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Background/Aims After cardiopulmonary disease, cancer accounts for the highest proportion of deaths in systemic sclerosis (SSc), exceeding deaths attributed to renal disease and/or infection. Few population-based studies have assessed the burden of cancer in SSc. The present study investigated the association between cancer and SSc using the Clinical Practice Research Datalink (CPRD). Methods A validated case ascertainment strategy using combinations of diagnostic Read codes was applied to identify SSc patients in the CPRD with >12 months of data within the time period 01/01/1998 to 31/12/2017. A cohort study design examined cancer occurrence following a diagnosis of SSc. Patients with SSc were matched to six non-SSc comparators by age, sex and GP practice using incident density sampling. Prevalent and incident cases of SSc were analysed separately. Information on date and type of diagnosis of cancer was recorded. Descriptive statistics and Cox analyses determined hazard ratios for cancer occurrence. Results From 10.1 million individuals in the CPRD, 1,588 of cases of SSc were identified (85.3% female). We identified 206 cancers that occurred following a diagnosis of SSc (116 in prevalent cohort and 90 amongst incident cohort) (Table). The three commonest cancers were mucocutaneous (4.5%), lung (2.1%) and breast (1.9%). Lung cancer was significantly more common in SSc (Table). Incidence of cancer was higher in SSc (17 vs. 13.8 per 1000 person years) with adjusted hazard ratios of 1.41 (95% CI 1.14-1.75) for prevalent cases and 1.32 (95% CI 1.04-1.67) for incident SSc cases. We did not identify a strong relationship between cancer occurrence and SSc onset. Incidence of cancer increased with age at SSc diagnosis and was higher in males. Death from any cause at 6 months was higher in patients with SSc and cancer. Conclusion We have identified an increased risk of cancer occurrence (primarily mucocutaneous and lung) in patients with SSc from the UK, particularly amongst males and patients with higher age at SSc diagnosis. These findings could support screening recommendations for cancer in SSc. Disclosure J.D. Pauling: Consultancies; Astra Zenaca, Janssen, Permeatus Inc., Sojournix Pharma, Boehringer Ingelheim. Honoraria; Janssen. Member of speakers’ bureau; Janssen. J. Snowball: None. N. McHugh: None. A. McGrogan: None.

Objectives The aim of this study was to comprehensively identify instruments within relevant domains employed to assess lcSSc since the endorsement of its consensus definition in 1988. The overall objective is to inform the creation of a Combined Response Index for Scleroderma Trials Assessing lcSSc (CRISTAL). Methods MEDLINE and Embase were searched using terms selected to comprehensively retrieve titles and abstracts mentioning both lcSSc and dcSSc, along with those only mentioning lcSSc, SSc sine scleroderma, limited SSc and/or CREST/CRST. Because our initial assessment of the literature revealed that very few studies included only lcSSc subjects, we also assessed literature that included both cutaneous subsets. A total of 3964 titles and abstracts were screened by two reviewers, and 270 articles were selected for data extraction. Results We identified 27 domains encompassing 459 instruments. Instruments from ‘Skin involvement’, ‘Pulmonary involvement’ and ‘Health-related quality of life and general functioning’ were the most frequently retrieved. Among the 15 most represented instruments announced as primary end points in efficacy or effectiveness studies, 7 were clinician-reported outcomes (ROs), 7 were patient ROs, and one was a performance outcome (6 min-walk test). The mean proportion of lcSSc patients in studies of lcSSc, including studies that mention both lcSSc and dcSSc, was 56.4%, demonstrating that this subset is underrepresented in the literature, given that the prevalence of lcSSc ranges from 60% to 80% in national registries and international cohorts. Conclusion This scoping literature review provides a comprehensive identification of domains and outcomes used to assess lcSSc. Our results also highlight that lcSSc is underrepresented in the literature.

