Patients' perspectives on systemic sclerosis-related Raynaud's phenomenon in the feet: A qualitative study from the OMERACT Foot and Ankle Working Group.

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.

A rare form of calcinosis in patients with systemic sclerosis-myositis overlap: report of four cases.

Objectives: Calcinosis is a well-described entity that occurs in patients with systemic sclerosis (SSc) and dermatomyositis (DM). Calcinosis in SSc typically occurs over pressure points and is usually nodular. We present a case series of four patients with SSc with a much rarer, diffuse form of calcinosis to illustrate this poorly recognized pattern of extensive and debilitating disease. Methods: Four patients with SSc and extensive calcinosis were identified from patients attending a tertiary rheumatology centre in the preceding 3 years. Their electronic case notes, radiographic images and medical photographs were reviewed. Results: All four patients had the diffuse cutaneous subtype of SSc (dcSSc) and additionally a myositis overlap. This was in the context of 102 of 461 (22%) patients with SSc whose clinical details had been recorded in the preceding 3 years having dcSSc. Their ages at diagnosis ranged from 27 to 65 years. Three were female, two were anti-Scl70 antibody positive, and two were anti-PMScl antibody positive. Development of calcinosis occurred between 1 and 6 years after onset of SSc. Plain radiography showed very extensive calcinosis in various sites, distributed in a pattern akin to sheets of calcium-containing deposits in the skin and subcutaneous tissue. Conclusions: Although calcinosis is common in SSc, extensive sheet-like calcinosis is very rare. Our experience suggests that when this form of calcinosis does occur, this is in the context of the diffuse cutaneous subtype of disease and with myositis overlap. The four cases described should raise awareness of this unusual and extensive pattern of disease.

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Clinical trajectories of hand function impairment in systemic sclerosis: an unmet clinical need across disease subsets.

BACKGROUND: Hand involvement is an early manifestation of systemic sclerosis (SSc), culprit of diagnosis and classification, and recognised major driver of disability. Impairment of hand function burdens both limited and diffuse cutaneous subsets and therefore could be targeted as 'basket' endpoint in SSc. Nevertheless, its natural history in current standard of care is not well characterised, limiting the design of targeted trials. The aim of this study is to describe prevalence, natural history and clinical factors associated with hand function deterioration in a longitudinal, multicentre, observational SSc cohort. METHODS: Hand function was captured through the validated Cochin Hand Function Scale in patients consecutively enrolled in a multicentre observational study and observed over 24 months. Minimal clinically important differences and patient acceptable symptom state were analysed as previously described. RESULTS: Three hundred and ninety-six consecutive patients were enrolled from 10 centres; 201 with complete follow-up data were included in the analysis. Median (IQR) disease duration was 5 (2-11) years. One hundred and five (52.2%) patients reported clinically significant worsening. Accordingly, the proportion of patients reporting unacceptable hand function increased over 2 years from 27.8% to 35.8% (p<0.001). Least absolute shrinkage and selection operator analysis identified male gender, disease subset, Raynaud's Condition Score, tenosynovitis and pain, as some of the key factors associated with worsening hand involvement. CONCLUSIONS: Hand function deteriorates over time in more than 50% of SSc patients despite available therapies. The analysis of factors associated with hand function worsening supports the involvement of both inflammation, vascular and fibrotic processes in hand involvement, making it a hallmark clinical manifestation of SSc. Our data are poised to inform the design of intervention studies to target this major driver of disability in SSc.

Enrichment strategies for clinical trials targeting skin fibrosis and interstitial lung disease in systemic sclerosis.

PURPOSE OF REVIEW: This review gives an update on enrichment strategies for clinical trials in patients with systemic sclerosis (SSc) in two contexts - skin fibrosis in early diffuse cutaneous disease, and SSc-related interstitial lung disease (ILD) - focusing on reports from the last 18 months. Lessons have been learnt from recent studies, making this review timely. RECENT FINDINGS: Recent trials have highlighted how patients included into trials must be carefully selected to include 'progressors', that is, those most likely to benefit from treatment, and how drug mechanism action of action will influence trial design. For skin fibrosis, current enrichment strategies are mainly on clinical grounds (including disease duration, extent of skin thickening, tendon friction rubs and anti-RNA polymerase III positivity). Gene expression signatures may play a role in the future. For ILD, current enrichment strategies (degree of lung involvement as assessed by pulmonary function and high-resolution computed tomography) may help to recruit the most informative patients, but should avoid being too stringent to be feasible or for findings to be generalizable. SUMMARY: Both skin fibrosis and ILD trials are challenging in SSc. Ongoing work on enrichment strategies should help to differentiate effective new treatments from placebo with smaller sample sizes than have been included in recent studies.

