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Objective: The aim of this study was to determine the impact of season, temperature and humidity on the severity of Raynaud phenomenon (RP) in systemic sclerosis., Methods: Data from the Australian Scleroderma Cohort Study were used 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 Short Form 36 instrument., Results: Among 1,972 patients with systemic sclerosis, RP was a near-universal finding, and worsened RP in the preceding month was reported in 26.7% of 9,175 visits. "Worsened RP" showed significant environmental variability. On multivariable analysis, worsened RP was associated with low mean maximum temperatures (odds ratio [OR] 0.91, 95% confidence interval [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, as well as demonstrating an association with anticentromere antibody and gastroesophageal reflux disease 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., (© 2024 American College of Rheumatology.)

Introduction/objectives: To identify the frequency, correlates and progression of frailty in systemic sclerosis (SSc)., Method: All Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria with a calculable FRAIL Scale score were included. FRAIL Scale scores were calculated annually and were used to group participants as 'robust', 'pre-frail' or 'frail'. Progression of frailty over time was examined by comparing first-recorded, highest-recorded and last-recorded FRAIL Scale scores for each participant. Determinants of frailty at each visit were evaluated with ordinal logistic regression. Survival was analysed using Cox hazard modelling., Results: Of 1703 participants, 14% and 53% met criteria for frailty or pre-frailty respectively, with 33% consistently robust. Among initially frail participants, 40% remained frail and 60% improved to pre-frailty/robustness. Of pre-frail participants, 15% became frail while 32% improved to robustness. One-third of initially robust participants progressed to pre-frailty/frailty. SSc-specific determinants of frailty included diffuse SSc (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.1-1.8, p < 0.01), pulmonary arterial hypertension (OR 7.1, 95% CI 5.1-9.9, p < 0.01), interstitial lung disease (OR 1.6, 95% CI 1.3-2.0, p < 0.01), proximal weakness (OR 1.5, 95% CI 1.2-2.0, p < 0.01) and lower-tract gastrointestinal symptoms (OR 1.5, 95% CI 1.3-1.8, p < 0.01). Older age (OR 1.1, 95% CI 1.1-1.2, p < 0.01), raised CRP (OR 1.7, 95% CI 1.4-2.0, p < 0.01) and anaemia (OR 1.4, 95% CI 1.2-1.7, p < 0.01) were also significantly associated with frailty. A graded risk of death was observed with the diagnosis of pre-frailty and frailty states (hazard ratio (HR) 3.5, 95% CI 2.6-4.8, p < 0.01; and HR 9.8, 95% CI 6.8-14.1, p < 0.01 respectively). Frailty and pre-frailty were associated with reduced health-related quality-of-life and physical function (p < 0.05)., Conclusions: Frailty and pre-frailty are common in SSc and contribute to morbidity and mortality. Both SSc and non-SSc determinants of frailty exist. Frailty in SSc is a dynamic phenomenon with potential to deteriorate or improve over time., Competing Interests: Compliance with ethical standards. Competing interests: SP has received honoraria from Janssen and Boehringer Ingelheim. JS and JW have received honoraria from Boehringer Ingelheim Pty Ltd. WS has received consultancies from Jansen and Boehringer-Ingelheim. MN has received honoraria or consultancies from Janssen, AstraZeneca, GlaxoSmithKlein, Boehringer-Ingelheim and Bristol-Myers Squibb. JF has received conference sponsorship from Pfizer and honoraria from Boehringer-Ingelheim. LH has been a paid speaker for the Limbic publication and received honoraria from Janssen and Abbvie. The other authors declare no competing interests. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: To define the frequency and associations of opioid use in SSc., Methods: Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc were included. Current or previous opioid use was recorded at each visit, with long-term use defined as use on two or more consecutive visits. Groups were compared using two-sample t -test, Wilcoxon rank sum test or chi-squared test. Generalised estimating equations were used to model longitudinal data., Results: Of 1951 participants with a mean age of 46.7 years (s.d. 14.4), 88% were female and 12% had ever received any opioids since SSc onset. Of these, 46% recorded opioid use across multiple consecutive study visits. Digital ulcers (63% vs 52%), synovitis (57% vs 38%), interstitial lung disease (37% vs 27%), gastrointestinal (GI) symptoms (upper 97% vs 88%, lower 90% vs 80%) and immunosuppression (59% vs 46%) were all more frequent in opioid-exposed groups ( P  < 0.05). In multivariable modelling, current opioid use at each study visit was associated with digital ulcers [odds ratio (OR) 1.5 (95% CI 1.1, 2.0), P  = 0.01], synovitis [OR 1.5 (95% CI 1.1, 2.1), P  = 0.02], lower GI symptoms [OR 1.8 (95% CI 1.3, 2.6), P  < 0.01] and poorer physical [OR 1.8 (95% CI 1.3, 2.4), P  < 0.01] and mental [OR 1.8 (95% CI 1.1, 3.0), P  = 0.02] quality of life (QoL). Current opioid use was associated with worse fatigue [regression coefficient (RC) 3.0 units (95% CI 1.2, 4.8), P  < 0.01], functional disability [RC 0.2 (95% CI 0.2, 0.3), P  < 0.01], dyspnoea [RC 2.0 (95% CI 0.8, 3.1), P  < 0.01], depression [RC 2.5 (95% CI 0.9, 4.0), P  < 0.01] and anxiety [RC 2.5 (95% CI 0.9, 4.0), P  < 0.01]., Conclusions: Opioid use in SSc was associated with musculoskeletal, GI and lung involvement. Opioid prescription was associated with poorer QoL and physical function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Organ damage in systemic sclerosis (SSc) in individual organs such as the lungs may be prevented by immunosuppressive drugs (IS). A new measure of global organ damage, the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI), has allowed us to investigate whether IS may reduce global organ damage accrual in early SSc., Methods: This was a retrospective study of patients with < 2 years disease duration in Canadian and Australian SSc cohorts. Patients with either limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) SSc were observed separately and divided into ever or never exposed to IS groups. The SCTC-DI was the outcome and inverse probability of treatment weighting (IPTW) was used to balance the study groups and to fit a marginal structural generalized estimating equation (GEE) model., Results: In the lcSSc cohort, there were 210 subjects of which 34% were exposed to IS at some time. Exposure to IS was associated with lower damage scores. In the dcSSc cohort, there were 192 subjects of which 76% were exposed to IS at some time. Exposure to IS was not associated with damage scores., Conclusion: In this retrospective observational cohort study, using IPTW to adjust for confounders, we found a protective effect of the use of IS on damage accrual in lcSSc. We were unable to determine such an effect in dcSSc but unknown confounders may have been present and prospective studies of IS in dcSSc should include the SCTC-DI to determine the possible effect of IS on damage accrual., (This article is protected by copyright. All rights reserved.)