To explore patient priorities and ranking of factors influencing patient decision-making concerning treatment escalation in the management of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc).Patients with SSc were invited to participate in an online survey disseminated through patient-led organizations and social media platforms.Responses from 747 individuals with self-reported SSc-RP were evaluable with broad international representation. The mean ± SD age (54.7 ± 12.1 years), clinical phenotype, and disease subsets distribution (limited cutaneous SSc [402 of 747, 53.8%], diffuse cutaneous SSc [260 of 747, 34.8%], and overlap disease [85 of 747, 11.4%]) were consistent with expected demographic information. Around one-half (56.3%) of patients reported that their SSc-RP symptoms were adequately controlled. The 5 highest ranked factors (of 13) that would prompt treatment escalation for SSc-RP were as follows: 1) inability to use the fingers properly; 2) emergence of new digital ulcer on ≥1 fingers; 3) worsening pain or discomfort from RP; 4) more severe attacks; and 5) if it may help with internal problems. Despite symptoms not being adequately controlled, 47.1% were concerned about potential treatment side effects and were more likely to accept mild (~20-40%) versus severe (2%) side effects. Patients were open to different management strategies for uncontrolled RP that included adding new treatment in combination with existing treatment (52.8%), drug substitution (40.9%), increasing the current dose (28.8%), or focusing on nonpharmacologic approaches (29.7%).We have identified the relative importance of different factors influencing patient preferences for treatment decision-making regarding SSc-RP. Side-effect profiles influence acceptability of drug treatments, and many patients report a preference for nonpharmacologic management of SSc-RP.

Objectives Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc. Methods PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. Results Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was −0.10 (97.5% CI: −0.29, 0.10), P = 0.254, and in mRSS −3.90 (97.5% CI: −8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. Conclusion PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.

COVID-19; Registries; Vaccination COVID-19; Registros; Vacunación COVID-19; Registres; Vacunació Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups. HC is supported by the National Institution for Health Research Manchester Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

Global assessments of disease by both patients and physicians are widely used in clinical studies of systemic sclerosis (SSc). They are commonly secondary endpoints in randomised controlled trials (RCTs) and are considered important items in composite measures of treatment response. A comprehensive literature review was conducted of the formats, wording, and clinimetric properties of the patient global assessments (PtGA) and physician global assessments (PhGA) used in RCTs of SSc. Marked heterogeneity was found in the wording and measurement scales of the global assessments applied in RCTs. These instruments were not developed using rigorous methodology and have not been fully validated. There is a pressing need for standardisation and validation of patient and physician global assessment tools in SSc to enable universal application of these measures to across RCTs in SSc. This article is protected by copyright. All rights reserved.

Objectives Men with SSc have a more severe clinical phenotype and reduced survival compared with women. No previous psychosocial studies have focused solely on men with SSc. This study aimed to explore experiences, coping strategies and support preferences of men with SSc. Material and methods An international qualitative research study comprising seven focus groups (three USA, four UK) of 25 men with SSc. Transcripts were analysed using reflexive thematic analysis. Results Three overarching themes and one underpinning theme were identified. In ‘impact of SSc on masculinity’, the men described an ‘impact on roles and activities’, reported ‘sex, intimacy, and erectile dysfunction’ as a salient issue that may be overlooked by clinicians, and experienced challenges to ‘masculine self-image’. ‘Dealing with SSc’ meant ‘always being prepared’, ‘becoming an expert’ and ‘balancing priorities’ in responsibilities, activities and symptom management. In ‘support for living with SSc’ men were selective in ‘(Not) talking about SSc’, would ‘(reluctantly) accept help’ and described ‘preferences for support’. Underpinning these experiences was ‘facing an uncertain future’ with some participants preferring not to focus on an unpredictable future, and others worrying about disease progression. Conclusion These novel data suggest SSc impacts male patients’ masculine identity and roles, and although they will accept practical help, they may mask the full emotional impact. Sex and intimacy are important overlooked issues with erectile dysfunction often not discussed at diagnosis. Further research should develop a self-management intervention for men with rheumatic diseases with a combination of disease-specific and common core components.

ObjectiveSystemic sclerosis (SSc) results in impaired function, disability, and reduced health-related quality of life. We investigated the effect of coping strategies on the patient global assessment of health (PtGA) and Health Assessment Questionnaire–Disability Index (HAQ-DI), after controlling for clinical characteristics and disease activity. We also explored the relationship between coping strategies and the correlation between the PtGA and physician global assessment (PGA) in SSc.MethodsWe undertook posthoc analyses using baseline data obtained from the Raynaud Symptom Study (RSS). The PtGA, Coping Strategies Questionnaire, Pain Catastrophizing Scale, and Scleroderma Health Assessment Questionnaire were collected alongside the PGA, clinical characteristics, and patient demographics. Multivariable linear regression models and correlations were used to evaluate the relationship between coping strategies with the PtGA, HAQ-DI, and PGA.ResultsOf the 107 patients with SSc enrolled in the RSS, there were sufficient data available for the analysis of 91 participants. The mean PtGA was 40/100 (SD 27) and the mean HAQ-DI was 0.87/3.0 (SD 0.73). After controlling for clinical and patient demographics, pain catastrophizing and maladaptive coping skills were significantly associated with the PtGA and HAQ-DI scores (P < 0.05 for both), but not the PGA.ConclusionThe effect of coping strategies on PtGA and HAQ-DI (but not PGA in SSc) could influence the result of composite measures incorporating these outcome measures. Interventions to improve patient coping skills may support increased resilience and improve patient-perceived functional status and PtGA in SSc.

