Outcomes of Patients With Diffuse Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation Treated With Conventional Therapy.

OBJECTIVE: The study objective was to determine the event-free survival (EFS) of Australian patients with diffuse cutaneous systemic sclerosis (dcSSc) who met eligibility criteria for autologous stem cell transplant (ASCT) in previously published randomized controlled trials but were not treated with ASCT. METHODS: Patients who met inclusion criteria for the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) and Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trials were identified from the multicenter Australian Scleroderma Cohort Study (ASCS). EFS (survival without cardiac, renal, or pulmonary failure or death) at 4 years was assessed. ASCS patients who had already undergone transplantation were excluded from analysis. RESULTS: Of the 492 patients with dcSSc in the ASCS, 56 met ASTIS inclusion criteria for ASCT (56 of 492 [11.4%]) and 30 met SCOT inclusion criteria (30 of 492 [6.1%]). An additional 11 patients met ASTIS or SCOT inclusion criteria, but they were excluded due to severe organ manifestations. EFS at 4 years in ASCS patients meeting ASTIS inclusion criteria was 83.3% and in ASCS patients meeting SCOT inclusion criteria was 81.2%. EFS at 4 years in ASCS patients who met ASTIS and SCOT inclusion but also exclusion criteria was 46.7% and 45.7%, respectively. CONCLUSION: ASCS patients meeting ASTIS and/or SCOT inclusion criteria who were not treated with ASCT have similar EFS at 4 years as patients receiving ASCT and better EFS than those receiving cyclophosphamide in the ASTIS and SCOT trials. This may reflect confounders unable to be controlled for, including survivor bias, but may also reflect improved standard of care for dcSSc over time.

Evaluation of the European Society of Cardiology Risk Assessment Score in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Patients with pulmonary arterial hypertension (PAH) may be stratified as low, intermediate, or high risk of 1-year mortality. In 2022, the European Society of Cardiology (ESC) updated and simplified its risk stratification tool, based on three variables: World Health Organization functional class, serum N-terminal pro-brain type natriuretic peptide and six-minute walk distance, applied at follow-up visits, intended to guide therapy over time. METHODS: We applied the 2022 ESC risk assessment tool at baseline and follow-up (within 2 years) to a multinational incident cohort of systemic sclerosis-associated PAH (SSc-PAH). Kaplan-Meier curves, Cox hazards regression, and accelerated failure time models were used to evaluate survival by risk score. RESULTS: At baseline (n = 260), the majority of SSc-PAH (72.2%) were graded as intermediate risk of death according to the 2022 tool. At follow-up, according to 2022 tool, half (55.5%) of the cohort were classified as low or intermediate-low risk. The 2022 risk model at follow-up was able to differentiate survival between risk strata. All three individual parameters (World Health Organization functional class, N-terminal pro-brain type natriuretic peptide, six-minute walk distance) were significantly associated with mortality at baseline and/or follow-up. CONCLUSION: The 2022 ESC risk assessment strategy applied at baseline and follow-up predicts survival in SSc-PAH. Treatment decisions for SSc-PAH should include risk assessments, aiming to achieve low-risk status according to the 2022 ESC guidelines.

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.

Associations of metabolic syndrome in SLE.

OBJECTIVES: To characterise the prevalence and associations of metabolic syndrome (MetS) in a multiethnic cohort of patients with SLE. METHODS: Using a standardised protocol, baseline demographics, per visit disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K) and treatment data, and annual recording of organ damage accrual (Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index) were captured on patients with SLE from a single tertiary centre. The presence of MetS, defined using modified updated joint consensus criteria, was assessed at the final visit from patient records. Serum concentrations of adipocytokines were measured by Quantibody. RESULTS: 116 patients, with median (Q1, Q3) age at enrolment of 39.5 (31.4-51.1) years and disease duration of 6.1 (1.4-12) years, were followed for a median of 6.7 (4.1-8.1) years. The prevalence of MetS was 29% (34/116), while the prevalence of MetS components varied: hypertension (59%), low high-density lipoproteins (HDLs) (51%), hypertriglyceridaemia (32%), obesity (16%) and hyperglycaemia (22%). In univariable analysis, MetS was associated with baseline organ damage (OR 4.34; 95% CI 1.80 to 10.48; p<0.01) and organ damage accrual (OR 2.34; 95% CI 1.02 to 5.36; p=0.04) but not with disease activity. In multivariable analysis, baseline organ damage remained significantly associated with MetS (adjusted OR 3.36; 95% CI 1.32 to 8.59; p=0.01). Glucocorticoid use was not associated with MetS or any of its five components. High serum concentrations of resistin were significantly negatively associated with MetS (OR 0.17; 95% CI 0.04 to 0.70; p=0.014). CONCLUSION: MetS was common in a multiethnic cohort of patients with SLE, with the most frequent components being hypertension and low HDL. An independent association was found between MetS and organ damage but not glucocorticoid exposure or disease activity.