Introduction: Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression., Methods: The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat., Results: VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing., Conclusions: The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat., Trial Registration: VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580)., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: D.K. is currently or in the recent past has been consultant to Amgen, Argenx, AstraZeneca, Boehringer Ingelheim, Chemomab, Cabaletta Bio, CSL Behring, GSK, Janssen, Merck, Novartis, Prometheus and Zura Bio. He has received grants from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim and Pfizer. J.d.V.-B. has received grant/research support to her institution from ReumaNederland (Dutch patient Society for Rheumatology), Nationale Vereniging voor mensen met lupus, APS, sclerodermie en MCTD (Dutch patient society), ARCH (Autoimmune Research and Collaboration Hub; Dutch interdisciplinary society for patients and caregivers), Roche, Galapagos, Janssen-Cilag and Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Janssen-Cilag and AbbVie (payments made to institution); speaker fees from Dutch Society of Rheumatology (payments made to institution), Boehringer Ingelheim (payments made to institution) and Janssen-Cilag (payments made to institution). A.-M.H.-V. has received research funding and/or consulting fees and/or other remuneration from Arxx, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, Janssen, Medscape, Merck Sharp & Dohme, Novartis, Pliant Therapeutics and Roche. She is also group leader for the EULAR study group on the lung in rheumatic and musculoskeletal diseases. M.K. has received consulting fees, speaking fees and/or research grants from Argenx, Asahi Kasei Parma, AstraZeneca, Boehringer Ingelheim, Chugai, GSK, Janssen, Kissei, MBL, Mochida, Ono Pharmaceuticals and Tanabe-Mitsubishi. A.H.L.L. has received consultancy funds from Boehringer Ingelheim and Janssen. She has received research grant support from Boehringer Ingelheim, National Medical Research Council, Asia-Pacific League of Associations for Rheumatology and Reverie Rheumatology Research Fund. She is medical advisor to Neuquin Biopharma Pte Ltd. S.P. has received research funding, consulting fees or speaker’s fees from Boehringer Ingelheim and Janssen. M.F., A.K. and N.F. are employees of Boehringer Ingelheim International GmbH. O.D. has/had a consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, AbbVie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Cantargia AB, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Nkarta Inc., Novartis, Orion, Prometheus, Redxpharma, Roivant, EMD Serono, Topadur and UCB. He has a patent issued: ‘mir-29 for the treatment of systemic sclerosis’ (US8247389, EP2331143) and is co-founder of CITUS AG., (© The Author(s) 2024.)

Objective: Accurate measurement of disease activity in systemic sclerosis (SSc) remains a significant clinical challenge. The Scleroderma Clinical Trials Consortium (SCTC) convened an Activity Index (AI) Working Group (WG) to develop a novel measure of disease activity (SCTC-AI)., Methods: Using consensus methodology, we developed a conceptual definition of disease activity. Literature review and expert consensus generated provisional SCTC-AI items, which were reduced by Delphi survey. Provisional items were weighted against a combined endpoint of morbidity and mortality, using time-dependent Cox proportional hazards regression analysis of the Australian Scleroderma Cohort Study (ASCS) (n = 1,254). External validation of the SCTC-AI was performed using data collected from 1,103 Canadian Scleroderma Research Group Study participants., Results: Disease activity in SSc was defined using consensus methodology as "aspects of disease that are reversible, or can be arrested, with time and, or effective therapy." One-hundred and forty-one provisional SCTC-AI items were generated and reduced using three rounds of Delphi survey and statistical reduction and weighting, against mortality and quality of life measures, yielding a final 24-item index with a maximum possible score of 140. Survival analysis in an external cohort showed a graded relationship between disease activity scores and survival (P < 0.01)., Conclusion: We present a novel instrument to quantify the burden of disease activity in SSc. We have employed a rigorous consensus-based process in combination with data-driven methods to develop an instrument that has face, content, and criterion validity. Further work is required to fully validate and confirm the construct and discriminative validity of the SCTC-AI., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups., Methods: Participants with sera, high-resolution CT and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. Twenty-seven of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc., Results: A total of 407 participants were identified, 252 (61.9%) with SSc-ILD. The median (interquartile range) follow-up after biomarker measurement was 6.31 (3.11-9.22) years. Sixteen biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality [hazard ratio (HR) 3.55; 95% CI 2.37-5.33; P < 0.001]. Five additional biomarkers had an HR >2: SP-D (2.28, 1.57-3.31; P < 0.001), E-selectin (2.19, 1.53-3.14; P < 0.001), IL-6 (2.15, 1.50-3.09; P < 0.001), MMP-3 (2.05, 1.42-2.95; P < 0.001) and ET-1 (2.03, 1.40-2.92; P < 0.001). Eleven biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at 1-year follow-up: CXCL4 (odds ratio 2.67, 1.46-4.88; P = 0.001), MMP-1 (2.56, 1.43-4.59; P = 0.002) and ET-1 (2.18, 1.24-3.83; P = 0.007)., Conclusion: Multiple biomarkers, especially VCAM-1, E-selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Scleroderma renal crisis (SRC) is associated with high morbidity and mortality and there remain unmet needs regarding early identification and treatment. We aimed to assess risk factors for and the outcomes of SRC at a large Australian tertiary hospital., Methods: Seventeen incident SRC cases were diagnosed between 2012 and 2022. Demographic, SSc manifestations and treatment data were extracted. Using data from the Australian Scleroderma Cohort Study ( n  = 483), logistic regression analysis was performed to identify risk factors for SRC., Results: The prevalence of SRC was 3.52%. The median SSc disease duration at SRC onset was 2 years [interquartile range (IQR) 1-4]. Peak creatinine occurred at a median of 11 days (IQR 5-14) post-SRC diagnosis, with a median peak creatinine of 144 µmol/l (IQR 86-306). Nine (52.94%) SRC patients had evidence of acute neurologic and/or cardiac complications. Acute haemofiltration was required in 3 (17.65%) patients. Over the follow-up period, 7 (41.18%) SRC patients died 2.75 years (IQR 0.74-7.25) after SRC onset. Patients with SRC were more likely to be male [odds ratio (OR) 9.73 (95% CI 3.57, 26.56)], have diffuse disease [OR 23.16 (95% CI 5.22, 102.80)] and have antibodies to Scl70 [OR 3.34 (95% CI 1.24, 9.04)] or RNA polymerase III (RNAPIII) [OR 5.15 (95% CI 1.91, 13.89)]., Conclusion: SRC is an uncommon manifestation, but outcomes remain poor. A significant proportion of patients presenting with SRC in Australia are positive for Scl70 or RNAPIII antibody. Despite relatively low peak serum creatinine and rates of renal replacement therapy, SRC was still associated with significant mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aims: Our previous work identified pain, fatigue, and independence as missing from the ACR/EULAR rheumatoid arthritis (RA) remission criteria from the patient perspective. Validated measures exist for pain and fatigue, but not for independence. As a first step towards developing such a measure, this study aimed to understand 'Independence' in the context of RA remission from the patient perspective., Methods: International qualitative research study comprising five focus groups of 19 participants with RA. Data were analysed using reflexive thematic analysis., Results: Five overarching themes were identified, underpinned by a construct of "stages of independence". Independence means at least being 'physically and functionally able' but may go beyond this and enable 'participation beyond function', 'cognitive independence', and 'having or taking control'. There was no agreement on whether assistance is an aid to independence or undermines ability to achieve independence ('assistance is complicated'). The construct "Stages of independence" acknowledges that Independence may mean different things to different patients and there may be other factors beyond disease activity that hold patients in each of these stages., Conclusion: These novel data suggest a desirable definition of independence includes full active participation without the need to consider or work around disease activity, and cognitive independence from thoughts of RA. Independence in RA remission is a complex concept and next steps will be to seek patient and professional agreement on the most important issues raised in these focus groups to take forward to developing a measure for independence in the context of RA remission from the patient perspective., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Flurey and Susanna Proudman reports financial support was provided by Arthritis Australia. Caroline Flurey reports a relationship with LUPUS UK that includes: funding