Objectives GCA is a large vessel vasculitis (LVV) presenting with headache, jaw claudication, musculoskeletal and visual involvement. Current treatment is glucocorticoids and anti-IL-6 tocilizumab in refractory disease. The objective of this study was to explore the impact of GCA and its treatment on people’s health-related quality of life (HRQoL), to inform the development of a disease-specific patient-reported outcome measure (PROM) for use in clinical trials and practice. Methods Participants from the UK and Australia, with biopsy- or imaging-confirmed GCA, were interviewed to identify salient aspects of HRQoL in relation to GCA and its treatment. Purposive sampling included a range of demographic and disease features (cranial, LVV-GCA and visual involvement). Inductive analysis identified individual themes of importance, then domains. Candidate questionnaire items were developed from the individual themes, refined by piloting, cognitive interviews and a linguistic translatability assessment. Results Thirty-six interviews were conducted to saturation with participants with GCA from the UK (25) and Australia (11). Mean age was 74 years, 23 (63.9%) were female, 13 (36.1%) had visual loss and 5 (13.9%) had LVV-GCA. Thirty-nine individual themes within five domains were identified: physical symptoms; activity of daily living and function; participation; psychological impact; and impact on sense of self and perception of health. Sixty-nine candidate items were developed from individual themes; piloting and refinement resulted in a 40-item draft questionnaire. Conclusion This international qualitative study underpins the development of candidate items for a disease-specific PROM for GCA. The draft questionnaire is now ready for psychometric testing.

Background The world symposium on pulmonary hypertension (PH) has proposed that PH be defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as assessed by right heart catheterisation (RHC). Transthoracic echocardiography (TTE) is an established screening tool used for suspected PH. International guidelines recommend a multi-parameter assessment of the TTE PH probability although effectiveness has not been established using real world data. Study aims To determine accuracy of the European Society of Cardiology (ESC) and British Society of Echocardiography (BSE) TTE probability algorithm in detecting PH in patients attending a UK PH centre. To identify echocardiographic markers and revised algorithms to improve the detection of PH in those with low/intermediate BSE/ESC TTE PH probability. Methods TTE followed by RHC (within 4 months after) was undertaken in patients for suspected but previously unconfirmed PH. BSE/ESC PH TTE probabilities were calculated alongside additional markers of right ventricular (RV) longitudinal and radial function, and RV diastolic function. A refined IMPULSE algorithm was devised and evaluated in patients with low and/or intermediate ESC/BSE TTE PH probability. Results Of 310 patients assessed, 236 (76%) had RHC-confirmed PH (average mPAP 42.8 ± 11.7). Sensitivity and specificity for detecting PH using the BSE/ESC recommendations was 89% and 68%, respectively. 36% of those with low BSE/ESC TTE probability had RHC-confirmed PH and BSE/ESC PH probability parameters did not differ amongst those with and without PH in the low probability group. Conversely, RV free wall longitudinal strain (RVFWLS) was lower in patients with vs. without PH in low BSE/ESC probability group (− 20.6 ± 4.1% vs − 23.8 ± 3.9%) (P Conclusion Existing TTE PH probability guidelines lack sensitivity to detect patients with milder haemodynamic forms of PH. Combining additional TTE makers assessing RV radial, longitudinal and diastolic function enhance identification of milder forms of PH, particularly in those who have a low BSE/ESC TTE PH probability.