Factors associated with damage accrual in patients with systemic lupus erythematosus with no clinical or serological disease activity: a multicentre cohort study.

BACKGROUND: Evaluating the contribution of glucocorticoid use to organ damage in systemic lupus erythematosus is confounded by glucocorticoid use in active disease. We sought to determine the independence of the contribution of glucocorticoid use to damage accrual from associations with disease activity by analysing patients without measurable disease activity. METHODS: Patients (age >18 years) who met the criteria for systemic lupus erythematosus were recruited from 13 centres in Australia, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand, and followed longitudinally. Disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and Physician Global Assessment [PGA] scores) and treatment details were recorded at each visit (at least once every 6 months), and organ damage measured annually according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Glucocorticoid use during the study period was recorded as any exposure to prednisolone, cumulative prednisolone exposure, and time-adjusted mean daily prednisolone dose. Multivariate survival analyses were used to examine time-dependent associations of glucocorticoid use with damage accrual (defined as an increase of ≥1 on SDI). A SLEDAI-2K score of 0 was taken to indicate the absence of clinical and serological disease activity; a subset of patients without disease activity during the study were defined by a time-adjusted mean SLEDAI-2K (AMS) score of 0. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited. Over a median observation period of 2·2 years (IQR 1·5-3·0), damage accrual events were observed in 255 (14·9%) patients. 1405 (82·3%) of patients were exposed to prednisolone, with a median time-adjusted mean prednisolone dose of 5·0 mg/day (IQR 1·9-8·8). As SLEDAI-2K and PGA scores were highly correlated, two multivariable models were set, each including one of these two variables. In the model including AMS score, baseline SDI damage (SDI >0) was independently associated with damage accrual (HR 1·32 [95% CI 1·01-1·73], p=0·0427). In the other model, time-adjusted mean PGA score was independently associated with damage accrual (1·05 [1·02-1·08], p=0·0012). In both models, factors independently associated with damage accrual included time-adjusted mean prednisolone dose, age at enrolment, and ethnicity (Asian vs non-Asians). 157 (9·2%) patients had an AMS score of 0 (no disease activity), among whom 103 (65·6%) had glucocorticoid exposure and the median time-adjusted mean prednisolone dose was 2·0 mg/day (IQR 0·0-5·0). Accrual of irreversible organ damage occurred in 21 (13·4%) of these patients and was independently associated with time-adjusted mean prednisolone dose (HR 1·14 [95% CI 1·03-1·26], p=0·0117), time-adjusted mean PGA score (1·13 [1·03-1·23], p=0·0144), and age at enrolment (1·04 [1·01-1·07], p=0·0061), but not baseline SDI damage (0·94 [0·43-2·06], p=0·8675). INTERPRETATION: Glucocorticoid use contributes to damage accrual in systemic lupus erythematosus independently of the presence of clinical or serological disease activity. FUNDING: UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca (to the Asia-Pacific Lupus Collaboration).

It hasn't gone away: the problem of glucocorticoid use in lupus remains.

The treatment of SLE remains complex, and management is constrained by a lack of safe, effective, targeted therapies. Physicians, also, are constrained by a lack of evidence-based approaches with existing agents, including glucocorticoids, utilized in the majority of patients. While Cushingoid side effects of glucocorticoids are widely recognized, emerging literature now suggests that glucocorticoid use actually contributes to harmful outcomes in SLE, over and above these effects. These studies provide a compelling case for a re-evaluation of the long-term use of glucocorticoids in SLE, focusing on minimizing glucocorticoid exposure as part of the strategy to improve long-term outcomes. In this article, we review the evidence for the harmful effects of glucocorticoids in SLE, and propose therapeutic options that reduce reliance on glucocorticoids. We propose that it is time for the lupus community to have a louder conversation about glucocorticoid use, and for any residual complacency about their risk-benefit ratio to be banished.

Independent association of glucocorticoids with damage accrual in SLE.

OBJECTIVES: To determine factors associated with damage accrual in a prospective cohort of patients with SLE. METHODS: Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. RESULTS: A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI. CONCLUSIONS: Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

Systemic lupus erythmatosus - When to consider and management options.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by multi-system manifestations. It is regarded as the prototypal connective tissue disease, where the key pathogenesis relates to a dysfunctional immune system that results in over-production of various autoantibodies. Most of its pathology is mediated by either direct or indirect effects of these autoantibodies, as well as other components of the innate and adaptive immune systems.