grants. Caroline Flurey reports a relationship with Pearson Global that includes: consulting or advisory. Caroline Flurey reports a relationship with Men and Boys Coalition that includes: board membership. Lynn March reports a relationship with OMERACT that includes: board membership. Lynn March reports a relationship with Australian Government medical research grants that includes: funding grants. Lynn March reports a relationship with Janssen Australia Pty Ltd that includes: funding grants. Lynn March reports a relationship with CLEARbridge Foundation that includes: funding grants. Lynn March reports a relationship with Northern Sydney Local Health District that includes: travel reimbursement. Lynn March reports a relationship with Australian Rheumatology Association that includes: board membership. Lynn March reports a relationship with Australian Arthritis & Autoimmune Biobank Collaborative that includes: board membership. Dorcas Beaton reports a relationship with OMERACT that includes: board membership. Beverley Shea reports a relationship with OMERACT that includes: board membership. Susanna Proudman reports a relationship with Boehringer-Ingelheim that includes: board membership, funding grants, and speaking and lecture fees. Susanna Proudman reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants and speaking and lecture fees. Peter Tugwell reports a relationship with Reformulary Group that includes: consulting or advisory. Peter Tugwell reports a relationship with OMERACT that includes: board membership. Peter Tugwell reports a relationship with UCB Biopharma GmbH & SPRL that includes: board membership. Peter Tugwell reports a relationship with Parexel International that includes: board membership. Peter Tugwell reports a relationship with Prahealth Sciences that includes: board membership. Peter Tugwell reports a relationship with AbbVie Inc that includes: funding grants. Peter Tugwell reports a relationship with AstraZeneca Pharmaceuticals LP that includes: funding grants. Peter Tugwell reports a relationship with Aurinia that includes: funding grants. Peter Tugwell reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Peter Tugwell reports a relationship with Centrexion that includes: funding grants. Peter Tugwell reports a relationship with GSK that includes: funding grants. Peter Tugwell reports a relationship with Horizon Pharmaceuticals Inc that includes: funding grants. Peter Tugwell reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Peter Tugwell reports a relationship with Novartis that includes: funding grants. Peter Tugwell reports a relationship with Pfizer Inc that includes: funding grants. Peter Tugwell reports a relationship with Sparrow Pharmaceuticals Inc that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Systemic sclerosis is a debilitating inflammatory condition synonymous with gastrointestinal symptoms which have the potential to impact dietary intake and nutritional status. This study aimed to describe symptoms experienced by patients with systemic sclerosis that may impact on dietary intake and assess nutrition education preferences in this cohort., Methods: A 24-item online qualitative and quantitative survey distributed via REDCap ® was conducted in adult patients (aged ⩾18 years) living with systemic sclerosis and attending outpatient services at a single healthcare setting from January to March 2022. Data were collected on demographics, symptoms that may impact dietary intake, nutrition priorities and preferred nutrition education models. Data are mean ± standard deviation or number (%)., Results: Of 322 eligible patients, 156 (48%) participated (63 ± 12 years, 86% female, body mass index 27 ± 7 kg/m 2 ). Most patients experienced gastrointestinal conditions (n = 123/155; 79%), which occurred daily in 26% (n = 40/155) of patients. A third of patients (n = 48/156; 31%) reported diet manipulation for symptom management. Recent weight loss was common (n = 36/154; 23% of patients). Less than a third of patients had seen a dietitian (n = 45; 29%), while 69% of patients (n = 107) desired dietetic consultancy. The preferred methods of consultation were written resources and face-to-face, respectively, and systemic sclerosis symptom management (n = 100; 64%) and losing weight (n = 53; 34%) were the most desired education topics reported., Conclusion: Gastrointestinal conditions are common and occur frequently in patients with systemic sclerosis. Patients want to engage with dietetics services to better manage symptoms via face-to-face consultations and written resources. These results will inform future dietetic service delivery., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Professor S.P. is on the Editorial Board of JSRD and is an author of this paper; therefore, the peer-review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process., (© The Author(s) 2024.)

Objective: Physician global assessments (PhyGAs) are variably applied in systemic sclerosis (SSc) clinical trials. The comparability of different PhyGA results is unknown. We sought to assess the comparability of results from three different PhyGA instruments simultaneously applied in the Australian Scleroderma Cohort Study (ASCS)., Methods: Using data from 1,965 ASCS participants, we assessed the correlation between results of three PhyGA assessments: (1) overall health, (2) activity, and (3) damage. We evaluated the concordance of change in each PhyGA between study visits. Ordered logistic regression analysis was used to evaluate the clinical associations of each PhyGA., Results: The absolute scores of each PhyGA were strongly correlated at individual study visits. Concordant changes of the PhyGA scores occurred between 50% of study visits. Only patient-reported breathlessness was associated with all three PhyGA scores (overall health: odds ratio [OR] 1.67, P < 0.01; activity: OR 1.44, P < 0.01; damage: OR 1.32, P < 0.01). Changes in physician-assessed activity scores were also associated with patient-reported worsening skin disease (OR 1.25, P = 0.03) and fecal incontinence (OR 1.23, P = 0.01), whereas damage scores were associated with respiratory disease (pulmonary arterial hypertension: OR 1.25, P = 0.03; chronic obstructive pulmonary disease: OR 1.37, P = 0.04), as well as skin scores (OR 1.02, P < 0.01) and fecal incontinence (OR 1.21, P = 0.02)., Conclusion: PhyGAs of overall health, activity, and damage are each associated with different SSc features, and changes in different PhyGA scores are discordant 50% of the time. Our findings suggest results of variably worded PhyGAs are not directly interchangeable and support the development of a standardized PhyGA., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The Australian Scleroderma Interest Group (ASIG) algorithm for screening pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) requires only respiratory function tests and serum N-terminal pro-brain natriuretic peptide as first-tier tests, and is recommended in international guidelines. In this communication, we present the findings of the application of the ASIG screening algorithm to a Singaporean cohort undergoing prospective annual screening for PAH, which shows a high negative predictive value. The ASIG algorithm may offer an alternative to more complex and costly SSc-PAH screening algorithms., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Objectives: To identify the trajectories and clinical associations of functional disability in systemic sclerosis (SSc)., Methods: Australian Scleroderma Cohort Study (ASCS) participants meeting ACR/EULAR criteria for SSc recruited within 5 years of disease onset, with ≥2 Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were included. Group based trajectory modelling (GBTM) was used to identify the number and shape of HAQ-DI trajectories. Between group comparisons were made using the chi-squared test, two-sample t-test or Wilcoxon rank-sum test as appropriate. Multiple logistic regression was used to identify features associated with trajectory group membership. Survival analyses were performed using Kaplan Meier and Cox proportional hazard modelling., Results: We identified two HAQ-DI trajectory groups within 426 ASCS participants with incident SSc: low-stable disability (n=221, 52%), and high-increasing disability (n=205, 48%). Participants with high-increasing disability were older at disease onset, more likely to have diffuse SSc (dcSSc), cardiopulmonary disease, multimorbidity, digital ulcers, and gastrointestinal involvement (all p≤0.01), as was use of immunosuppression (p<0.01). Multimorbidity was associated with high-increasing trajectory group membership (OR3.1, 95%CI1.1-8.8, p=0.04); independently, multiple SSc features were also strongly associated including dcSSc (OR2.3, 95%CI1.3-4.2, p<0.01), proximal weakness (OR7.3, 95%CI2.0-27.1, p<0.01) and joint contractures (OR2.7, 95%CI1.3-5.3, p<0.01). High-increasing physical disability was associated with an almost two-fold increased risk of mortality (HR1.9, 95%CI1.0-3.8, p=0.05), and higher symptom burden., Conclusions: Two trajectories of functional disability in SSc were identified. Those with high-increasing functional disability had a distinct clinical phenotype and worse survival compared to those with low-stable functional disability. These data highlight the pervasive nature of physical disability in SSc, and its prognostic importance.