Systemic sclerosis (systemic scleroderma) is characterized by a heterogeneous range of clinical manifestations. Systemic sclerosis is classified into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis subgroups based on the extent of skin involvement. Randomized controlled trials in scleroderma have mainly focused on diffuse cutaneous systemic sclerosis partly because the measurement of skin involvement, critical for evaluating a therapeutic intervention, is more dynamic in this subset. Nonetheless, limited cutaneous systemic sclerosis, the most common cutaneous subset (about two-third), is also associated with significant morbidity and detrimental impact on health-related quality of life. The lack of interventional studies in limited cutaneous systemic sclerosis is partly due to a lack of relevant outcome measures to evaluate this subgroup. Combining several clinically meaningful outcomes selected specifically for limited cutaneous systemic sclerosis may improve representativeness in clinical trials and responsiveness of outcomes measured in randomized controlled trials. A composite index dedicated to limited cutaneous systemic sclerosis combining such relevant outcomes could advance clinical trial development for limited cutaneous systemic sclerosis by providing the opportunity to test and select among candidate drugs that could act as disease-modifying treatments for this neglected subgroup of systemic sclerosis. This proposed index would include items selected by expert physicians and patients with limited cutaneous systemic sclerosis across domains grounded in the lived experience of limited cutaneous systemic sclerosis. This article reviews the reasons behind the relative neglect of limited cutaneous systemic sclerosis, discusses the current state of outcome measures for limited cutaneous systemic sclerosis, identifies challenges, and proposes a roadmap for a combined limited cutaneous systemic sclerosis-specific treatment response index.

Background: Raynaud's phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), Laser Doppler Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for SSc-RP and/or SSc-DU clinical trials. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy. Methods: Standardized searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult subjects with SSc. Data was extracted (by >2 reviewers) on study design, laser endpoints, and reported outcomes. Study quality was assessed using validated instruments (PROSPERO 2019:CRD42019142409). Results: Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and 14 non-randomized trials (total of 689 SSc patients with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The studies were published between 1987 and 2019 (17/29 since 2010) and incorporated LDF (11/29), LDI (15/29) and LSCI (4/29, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials. Most studies (16/29, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes. Conclusions: Establishing laser-derived methods as a surrogate for SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy.

Antiphospholipid syndrome (APS) is an acquired, autoimmune thrombophilia that can occur as a primary disorder (with no associated disease) or secondary to infection, medication usage and autoimmune rheumatic diseases (ARDs). The association between APS and systemic lupus erythematosus (SLE) is well established, and practicing rheumatologists check for APS antibodies in the routine assessment of SLE, particularly if clinical features such as thrombotic events or pregnancy loss are present. APS secondary to systemic sclerosis (SSc)-related disorders is less widely recognised and easily overlooked. We describe 5 cases that highlight the varied breadth of clinical manifestations of APS in the context of SSc and related disorders. These cases range from uncomplicated Raynaud’s phenomenon, digital ulceration/necrosis, critical digital ischaemia/gangrene and rare internal organ complications of APS in SSc-spectrum disorders. To our knowledge, our cases include the first reported case of secondary APS contributing to digital necrosis in the context of RACAND syndrome (Raynaud’s phenomenon, anti-centromere antibodies and necrosis of the digits) and the first reported case of secondary APS in SSc causing posterior reversible encephalopathy syndrome (PRES). The case series is accompanied by a comprehensive review of the literature relevant to each case. Rheumatologists should be alert to the possibility of APS in SSc-spectrum disorders and should routinely check APS antibodies in all patients at diagnosis, and again later in the disease course if new features emerge that could indicate the presence of thrombotic events or other recognised APS manifestations.Key points• APS should be considered in all patients with digital ischaemic symptoms.• APS may be an important driver of SSc-related digital ulceration/necrosis.• Identification of SSc-associated APS opens up new therapeutic options for acute management and secondary prevention.

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high-intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc.

Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including ‘red flags’ that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.

