. For women, HBI outcomes were predominantly worse than UC outcomes. In men, HBI was associated with reduced risk of cardiovascular hospitalization (adjusted hazard ratio, 0.68; 95% confidence interval, 0.46-0.99; P=0.044) with less cardiovascular hospitalizations (192 versus 269; P=0.054) and costs ($2.49 versus $3.53 million; P=0.046). CONCLUSIONS: HBI did not reduce recurrent all-cause hospitalization compared with UC in privately insured cardiac patients overall. However, it did convey some benefits in cardiac outcomes for men. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Unique Identifier: 12608000014358. URL: http://www.anzctr.org.au/trial_view.aspx?id=82509.

Patient preferences and willingness-to-pay for a home or clinic based program of chronic heart failure management: findings from the Which? trial.

BACKGROUND: Beyond examining their overall cost-effectiveness and mechanisms of effect, it is important to understand patient preferences for the delivery of different modes of chronic heart failure management programs (CHF-MPs). We elicited patient preferences around the characteristics and willingness-to-pay (WTP) for a clinic or home-based CHF-MP. METHODOLOGY/PRINCIPAL FINDINGS: A Discrete Choice Experiment was completed by a sub-set of patients (n = 91) enrolled in the WHICH? trial comparing home versus clinic-based CHF-MP. Participants provided 5 choices between hypothetical clinic and home-based programs varying by frequency of nurse consultations, nurse continuity, patient costs, and availability of telephone or education support. Participants (aged 71±13 yrs, 72.5% male, 25.3% NYHA class III/IV) displayed two distinct preference classes. A latent class model of the choice data indicated 56% of participants preferred clinic delivery, access to group CHF education classes, and lower cost programs (p<0.05). The remainder preferred home-based CHF-MPs, monthly rather than weekly visits, and access to a phone advice service (p<0.05). Continuity of nurse contact was consistently important. No significant association was observed between program preference and participant allocation in the parent trial. WTP was estimated from the model and a dichotomous bidding technique. For those preferring clinic, estimated WTP was ≈AU$9-20 per visit; however for those preferring home-based programs, WTP varied widely (AU$15-105). CONCLUSIONS/SIGNIFICANCE: Patient preferences for CHF-MPs were dichotomised between a home-based model which is more likely to suit older patients, those who live alone, and those with a lower household income; and a clinic-based model which is more likely to suit those who are more socially active and wealthier. To optimise the delivery of CHF-MPs, health care services should consider their patients' preferences when designing CHF-MPs.

Exploring the potential to remain "Young @ Heart": initial findings of a multi-centre, randomised study of nurse-led, home-based intervention in a hybrid health care system.

BACKGROUND: Disease management programs have been shown to improve health outcomes in high risk individuals in many but not all health care systems. METHODS: Young @ Heart is a multi-centre, randomised controlled study of a nurse-led, home-based intervention (HBI) program vs. usual care (UC) in privately insured patients in Australia aged ≥ 45 years following an acute cardiac admission. Intensity of HBI is tailored to an individual's clinical stability, management and risk profile. The primary endpoint is the rate of all-cause stay during a mean of 2.5 years follow-up. RESULTS: A target of 602 adults (72% men) were randomised to HBI (n=306) or UC (n=296); their initial profiles being well matched. At baseline, 71% were overweight (body mass index 29.7 ± 3.9 kg/m(2)) and 66% had an elevated blood pressure (153 ± 18/89 ± 7 mm Hg). Over half had a history of smoking and 39% had a sub-optimal total cholesterol level >4 mmol/L. Overall, 62% (376 cases) were treated for coronary artery disease (27% with multi-vessel disease and 39% underwent cardiac revascularisation). A further 20% (120 cases) were treated for a cardiac arrhythmia (predominantly atrial fibrillation) and 19% type 2 diabetes mellitus. At 7-14 days post-discharge, 293 (96%) HBI patients received a home visit triggering urgent clinical review and/or enhanced clinical management in many patients. CONCLUSIONS: The Young @ Heart intervention is a well accepted and potentially effective intervention to reduce recurrent hospital stay in privately insured cardiac patients in Australia.

Protective role of coenzyme Q10 in two models of rat lung injury.

BACKGROUND: Ischaemia-reperfusion injury is a life-threatening complication of lung transplantation. Attempts to ameliorate this injury have included optimization of donor management and improving techniques of lung preservation. However, few investigators have sought to pretreat potential recipients. Coenzyme Q(10) (CoQ(10)) is a potent antioxidant and cellular energizer that has been shown to protect the heart against injury. However, its protective effect in the lung is unknown. We therefore set out to study the impact of Coenzyme Q(10) pretreatment in a model of mild and severe lung injury. METHODS: We evaluated the impact of CoQ(10) in a two-stage laboratory study. In the first stage, in order to measure the magnitude of increase in tissue and plasma CoQ(10) following oral therapy we administered high-dose oral CoQ(10) to rats (n = 6). In the second stage we evaluated the impact of CoQ(10) in the rat lung (n = 10) that was subjected to 230 min of normoxic lung injury or 90 min of warm ischaemia and 120 min of reperfusion in a model of lung transplantation. RESULTS: High-dose oral CoQ(10) for 7 days produced a 15-fold increase in plasma and a 3-fold increase in lung CoQ(10). In the normoxic lung, the injury-induced rise in peak airway pressure was reduced by CoQ(10) treatment at 90 min (P = 0.037) and at 120 min (P = 0.005) without any change in arterial oxygen. In the lung subjected to severe ischaemia-reperfusion injury, CoQ(10) did not reduce the injury-induced increase in peak airway pressure (P = 0.599) nor the decrease in arterial oxygen (P = 0.844). However, CoQ(10) markedly reduced the increase in tumour necrosis factor-alpha in ischaemic compared with normoxic lung (P = 0.027). CONCLUSIONS: The effect of CoQ(10) pretreatment is insufficient to protect the lung against severe ischaemia-reperfusion as may occur in lung transplantation. However, in the setting of less severe pulmonary injury as in anaesthesia and non-transplant surgery, CoQ(10) may have a protective role.

High-flow endobronchial cooled humidified air protects non-heart-beating donor rat lungs against warm ischemia.

OBJECTIVE: Lungs from non-heart-beating donors for transplantation require protection against warm ischemic damage. Minimally invasive techniques are required to reduce organ damage during the warm ischemic period because invasive surgical procedures are often not feasible at this time. This study investigated the preservative effect of high-flow endobronchial cooled humidified air during warm ischemia in non-heart-beating donor rat lungs. METHODS: Fourteen animals were divided into a Cooling group (n = 7), which received cooled air/saline spray during a 2-hour warm ischemic period, and a Control group (n = 7), which received no cooling. After ischemia the lungs were reperfused on an isolated lung perfusion apparatus. RESULTS: Endobronchial temperatures in the Cooling and Control groups were 8 degrees C and 36 degrees C at 10 minutes, and 5 degrees C and 35 degrees C at 20 minutes, respectively (P < .0001). Lung core and surface temperatures in the Cooling group were also lower than those in the corresponding Control group (P < .0001). After reperfusion, pulmonary arterial pressure (P = .003) and peak airway pressure (P = .002) were lower in the Cooling group than in the Control group. Higher pulmonary venous PO2 (P = .02), higher adenosine triphosphate levels (P = .01), and lower wet/dry lung weight ratio (P = .003) were seen in the Cooling group compared with the Control group. CONCLUSIONS: High-flow endobronchial cooled humidified air can decrease lung temperature and improve post-ischemic pulmonary function and adenosine triphosphate levels in non-heart-beating donor lungs.