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., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To investigate the burden and clinical associations of fatigue in systemic sclerosis (SSc) as measured by FACIT-Fatigue scores., Methods: Australian Scleroderma Cohort Study participants with ≥1 FACIT-Fatigue score were included. Participants were divided into those with incident SSc (≤5 years SSc duration at recruitment and FACIT-Fatigue score recorded within 5 years of disease onset) or prevalent SSc (first FACIT-Fatigue score recorded >5 years after SSc onset). Generalised estimating equations were used to model change in FACIT-Fatigue scores over time, expressed as an increasing (improving) or decreasing (worsening) score., Results: Of 859 participants, 215 had incident SSc and 644 prevalent SSc. First-recorded FACIT-Fatigue scores were similar in those with incident (37 units, IQR 25-45.5) and prevalent SSc (36 units, IQR 23-44; p=0.17), as were lowest-ever recorded FACIT-Fatigue scores (incident 23 units; prevalent 22 units, p=0.75). In incident SSc, higher skin scores (regression coefficient (RC) -1.5 units, 95%CI -2.3 to -0.8), PAH (RC -8.2, 95%CI -16.5 to 0.1) and reduced left ventricular function (RC -10.6, 95%CI -18.3 to -2.8) were associated with more severe fatigue. In prevalent SSc, higher skin scores (RC -0.6, 95%CI -1.3 to 0), gastrointestinal symptoms (RC -6.6, 95%CI -9.0 to -4.2), hypoalbuminaemia (RC -2.8, 95%CI -5.0 to -0.7), BMI<18.5kg/m2 (RC -6.3, 95%CI -10.3 to -2.2), raised CRP (RC -3.1, 95%CI -4.7 to -1.5), and anaemia (RC -1.7, 95%CI -3.5 to 0.1) were associated with more severe fatigue., Conclusions: The burden of fatigue is substantial in both incident and prevalent SSc. Cardiopulmonary and gastrointestinal involvement are associated with worse fatigue.

Objective: To describe the frequency of progressive pulmonary fibrosis (PPF) in an incident cohort of systemic sclerosis (SSc)-related interstitial lung disease (ILD) and its impact on survival., Methods: Incident ILD was defined as the new development of characteristic fibrotic changes on chest HRCT scan. PPF was defined as per the 2022 American Thoracic Society. Determinants of PPF were identified using generalised estimating equations. Impact on survival was analysed using accelerated failure time regression modelling., Results: Of our incident SSc-ILD cases, 38.8% (n = 180) experienced PPF within a 12-month period after ILD diagnosis. Determinants of PPF included older age (OR 1.02, 95%CI 1.00-1.03, P = 0.011), dcSSc (OR 1.54, 95% CI 1.06-2.25, P = 0.024) and SSc-specific antibodies (anticentomere antibody OR 0.51, 95%CI 0.29-0.91, P = 0.021 and anti-Scl-70 antibody OR 1.46, 95%CI 1.01-2.09, P = 0.043). Raised CRP was numerically associated with PPF but did not reach statistical significance (OR 1.29, 95%CI 0.99-1.68, P = 0.064) nor did GORD or dysphagia (OR 1.18, 95%CI 0.57-2.42, P = 0.658 and OR 1.17, 95%CI 0.57-2.40, P = 0.664, respectively). The presence of PPF significantly impacted survival in SSc-ILD (hazard ratio 2.66, 95%CI 1.59-4.41, P < 0.001)., Conclusions: PPF occurred in a third of our incident SSc-ILD cohort; however, its occurrence was significantly associated with mortality indicating an at-risk group who may be suitable for earlier introduction of immunosuppressive and/or antifibrotic therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The importance of early integration of palliative care in the management of complex multisystem diseases has been recognized. In this study, we aimed to quantify the need for specialist palliative care in patients with systemic sclerosis (SSc)., Methods: Using data from 875 patients enrolled in the Australian Scleroderma Cohort Study, we defined the need for palliative care as a high symptom burden at two or more consecutive study visits, at ≥50% of overall study visits, or at the study visit immediately before death. Symptoms of interest included breathlessness, fatigue, pain, depression, anxiety, constipation, and diarrhea. Logistic regression analyses evaluated the association between individual symptoms and SSc manifestations. Linear regression analysis evaluated the relationship between palliative care needs and quality of life (QoL) and function., Results: Almost three-quarters of patients (72.69%) met the threshold for specialist palliative care needs. Severe fatigue (54.17%) was most common, followed by breathlessness (23.66%) and severe constipation (21.14%). Concurrent severe symptoms were frequently observed. Severe breathlessness (coefficient [coef] -7.95, P < 0.01) and pain (coef -7.70, P < 0.01) were associated with the largest reductions in physical QoL. Severe mood symptoms were associated with the greatest reduction in mental QoL (coef -12.91, P < 0.01). Severe pain (coef 0.56, P < 0.01), breathlessness (coef 0.49, P < 0.01), and mood symptoms (coef 0.40, P < 0.01) had a significant impact on function., Conclusion: SSc is frequently associated with multiple severe symptoms that may be amenable to palliative care intervention. Given the strong association between symptom burden and impaired QoL targeted, effective symptom management in parallel with standard-of-care treatments may improve overall patient outcomes., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Tocilizumab (TCZ) is increasingly used as a steroid-sparing agent in giant cell arteritis (GCA), but there are strict Pharmaceutical Benefits Scheme (PBS) restrictions for its use in Australia. Patients who do not meet the PBS criteria can obtain TCZ through public hospital individual patient use (IPU) schemes which may not be universally accessible. We compared patients receiving IPU-approved TCZ with patients receiving PBS-subsidised TCZ and found IPU approvals were granted mainly for visual loss, a serious complication of GCA, in patients who otherwise failed to meet PBS criteria. Further studies demonstrating that TCZ is comparatively more effective than prednisolone monotherapy, as well as cost-effective, are needed to substantiate the rationale for expanding PBS approval criteria., (© 2024 Royal Australasian College of Physicians.)