Background/Aims Giant cell arteritis (GCA) is a systemic vasculitis involving large and medium-sized blood vessels. Patients can present with cranial, ocular or large vessel (LVV-GCA) involvement. Treatment is with high dose glucocorticoids. Steroid-sparing agents and tocilizumab (TCZ) are used for refractory or relapsing cases. NHS England requires all GCA patients to be discussed in a regional multidisciplinary team meeting (MDT) prior to commencing TCZ. We reviewed the case mixture of patients referred to the Bristol and Bath regional MDT. Methods The Bristol and Bath regional MDT started in November 2018 and runs monthly. A referral proforma was designed, adapted from the NHS England Blueteq approval form for TCZ in GCA (definitions of refractory and relapsing disease), with tick boxes for clinical features, investigations, treatment, glucocorticoid adverse events and a free text clinical vignette. All referral proformas were reviewed. Results Audit data from all cases referred, between November 2018 and September 2021, were analysed. 38 cases of GCA were discussed with 31 cases approved for TCZ usage. Of the approved, 100% fulfilled the criteria for either refractory (n = 11) or relapsing (n = 20) disease. Mean age of approved cases was 74 years with three quarters being female (74.2%). Average disease duration was 161.5 days for the refractory group and 827.3 days for the relapsing group. Over three quarters of cases (77.4%) had cranial GCA, 48.4% had LVV-GCA, 45.2% had visual symptoms (reduction in visual acuity, blurring or diplopia) and 25.8% had ischaemic visual loss. The positive investigations were PET-CT (48.4%), temporal artery ultrasound (41.9%) and temporal artery biopsy (32.3%). Almost two-thirds (64.5%) had previously had a steroid-sparing agent (61.3 % methotrexate, 9.7% azathioprine, 6.5% leflunomide), one third (35.5%) had received intravenous methylprednisolone and more than half (58%) were receiving greater than 40mg prednisolone at the time of referral. Common glucocorticoid adverse effects (each seen in 19.4% of cases) included osteoporosis, weight gain, cataracts or hypertension, whilst diabetes, neuropsychiatric symptoms or sleep disturbance were each reported in 16.1% of cases. The majority of patients with ocular involvement had cranial symptoms (71%). Patients with ocular involvement tended to be referred earlier than those with no ocular involvement (478.2 days vs 648.1 days), were on a higher dose of glucocorticoids at time of referral (71.4% vs 47.1% on more than 40mg) and had fewer steroid-sparing agents prior to referral. Conclusion All patients approved for TCZ in the GCA MDT fulfilled NHS England criteria for either relapsing or refractory disease. The majority of cases had cranial disease, but almost half had either ocular or large vessel vasculitis involvement, reflecting a severe spectrum of disease. Cases showed a high burden of glucocorticoid toxicity. Patients with ocular involvement were referred slightly earlier with less use of other steroid sparing treatments prior to TCZ in our cohort. Disclosure C. Jayatilleke: None. S. Janagan: None. R. Marshall: Other; Has received sponsorship from UCB Pharma to attend educational conferences in the last 2 years. S. Skeoch: None. C.M. Guly: None. F. En Sin: None. L. AL Sweedan: None. A. Anilkumar: None. K. Austin: None. A. Bourn: None. L. Clarke: None. H. Gunawardena: None. A. Johnson: None. S. Knights: None. J.D. Pauling: None. E. Reilly: None. T.D. Reynolds: None. S. Villar: None. J.C. Robson: None.

Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

ObjectiveUltrasound is a promising tool to foster much-needed improvement of skin assessment in systemic sclerosis (SSc). Our aim was to develop evidence and expert opinion-based recommendations to promote the standardisation and harmonisation of technical execution and reporting of skin ultrasound studies in SSc.MethodsA multidisciplinary task force of 16 members from five European countries and Japan was convened under the auspices of World Scleroderma Foundation. First, a systematic literature review (SLR) was performed. Then, each member proposed and formulated items to the overarching principles, recommendations and research agenda. Two rounds of mails exchange for consensus as well as an on-line meeting were performed to debate and refine the proposals. Two Delphi rounds of voting resulted in the final recommendations. Levels of evidence and strengths of recommendations were assigned, and task force members voted anonymously on the level of agreement with each of the items.ResultsFive overarching principles and seven recommendations were developed, based on an SLR and expert opinion, through consensus procedures. The overarching principles highlight the promising role of skin ultrasound in SSc assessment, the need for standardisation of technical aspects, sufficient training and adequate equipment. The recommendations provide standards for the execution and reporting of skin ultrasound in SSc. The research agenda includes the need for more research into unmet needs according to Outcome Measures in Rheumatology Algorithm requirements.ConclusionThese are the first recommendations providing guidance on the execution and reporting of skin ultrasound in SSc patients, aiming at improving the interpretability, reliability and generalisability of skin ultrasound, thus consolidating its role in research and practice.