Objective: To describe the epidemiology, associations, and impact of inflammatory arthritis (IA) in systemic sclerosis (SSc)., Methods: Patients with SSc prospectively enrolled in the Australian Scleroderma Cohort Study were included. IA was defined clinically as the presence of synovitis on examination. Logistic regression was used to determine the associations of IA with SSc manifestations and serological parameters. Patient-reported outcome measures were used to capture physical function and health-related quality of life (HRQoL)., Results: IA was a common SSc manifestation affecting one-third (33.3%) of patients over a median follow-up of 4.3 (1.7-8.4) years. Associations of IA included diffuse SSc (odds ratio [OR] 1.33, 95% confidence interval [95% CI] 1.01-1.74, P = 0.042), concurrent musculoskeletal manifestations (joint contractures and tendon friction rubs, OR 1.70, 95% CI 1.34-2.15, P < 0.001); myositis (OR 2.11, 95% CI 1.39-3.20, P < 0.001), and sicca symptoms (OR 1.57, 95% CI 1.14-2.16, P = 0.006), whereas IA was negatively associated with pulmonary arterial hypertension (OR 0.52, 95% CI 0.35-0.78, P = 0.002). Neither the presence of rheumatoid factor nor U1 small nuclear RNP were associated with IA (OR 1.13, 95% CI 0.88-1.44, P = 0.331, OR 1.46, 95% CI 0.89-2.39, P = 0.129 respectively). Positive anticyclic citrullinated protein antibodies, although at low frequency, were more common in those with IA compared with those without IA (7.5% vs 1.5%, P < 0.001). IA was associated with significantly lower HRQoL score (P < 0.001) and more physical disability than in those without IA (P < 0.001)., Conclusion: IA is a common disease manifestation that is more frquently seen in diffuse disease. IA is associated with poor HRQoL and physical disability. Further research is needed into the effective management of IA in SSc., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: We systematically examined comparative gout flare risk after initiation or escalation of different urate-lowering therapies (ULTs), comparative flare risk with and without concomitant flare prophylaxis, adverse event rates associated with flare prophylaxis, and optimal duration of flare prophylaxis., Methods: We searched the Medline, Embase, Web of Science, and Cochrane databases and clinical trial registries from inception to November 2021 for trials investigating adults with gout initiating or escalating ULT. We performed random effects network meta-analyses and calculated risk ratios (RRs) between treatments. Bias was assessed using the revised Cochrane risk-of-bias tool., Results: We identified 3,775 records, of which 29 publications (27 trials) were included. When compared to placebo plus prophylaxis, the RR of flares ranged from 1.08 (95% confidence interval [CI] 0.87-1.33) for febuxostat 40 mg plus prophylaxis to RR 2.65 [95% CI 1.58-4.45] for febuxostat 80 mg plus lesinurad 400 mg plus prophylaxis. Compared to ULT alone, the RR of flares was lower for ULT plus rilonacept 160 mg (RR 0.35 [95% CI 0.25-0.50]), ULT plus rilonacept 80 mg (RR 0.43 [95% CI 0.31-0.60]) and ULT plus colchicine (RR 0.50 [95% CI 0.35-0.72]). There was limited evidence for other flare prophylaxis and on prophylaxis harms and optimal duration. Primarily because of missing outcome data and bias in the selection of reported results, 71.4% and 63.4% of studies were assessed as high risk of bias for flares and adverse events, respectively., Conclusion: The RR of flares when introducing ULT varies depending on ULT drug and dosing strategies. There were limited data on ULT escalation. Flare prophylaxis with colchicine and rilonacept reduces flare incidence. More research is required on the harms and optimal duration of prophylaxis., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To quantify the frequency and clinical implications of systemic sclerosis (SSc)-associated left ventricular function (LV) impairment., Methods: Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc with ≥1 echocardiographic LVEF measurement were included. Overt LV dysfunction was indicated by reduced LV ejection fraction (LVEF) and subclinical LV dysfunction was measured using impaired LV global longitudinal strain (LV-GLS>-16 %). Those with secondary causes of LV dysfunction (myocardial ischaemia, valvulopathy and pulmonary arterial hypertension) were excluded. Chi-squared tests, two-sample t-tests or Wilcoxon rank-sum tests were used for between-group comparison as appropriate. Generalised estimating equations(GEE) were used to model longitudinal data. Kaplan-Meier and Cox proportional hazard models were used for survival analyses., Results: Of 1141 participants with no co-morbid cardiac disease, 2.4 % ever recorded a LVEF<50 %, while only 0.6 % ever recorded a LVEF≤40 %. LV-GLS data were available for 90 % of participants at one centre (n = 218). Impaired LV-GLS was detected in 21 % despite LVEF≥50 %. Those with a LVEF<50 % were more frequently male (p = 0.01) with dcSSc (p < 0.01), higher inflammatory markers (p < 0.02) and skeletal muscle disease (p < 0.05). In multivariable analyses, recording a LVEF<50 % was associated with increased mortality (HR2.3, 95 %CI1.0-4.8, p = 0.04). Impaired LV-GLS was also associated with poorer survival in univariable analyses (HR3.4, 95 %CI1.0-11.8, p = 0.05). Those with a LVEF<50 % more frequently recorded WHO Class III/IV dyspnoea (OR3.5, 95 %CI1.6-7.7, p < 0.01), with shorter six-minute walk distance (p = 0.01), higher Health Assessment Questionnaire-Disability Index scores (p < 0.01) and lower Short Form-36 Physical Component Summary scores (p = 0.02). Increased dyspnoea (WHO Class III/IV dyspnoea; OR3.6, 95 %CI1.4-9.2, p < 0.01) was also seen in those with impaired LV-GLS., Conclusions: Both overt and subclinical SSc-associated LV dysfunction are associated with worse survival and impaired physical function. The frequency of abnormal LV-GLS in those with consistently normal LVEF suggests an under-appreciated burden of subtle LV systolic dysfunction in SSc that has a significant impact on patient symptomatology., Competing Interests: Declaration of competing interest The Australian Scleroderma Interest Group received research support grants from Actelion. WS has received consulting fees from Boehringer Ingelheim. MN has received consulting fees from Janssen, Boehringer Ingelheim, Astra Zeneca and GSK, and honoraria from Janssen, Boehringer Ingelheim and GSK. JF has received honoraria from Boehringer Ingelheim and conference sponsorship from Pfizer. DP has received speaker fees/honoraria from Boehringer Ingelheim, Novartis and Janssen. LH has been a paid speaker for the Limbic publication and Abbvie. SP has received honoraria from Janssen and Boehringer Ingelheim. JS and JW have received honoraria from Boehringer Ingelheim Pty Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: In this prospective cohort study, we provide several prognostic models to predict functional status as measured by the modified Health Assessment Questionnaire (mHAQ). The early adoption of the treat-to-target strategy in this cohort offered a unique opportunity to identify predictive factors using longitudinal data across 20 years., Methods: A cohort of 397 patients with early RA was used to develop statistical models to predict mHAQ score measured at baseline, 12 months, and 18 months post diagnosis, as well as serially measured mHAQ. Demographic data, clinical measures, autoantibodies, medication use, comorbid conditions, and baseline mHAQ were considered as predictors., Results: The discriminative performance of models was comparable to previous work, with an area under the receiver operator curve ranging from 0.64 to 0.88. The most consistent predictive variable was baseline mHAQ. Patient-reported outcomes including early morning stiffness, tender joint count (TJC), fatigue, pain, and patient global assessment were positively predictive of a higher mHAQ at baseline and longitudinally, as was the physician global assessment and C-reactive protein. When considering future function, a higher TJC predicted persistent disability while a higher swollen joint count predicted functional improvements with treatment., Conclusion: In our study of mHAQ prediction in RA patients receiving treat-to-target therapy, patient-reported outcomes were most consistently predictive of function. Patients with high disease activity due predominantly to tenderness scores rather than swelling may benefit from less aggressive treatment escalation and an emphasis on non-pharmacological therapies, allowing for a more personalized approach to treatment. Key Points • Long-term use of the treat-to-target strategy in this patient cohort offers a unique opportunity to develop prognostic models for functional outcomes using extensive longitudinal data. • Patient reported outcomes were more consistent predictors of function than traditional prognostic markers. • Tender joint count and swollen joint count had discordant relationships with future function, adding weight to the possibility that disease activity may better guide treatment when the components are considered separately., (© 2024. The Author(s).)

Objective: Paediatric proximal humerus fractures (PHFs) have historically been treated non-operatively. However, the management of severely displaced PHFs in older children has been debated over the years, with contemporary studies advocating for surgery. The purpose of this study was to review the outcomes of a cohort of paediatric patients treated for a PHF to guide management of future paediatric PHFs., Methods: The records of the Women's and Children's Hospital in South Australia were reviewed to identify paediatric PHFs occurring between 1 January 2010 and 1 June 2020. Participants completed the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), the Shoulder Pain and Disability Index, and the Paediatric Outcomes Data Collection Instrument via phone interview. Participants' shoulder range-of-motion was assessed via telehealth using Zoom. Multivariable logistic regression was used to identify patient and clinical variables that were associated with a poorer outcome., Results: Of 307 patients contacted, 125 participated. Forty-six patients met the definition of a poorer clinical outcome, defined as a QuickDASH score of ≥2. Fractures of greater severity were predictive of a poorer outcome, and patients aged ≥12 years old at the time of injury had higher total QuickDASH scores. The findings did not suggest that these subgroups of patients have superior outcomes if treated surgically., Conclusion: The majority of paediatric PHFs have an acceptable clinical outcome, irrespective of treatment methodology. Multicentre prospective studies are required to establish the indications for surgery for adolescent patients with severely displaced PHFs., (© 2024 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Objective: To explore, from patients' perspectives, the symptoms and impact of Raynaud's phenomenon (RP) on the feet of patients with systemic sclerosis (SSc-RP), and to identify which foot-related domains are important to patients., Methods: Forty participants (34 women) with SSc-RP took part in one of six focus groups held in the United Kingdom or United States. Participants were purposively sampled to ensure diversity in disease type, duration, and ethnicity. The topic guide included questions on RP impact, self-management, and treatment expectations. Qualitative content analysis was employed to identify key concepts in the data relating to foot-specific symptoms and their impact. Themes were organized by corresponding domains of potential importance., Results: Twenty-eight participants (70 %) reported experiencing RP in their feet. Five themes were identified corresponding to domains of potential importance: temperature changes, pain, cramping and stiffness, numbness, and color changes. These issues negatively affected participants' lives, impairing walking, driving, and socializing, and causing issues with footwear and hosiery., Conclusions: This large qualitative study exploring the experiences of patients with SSc-RP in the feet identified several key domains of high importance to patients. SSc-RP is common in the feet, presents in several patterns, and impacts multiple aspects of patients' lives. These findings indicate where future foot-specific interventions for RP could be targeted. Findings from this study improve understanding of what domains are important to patients with SSc-RP affecting the feet and will contribute to the development of a core outcome set for foot and ankle disorders in rheumatic and musculoskeletal diseases., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the frequency, clinical correlates and implications of clinical evidence of muscle disease in systemic sclerosis (SSc)., Methods: Australian Scleroderma Cohort Study participants with ≥1 creatine kinase (CK) and proximal power assessment were subdivided according to presence of proximal weakness (PW: proximal muscle power<5/5) and CK elevation(≥140IU/L). Participants were assigned to one of four groups: concurrent PW&CK elevation, PW alone, CK elevation alone or neither. Between-group comparisons were made with chi-squared, ANOVA or Kruskal-Wallis tests. Survival analysis was performed using time-varying-covariate Cox regression modelling. Longitudinal data were modelled using multinomial logistic and linear regression., Results: Of 1786 participants, 4 % had concurrent PW&CK elevation, 15 % PW alone, 24 % CK elevation and 57 % neither. Participants with PW&CK elevation displayed a severe, inflammatory SSc phenotype, with more frequent dcSSc(p < 0.01), tendon friction rubs(p < 0.01), synovitis(p < 0.01) and digital ulceration(p = 0.03). Multimorbidity(p < 0.01) and cardiopulmonary disease, including ischaemic heart disease(p < 0.01) and pulmonary arterial hypertension(p < 0.01), were most common in those with PW, with and without CK elevation. Men with anti-Scl70 positivity most frequently had CK elevation alone, without other significant clinical differences. Multivariable modelling demonstrated 3.6-fold increased mortality in those with PW&CK elevation (95 %CI 1.9-6.6, p < 0.01) and 2.1-fold increased mortality in PW alone (95 %CI 1.4-3.0, p < 0.01) compared to those without PW or CK elevation. CK elevation alone conferred better survival (HR 0.7, 95 %CI 0.4-1.1, p = 0.09) compared to those with no PW or CK elevation. PW regardless of CK elevation was associated with impaired physical function, with reduced six-minute-walk-distance (p < 0.01), higher HAQ-DI scores (p < 0.01) and increased patient-reported dyspnoea (p = 0.04)., Conclusion: Clinical features of myopathy are highly prevalent in SSc, affecting almost half of our study cohort. Detection of PW and elevated CK alone, even without imaging or histopathological identification of SSc-myopathy, identified important clinical associations and are associated with poorer function and overall prognosis., Competing Interests: Declaration of competing interest SP has received honoraria from Janssen. JS and JW have received honoraria from Boehringer Ingelheim Pty Ltd. WS has received consultancies from Jansenn and Boehringer-Ingelheim. MN has received honoraria or consultancies from Janssen, AstraZeneca, GlaxoSmithKlein, Boehringer-Ingelheim and Bristol-Myers Squibb. JF has received conference sponsorship from Pfizer and honoraria from Boehringer-Ingelheim. LH has been a paid speaker for the Limbic publication., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To quantify the frequency and impact of malnutrition in systemic sclerosis (SSc), as diagnosed by the Global Leadership Initiative on Malnutrition (GLIM) criteria, based on weight loss, body mass index (BMI) and muscle atrophy., Methods: Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc with ≥1 concurrent weight and height measurement were included. Chi-squared tests, two-sample t-tests or Wilcoxon rank-sum tests were used for between-group comparison as appropriate. Multivariable logistic regression models were used to establish the determinants of malnutrition diagnosis. Kaplan-Meier and Cox proportional hazard models were used for survival analyses, based on malnutrition diagnosis, and individual GLIM criteria (% weight loss, BMI thresholds and presence of muscle atrophy)., Results: In this study of 1903 participants, 43% were diagnosed with malnutrition according to GLIM criteria, of whom 33% had severe malnutrition. Participants diagnosed with malnutrition were older, and more likely to have dcSSc, higher SSc severity scores and RNA polymerase-3 positivity. Gastrointestinal (GI) involvement, multimorbidity, cardiopulmonary disease, raised inflammatory markers, hypoalbuminaemia and anaemia were more common in malnourished participants (p< 0.01). Multimorbidity (OR1.6, 95%CI1.2-2.0, p< 0.01), pulmonary arterial hypertension (OR2.1, 