Objectives: To undertake the first systematic review examining the performance of artificial intelligence (AI) applied to cross-sectional imaging for the diagnosis of acquired pulmonary arterial hypertension (PAH). Methods: Searches of Medline, Embase and Web of Science were undertaken on 1 July 2020. Original publications studying AI applied to cross-sectional imaging for the diagnosis of acquired PAH in adults were identified through two-staged double-blinded review. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies and Checklist for Artificial Intelligence in Medicine frameworks. Narrative synthesis was undertaken following Synthesis Without Meta-Analysis guidelines. This review received no funding and was registered in the International Prospective Register of Systematic Reviews (ID:CRD42020196295). Results: Searches returned 476 citations. Three retrospective observational studies, published between 2016 and 2020, were selected for data-extraction. Two methods applied to cardiac-MRI demonstrated high diagnostic accuracy, with the best model achieving AUC=0.90 (95% CI: 0.85–0.93), 89% sensitivity and 81% specificity. Stronger results were achieved using cardiac-MRI for classification of idiopathic PAH, achieving AUC=0.97 (95% CI: 0.89–1.0), 96% sensitivity and 87% specificity. One study reporting CT-based AI demonstrated lower accuracy, with 64.6% sensitivity and 97.0% specificity. Conclusions: Automated methods for identifying PAH on cardiac-MRI are emerging with high diagnostic accuracy. AI applied to cross-sectional imaging may provide non-invasive support to reduce diagnostic delay in PAH. This would be helped by stronger solutions in other modalities. Advances in knowledge: There is a significant shortage of research in this important area. Early detection of PAH would be supported by further research advances on the promising emerging technologies identified.

Objective: To summarize the published evidence in the literature on the role of ultrasound and elastography to assess skin involvement in systemic sclerosis (SSc).Methods: A systematic literature review (SLR) was performed within the "Skin Ultrasound Working Group" of the World Scleroderma Foundation, according to the Cochrane Handbook. A search was conducted in Pubmed, Cochrane Library and Embase databases from 1/1/1979 to 31/5/2021, using the participants, intervention, comparator and outcomes (PICO) framework. Only full-text articles involving adults, reported in any language, assessing ultrasound to quantify skin pathology in SSc patients. Two reviewers performed the assessment of risk of bias, data extraction and synthesis, independently.Results: Forty-six studies out of 3248 references evaluating skin ultrasound and elastography domains were included. B-mode ultrasound was used in 30 studies (65.2%), elastography in nine (19.6%), and both methods in seven (15.2%). The ultrasound outcome measure domains reported were thickness (57.8%) and echogenicity (17.2%); the elastography domain was stiffness (25%). Methods used for image acquisition and analysis were remarkably heterogeneous and frequently under-reported, precluding data synthesis across studies. The same applies to contextual factors and feasibility. Our data syntheses indicated evidence of good reliability and convergent validity for ultrasound thickness evaluation against mRSS and skin histological findings. Stiffness and echogenicity have limited evidence for validity against histological findings. Evidence for sensitivity to change, test-retest reliability, clinical trial discrimination or thresholds of meaning is limited or absent for reported ultrasound domains.Conclusion: Ultrasound is a valid and reliable tool for skin thickness measurement in SSc but there are significant knowledge gaps regarding skin echogenicity assessment by ultrasound and skin stiffness evaluation by elastography in terms of feasibility, validity and discrimination. Standardization of image acquisition and analysis is needed to foster progress. (c) 2022 Elsevier Inc. All rights reserved.

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Patient-reported outcome instruments provide valuable insight into disease-related morbidity known only to the patient and complement more objective outcome tools in the clinical trial setting. They are of particular importance in systemic sclerosis owing to the challenges around defining disease activity, the episodic nature of many disease-specific manifestations and the paucity of validated objective surrogate outcome measures for use in clinical trials. Early clinical trials of systemic sclerosis often incorporated legacy patient-reported outcome instruments, but the last 20 years has witnessed the emergence of several scleroderma-specific instruments that are now being routinely used alongside other outcomes in systemic sclerosis clinical trials. More recently, the value of patient-reported outcomes has been highlighted by their prominence in the American College of Rheumatology Combined Response Index for Systemic Sclerosis that has been utilized as the primary endpoint of recent clinical trials of early diffuse systemic sclerosis. This review considers the role and performance of the various patient-reported outcome instruments utilized in systemic sclerosis clinical trials, the current positioning of patient-reported outcome instruments within clinical trial endpoint models across the range of systemic sclerosis disease manifestations and, where applicable, we shall highlight areas for future research.

Raynaud's phenomenon (RP) is used to describe a symptom complex caused by digital vascular compromise. RP is a clinical diagnosis. The typically episodic nature of RP has resulted in a reliance upon patient self-report for diagnosis. The term 'primary RP' is generally applied when no underlying pathology can be demonstrated. Whilst 'primary RP' is currently considered a distinct disorder, there is evidence that the term may comprise several entities that include a functional vasospastic disorder, a physiologically appropriate thermoregulatory response, subclinical atherosclerosis and 'cold intolerance'. Optimal management may differ depending on cause. The term 'secondary RP' encompasses a broad range of rheumatological, haematological, endocrinological and vascular pathology. RP can range from relatively benign but intrusive vasospasm, to the progressive obliterative microangiopathy of systemic sclerosis (SSc), in which severe digital ischaemia can threaten tissue viability. SSc has formed the focus of much of the research into RP but, consistent with most medical symptom complexes, the aetiopathogenesis of RP varies greatly dependent on cause. Vasospasm within the digital macro- and microvasculature occurs in SSc, but digital ischaemia is further compounded by a progressive obliterative microangiopathy. Recent work exploring the patient experience of SSc-RP is challenging the 'episodic' paradigm of 'Raynaud's', with important implications for clinical trials utilising diary-based patient-reported outcome instruments for assessing Raynaud's symptoms. This review shall examine the causes, pathogenesis, clinical features, classification and management of RP. A practical approach to the evaluation and management of RP is outlined, highlighting important knowledge gaps and unmet research needs where applicable. Key Points • Raynaud's phenomenon is a symptom complex related to digital vascular compromise secondary to broad-ranging pathology. • Raynaud's phenomenon, as currently classified, likely encompasses a number of aetiopathogenic processes. • Raynaud's phenomenon causes significant disease-related morbidity in autoimmune rheumatic diseases such as systemic sclerosis.

BACKGROUND: Gastrointestinal involvement in systemic sclerosis is common and a major cause of disease-related morbidity. Patients increasingly enquire about dietary modifications that may help with gastrointestinal symptoms. Many clinical practice reviews and treatment guidelines make specific reference to dietary modifications in the management of gastrointestinal involvement in systemic sclerosis. We report the findings of a systematic literature review designed to evaluate the evidence to support dietary modification in the management of gastrointestinal symptoms of systemic sclerosis.METHODS: A systematic literature review protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered with the International prospective register of systematic reviews (CRD42018103549). Standardised searches of EMBASE and MEDLINE were undertaken to identify studies reporting the outcome of dietary modification in the management of gastrointestinal symptoms of systemic sclerosis. Wide heterogeneity in study design, interventions and study outcomes necessitated a qualitative data synthesis.RESULTS: Our standardised searches identified 1032 articles, of which 3 were deemed eligible for full data extraction. These studies were small (mean 19 subjects per study), single centre, short-term (mean 6 week duration) open-label non-randomised studies examining the role of probiotics, low-fermentable oligo-saccharides, disaccharides, monosaccharides, and polyol (low-FODMAP) diet and highly individualised medical nutrition therapy counselling, respectively. Improvements in patient-reported outcome assessment of gastrointestinal symptoms were reported after intervention with probiotic therapy and low-FODMAP diet but not following tailored dietary and nutritional counselling. The Risk of Bias Assessment Tool for Nonrandomized Studies identified high risk-of-bias for confounding variables and blinding of assessors in each of the three studies evaluated.CONCLUSIONS: The evidence-base to support dietary modification for gastrointestinal involvement in systemic sclerosis is currently limited and clinical practice guidelines should take a measured approach to such recommendations. The emergence of large patient registries could facilitate the capture of vital practice-based evidence regarding the efficacy of dietary modification in the management of gastrointestinal involvement in systemic sclerosis to inform future clinical practice guidelines.