95%CI1.4-2.0, p< 0.01) and upper GI symptoms (OR1.6, 95%CI1.3-2.0, p< 0.01) were all associated with malnutrition.Health-related quality-of-life (HRQoL) and physical function were poorer in malnourished participants. Survival was worse in those with malnutrition after adjusting for age, sex and dcSSc (HR 1.4, 95%CI1.1-1.7, p< 0.01)., Conclusions: Malnutrition is common in SSc and confers poorer survival, HRQoL and physical function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To identify those with concurrent pulmonary hypertension (PH) and interstitial lung disease (ILD) in systemic sclerosis (SSc) and determine their disease severity, therapeutic approach, and survival., Methods: Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study (ASCS) who were diagnosed on right heart catherisation with pulmonary hypertension were included. Logistic regression was used to determine the associations of ILD with PH hemodynamic parameters and therapeutic approach. Kaplan-Meier survival curves were used to estimate survival., Results: Of 1,883 SSc patients, 164 (8.7%) developed incident PH over a median follow up of 4.3 (1.7-7.9) years. Of these, 43.9% had concurrent ILD at PH diagnosis (PH-ILD) and 56.1% had Group 1 PAH. Extensive ILD was present at PH diagnosis in 40.3%. Despite these distinct PH cohorts, a similar frequency of each PH cohort was treated with vasodilatory therapy at PH diagnosis, regardless of the presence or severity of ILD. The majority (87.5%) of those with extensive ILD and PH received upfront vasodilatory therapy at PH diagnosis with no difference in its tolerability or therapy cessation compared with Group 1 PAH. Although vasodilator therapy was not associated with a survival advantage in those with extensive ILD, its use was associated with an improvement in symptoms, physical function, and quality of life (QoL)., Conclusion: Despite vasodilator therapy, survival in SSc-PH is poor, with the presence of concurrent ILD associated with worse survival. Although vasodilator therapy commenced at PH diagnosis does not portray an improved survival in PH with extensive ILD, it appears well tolerated and may improve symptoms, physical function, and QoL., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Objective: Patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) have a poor prognosis, accounting for 30% of all SSc-related deaths. Guidelines recommend annual screening for PAH regardless of symptoms, as early treatment improves outcomes. Current protocols include combinations of clinical features, biomarkers, pulmonary function tests, and echocardiography. None include exercise testing, although early-stage PAH may only be evident during exercise. This systematic review assessed the performance of exercise tests in predicting the presence of PAH in patients with SSc, where PAH was confirmed through right heart catheterisation (RHC)., Methods: Comprehensive literature searches were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trails, CINAHL, Scopus and Web of Science from inception to May 2023. Articles were screened for eligibility by two independent reviewers. Eligibility criteria included the use of a non-invasive exercise test to screen adult patients to detect PAH in a population without a previous diagnosis of PAH, with diagnosis confirmed by RHC., Results: Eight studies met the inclusion criteria, describing at least one of three different non-invasive exercise tests: cardiopulmonary exercise test, six-minute walk test and stress Doppler echocardiography. All studies found that exercise tests had some ability to predict the presence of PAH, with sensitivity between 50% and 100% and specificity from 73% to 91%., Conclusion: Exercise tests are infrequently used for screening for PAH in SSc but can predict the presence of PAH. More data are required to establish which tests are most effective., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p < 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p < 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p < 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU., (© 2023. The Author(s).)

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., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Damage accrual in SSc can be tracked using the Scleroderma Clinical Trials Consortium Damage Index (DI). Our goal was to develop a prediction model for damage accrual in SSc patients with early disease., Methods: Using patients with <2 years disease duration from Canada and Australia as a derivation cohort, and from the Netherlands as a validation cohort, we used group-based trajectory modelling (GBTM) to determine 'good' and 'bad' latent damage trajectories. We developed a prediction model from this analysis and applied it to patients from derivation and validation cohorts. We plotted the actual DI trajectories of the patients predicted to be in 'good' or 'bad' groups., Results: We found that the actual trajectories of damage accumulation for lcSSc and dcSSc were very different, so we studied each subset separately. GBTM found two distinct trajectories in lcSSc and three in dcSSc. We collapsed the two worse trajectories in the dcSSc into one group and developed a prediction model for inclusion in either 'good' or 'bad' trajectories. The performance of models using only baseline DI and sex was excellent with ROC AUC of 0.9313 for lcSSc and 0.9027 for dcSSc. Using this model, we determined whether patients would fall into 'good' or 'bad' trajectory groups and then plotted their actual trajectories which showed clear differences between the predicted 'good' and 'bad' cases in both derivation and validation cohorts., Conclusions: A simple model using only cutaneous subset, baseline DI and sex can predict damage accumulation in early SSc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: In patients with systemic sclerosis (SSc), we investigated composite serum biomarker panels for the diagnosis and risk stratification of SSc-associated interstitial lung disease (SSc-ILD)., Methods: We analyzed 28 biomarkers in 640 participants: 259 patients with SSc-ILD and 179 SSc patients without ILD (Australian Scleroderma Cohort Study), 172 patients with idiopathic pulmonary fibrosis (IPF-controls) (Australian IPF Registry), and 30 healthy controls. A composite index was developed from biomarkers associated with ILD in multivariable analysis derived at empirical thresholds. We evaluated the performance of the index to identify ILD, and specifically SSc-ILD, and its association with lung function, disease extent on radiography, and patient health-related quality of life in derivation and validation cohorts. Biomarkers to distinguish SSc-ILD from IPF-controls were identified., Results: A composite biomarker index, comprising surfactant protein D (SP-D), Ca15-3, and intercellular adhesion molecule 1 (ICAM-1), was strongly associated with SSc-ILD diagnosis, independent of age, sex, smoking history, and lung function (for biomarker index score 3, pooled adjusted odds ratio was 12.72 (95% confidence interval 4.59-35.21) (P < 0.001). The composite index strengthened the performance of individual biomarkers for SSc-ILD identification. In SSc patients, a higher index was associated with worse baseline disease severity (for biomarker index score 3 relative to biomarker index score 0, the adjusted absolute change in forced vital capacity percent predicted was -17.84% and the diffusing capacity for carbon monoxide percent predicted was -20.16%; both P < 0.001)., Conclusion: A composite serum biomarker index, comprising SP-D, Ca15-3, and ICAM-1, may improve the identification and risk stratification of ILD in SSc patients at baseline., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Raynaud's