Objective.Raynaud phenomenon (RP) in systemic sclerosis (SSc) could be influenced by clinical phenotype, environmental factors (e.g., season), and personal factors (e.g., coping strategies and ill-health perceptions). We studied the relative influence of a range of putative factors affecting patient-reported assessment of SSc-RP severity.Methods.SSc patients were enrolled at UK and US sites. Participants completed the 2-week Raynaud Condition Score (RCS) diary alongside collection of patient demographics, clinical phenotype, the Coping Strategies Questionnaire, Pain Catastrophizing Scale, Scleroderma Health Assessment Questionnaire (SHAQ), and both patient/physician visual analog scale (VAS) assessments for RP, digital ulcer disease, and global disease. Environmental temperature data were obtained at each site. A second RCS diary was completed 6 months after enrollment.Results.We enrolled 107 patients (baseline questionnaires returned by 94). There were significant associations between RCS diary variables and both catastrophizing and coping strategies. There were significant associations between RCS diary outcomes and both environmental temperature and season of enrollment. Age, disease duration, sex, disease subtype, smoking, and vasodilator use were not associated with RCS diary outcomes. The best-fitting multivariate model identified the patient RP VAS, SHAQ pain VAS, and SHAQ gastrointestinal VAS subscales as the strongest independent predictors of the RCS.Conclusion.Patient-reported assessment of SSc-RP severity is associated with a number of factors including pain, catastrophizing, and coping strategies. The effects of seasonal variation in environmental temperature on SSc-RP burden has implications for clinical trial design. Treatments targeting SSc-RP pain and the development of behavioral interventions enhancing coping strategies may reduce the burden of SSc-RP.

Digital vascular complications are a major cause of disease-related morbidity in systemic sclerosis (SSc). Demonstrating treatment efficacy in the management of cutaneous vascular manifestations of SSc has been challenging. The contrasting findings of clinical trials of Raynaud’s phenomenon (RP) and digital ulcers (DU) for within-class medications have led to doubt on likely efficacy; with geographic variation in reimbursement policies and variation in clinical practice. In this paper, we compare the contrasting trials of phosphodiesterase inhibitors in the management of SSc-RP and endothelin receptor antagonists in the management of SSc-DU to help identify potential barriers for future successful clinical trials in these fields. Scrutiny of the contrasting clinical trials in these fields has identified a number of important differences in trial design and patient characteristics that may account for differences in clinical trial outcomes. These factors include differences in patient selection, impact of seasonal variation in weather, and the definitions applied to SSc manifestations. The contrasting findings of clinical trials of within-class medications for the management of digital vascular manifestations of SSc have been disappointing but can provide investigators with valuable insight into treatment response in SSc and the pre-requisites for future effective clinical trial design.

Raynaud's phenomenon (RP) and digital ulcers (DUs) are important disease manifestations of systemic sclerosis (SSc) that can lead to significant pain and disability. It is essential when studying these disease features to utilize outcome measures that fully evaluate the complexities of RP and DUs . The Outcome Measures in Rheumatology (OMERACT) Vascular Disease in SSc Working Group is applying the OMERACT filter 2.1 to identify a core set of disease domains that encompass the full burden of SSc-related RP and DUs. Progress to date and future research plans were presented during a Special Interest Group held in December 2020.

Background/Aims Raynaud’s phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for clinical trials in SSc-RP and/or SSc-DU. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy. Methods Standardised searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult patients with SSc. Data were extracted by > 2 reviewers on study design, laser endpoints, and reported outcomes. Study quality was assessed using Cochrane risk of bias tools for randomized trials and the risk-of-bias assessment tool for non-randomized studies (RoBANS) (PROSPERO 2019:CRD42019142409). An additional search was undertaken following external peer review to examine the impact of extending the search terms. Results Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and fourteen non-randomized trials (total of 689 patients with SSc with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The extended search identified an additional two manuscripts reporting the use of LDF to measure perfusion of a single digit in SSc. One was a randomised trial (of 25 patients) and the second an open label study (of 13 patients). These additions did not alter the principal findings of the main review. Combining the two searches, the 31 studies were published between 1987-2019 (17/31 since 2010) and incorporated LDF (13/31), LDI (15/31) and LSCI (4/31, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials (13/18 since 2010). Most studies (17/31, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes. Study quality has improved over time, with 7/11 studies published between 2015-2019 having low risk of bias across all study quality domains. Conclusion Establishing laser-derived methods as an objective, non-invasive assessment of SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy. Disclosure N. Hackett: None. A. Guida: None. J.D. Pauling: Consultancies; Boehringher-Ingelheim, Sojournix Pharma and Actelion pharmaceuticals. Honoraria; Actelion pharmaceuticals. Grants/research support; Actelion pharmaceuticals. P.A. Merkel: Consultancies; AbbVie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Kiniksa, Pfizer, Sparrow, and Talaris. Grants/research support; AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Kypha.