phenomenon (RP) is a cardinal feature of SSc and is associated with significant disease-related morbidity that impacts on quality of life. The assessment of SSc-RP is challenging. The aim of this scoping review was to evaluate the outcome domains studied and outcome measures used in clinical studies of SSc-RP., Methods: Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were used to identify randomized control trials (RCTs), quasi-randomized studies, case-control studies, prospective and retrospective cohort studies, case series, and cross-sectional studies of adult participants with SSc-associated RP, written in English. A minimum of 25 participants for studies of imaging modalities and 40 participants for questionnaire-based studies was required for inclusion. Basic laboratory and genetic studies were excluded. No limitations were imposed based on intervention, comparator, or study setting. Study characteristics and primary and secondary target domains in each study were recorded., Results: 58 studies (24 randomized clinical trials) were included in the final analysis. The commonest domains captured were severity of attacks (n=35), frequency of attacks (n=28), and duration of attacks (n=19). Objective assessments of digital perfusion were also commonly used in studies of SSc-RP., Conclusion: The outcome domains and the associated outcomes used to assess the impact of SSc-RP in research studies are broad and have varied across studies. The results of this study will inform the OMERACT Vascular Disease in Systemic Sclerosis Working Group to establish a core set of disease domains encompassing the impact of RP in SSc., Competing Interests: Declaration of Competing Interest Dr Hughes reports speaking fees from Actelion Pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work. Research funding from Janssen. Member of a Data and Safety Monitoring Board for Certa Therapeutics. Dr. Pauling reports grants and personal fees from Janssen, outside the submitted work; Dr Pauling reports personal and consultancy fees from Boehringer Ingelheim, Sojournix Pharma, Astra Zeneca, IsoMab and Permeatus, Inc. Dr Proudman reports receiving funds for the following activities: advisory board: Boehringer-Ingelheim, Janssen, Gossamer. Research Support: Janssen. Dr. Merkel reports receiving funds for the following activities: Consulting: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, Novartis, Pfizer, Sparrow, Takeda, Talaris. Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi. Royalties: UpToDate. Dr Herrick reports research funding from Gesynta Pharma, consultancies with Arena, Boehringer-Ingelheim, Camurus, CSL Behring, Gesynta Pharma and speaker's fees from Janssen., (Copyright © 2023. Published by Elsevier Inc.)

Background: Digital ulcers (DUs) are a major cause of pain and disability in patients with systemic sclerosis (SSc). The aim of this scoping review was to evaluate the outcome domains used in studies of SSc-associated DUs., Methods: Electronic databases (EMBASE, MEDLINE and the Cochrane Library) were searched for articles written (1947 onwards) in English relating to SSc-DUs. A minimum of 15 participants for studies of imaging and 25 participants for questionnaire-based studies was required for inclusion. Information on all primary and secondary domains was extracted., Results: 4869 manuscripts were identified, of which 40 met the eligibility criteria and were included in the synthesis. Most studies were randomized controlled trials (n=13), or prospective (n=12)/retrospective (n=8) observational studies. Interventions included oral or intravenous drugs (n=25), topical/local treatments (n=5), and surgical interventions (n=2). Approximately half the studies assessed either the count/number of DUs (n=23) and/or improvement in DUs (n=20). Functional impact of DUs was examined in 25% (n=10) of studies. Other domains were related to complications of DUs (n=7), pain (n=6), health-related quality of life (n=4), microvascular assessment/pathophysiology (n=4), global assessment of DUs (n=2), and histopathology (n=1)., Conclusion: This scoping review identified a broad range of disease-related domains used to study SSc-DUs. There is significant heterogeneity in these domains. These data will inform the ongoing work of the OMERACT Vascular Disease in Systemic Sclerosis Working Group to define a core set of disease broad domains to capture the burden of DUs in SSc., Competing Interests: Declaration of Competing Interest Dr Hughes reports speaking fees from Actelion Pharmaceuticals, Eli Lilly, Janssen, and Pfizer. Research funding from Janssen. Member of a Data and Safety Monitoring Board for Certa Therapeutics. Dr. Pauling reports grants and personal fees from Janssen, outside the submitted work; Dr Pauling reports personal fees from Astra Zenaca, Boehringer Ingelheim, Sojournix Pharma and Permeatus, Inc. Dr Proudman reports receiving funds for the following activities: advisory board: Boehringer-Ingelheim, Janssen, Gossamer. Research Support: Janssen. Dr. Merkel reports receiving funds for the following activities in the past 2 years: Consulting: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, GlaxoSmithKline, InflaRx, Jannsen, Jubilant, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, NS Pharma, Pfizer, Q32, Regeneron, Sparrow, Takeda, Vistera. Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Electra, Forbius, Genentech/Roche, GlaxoSmithKline, InflaRx, Sanofi, Star, Takeda. Stock options: Kyverna. Royalties: UpToDate. Professor Herrick reports research funding from Gesynta Pharma, consultancies with Arena, Boehringer-Ingelheim, Camurus, CSL Behring, Galderma, Gesynta Pharma and speaker's fees from Janssen., (Copyright © 2023. Published by Elsevier Inc.)

Background: Bronchiectasis has been observed in association with systemic sclerosis (SSc). Theorised aetiology includes aspiration related to oesophageal dysmotility, immunosuppressant medication use and the direct effect of collagen deposition on airway calibre., Aims: To detail bronchiectasis prevalence in an SSc population who have had a high-resolution computed tomography (HRCT) of the thorax. We assessed whether oesophageal dysmotility, demographic variables, SSc duration or subclass were associated with bronchiectasis., Methods: Participants in the Australian Scleroderma Cohort Study (ASCS) with a HRCT were included. The ASCS provided demographic and clinical data. HRCT studies were reviewed for bronchiectasis, oesophageal dilatation and interstitial lung disease (ILD). Traction bronchiectasis associated with ILD was recorded as a separate entity to bronchiectasis. Oesophageal dysmotility was defined by symptoms and/or oesophageal dilatation., Results: Of the 256 participants, 16.4% (n = 42) had bronchiectasis. Logistic regression analysis revealed no significant association between bronchiectasis and oesophageal dysmotility (observed in 95.7%), any demographic variable, SSc duration or subclass. A negative association between bronchiectasis and ILD was observed (P = 0.009; odds ratio 0.322; 95% confidence intervals 0.137-0.756)., Conclusion: Those with SSc appear to have an increased risk for bronchiectasis. Since bronchiectasis was not more frequent in participants with a longer duration of SSc, we hypothesise that its development is not related to immunosuppression alone. Oesophageal dysmotility was almost universal in our population such that its effect on bronchiectasis development could not be concluded. A negative association between bronchiectasis and ILD reflects that bronchiectasis occurring alongside ILD was recorded as a separate entity., (© 2021 Royal Australasian College of Physicians.)

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).)