Non-invasive imaging and clinical skin scores in juvenile localised scleroderma.

OBJECTIVES: To evaluate whether in juvenile localised scleroderma (JLS), non-invasive imaging can differentiate affected from non-affected skin and whether imaging correlates with a validated skin score (Localised Scleroderma Cutaneous Assessment Tool, LoSCAT). METHODS: 25 children with JLS were recruited into a prospective study and a single 'target' lesion selected. High frequency ultrasound (HFUS, measuring skin thickness), infrared thermography (IRT, skin temperature), laser Doppler imaging (LDI, skin blood flow) and multispectral imaging (MSI, oxygenation), were performed at four sites: two of affected skin (centre and inner edge of lesion) and two of non-affected skin (one cm from edge of lesion 'outer' and contralateral non-affected side), at 4 visits at 3 monthly intervals. RESULTS: Differences between affected and non-affected skin were detected with all 4 techniques. Compared with non-affected skin, affected skin was thinner (p< 0.001) with higher temperature (p< 0.001-0.006), perfusion (p< 0.001-0.039) and oxygenation (p< 0.001-0.028). Lesion skin activity (LoSCAT) was positively correlated with centre HFUS (r = 0.32; 95% CI [0.02, 0.61]; p= 0.036) and negatively correlated with centre LDI (r=-0.26; 95% CI [-0.49, -0.04]; p= 0.022). Lesion skin damage was positively correlated with centre and inner IRT (r = 0.43; 95% CI [0.19, 0.67]; p< 0.001, r = 0.36, 95% CI [0.12, 0.59]; p= 0.003, respectively) and with centre and inner LDI (r = 0.37; 95% CI [0.05, 0.69]; p= 0.024, r = 0.41; 95% CI [0.08, 0.74]; p= 0.015, respectively). CONCLUSION: Non-invasive imaging can detect differences between affected and non-affected skin in JLS and may help to differentiate between activity (thicker, less well perfused skin) and damage (thinner, highly perfused skin).

Construct validity and reliability of the assessment of systemic sclerosis-associated raynaud's phenomenon (ASRAP) questionnaire.

OBJECTIVES: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic sclerosis-associated RAynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1-week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. RESULTS: Four hundred and twenty SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, p< 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, p< 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, p< 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (p< 0.05 for all comparisons). There was excellent repeatability at 1-week amongst patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, p< 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77 respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53-7.81, p= 0.029) was estimated. CONCLUSION: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

Risk of Malnutrition in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease Treated With Nintedanib in the Randomized, Placebo-Controlled SENSCIS Trial.

OBJECTIVE: To assess adverse events (AEs) in relation to baseline body mass index (BMI) and the risk of malnutrition in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) treated with nintedanib. METHODS: Among patients with SSc-ILD randomized to receive nintedanib or placebo in the SENSCIS trial, we assessed AEs in subgroups by baseline BMI ≤20 kg/m2 and BMI >20 kg/m2 , and the risk of malnutrition using a modified version of the Malnutrition Universal Screening Tool (MUST), over 52 weeks. RESULTS: The AE profile of nintedanib was similar between subgroups with a baseline BMI ≤20 kg/m2 (n = 61) and a baseline BMI >20 kg/m2 (n = 515). In these subgroups, respectively, AEs led to treatment discontinuation in 16.7% and 15.9% of the nintedanib group and 13.5% and 8.0% of the placebo group, respectively. Based on the modified MUST, the proportions of patients who had a low risk of malnutrition at baseline and at their last assessment were 74.0% in the nintedanib group and 78.1% in the placebo group, while the proportions who were classified as at low risk at baseline but at high risk by their last assessment were 4.5% in the nintedanib group and 1.0% in the placebo group. CONCLUSION: In the SENSCIS trial, most patients with SSc-ILD remained at low risk of malnutrition over 52 weeks, but the proportion at high risk was higher in patients who received treatment with nintedanib compared to those who received placebo. Management of disease manifestations and AEs that may be associated with weight loss is important to reduce the risk of malnutrition in patients with SSc-ILD.

Pharmacological management of digital ulcers in systemic sclerosis - what is new?

INTRODUCTION: Digital ulcers (DUs) develop in approximately 50% of patients with systemic sclerosis (SSc). DUs are painful and disfiguring, with a major impact on hand function and quality of life. Although some pharmacological treatments have been shown to confer benefit, new treatments are badly needed: SSc-related DUs are an area of major unmet clinical need. This review focuses on advances in pharmacological management. AREAS COVERED: DU definition, types of DU, and clinical burden are briefly described and the general approach to multidisciplinary management, followed by a more detailed description of pharmacological management, with particular reference to blocking the endothelin pathway, and supplementing the nitric oxide and prostacyclin pathways. Other aspects of pharmacological management, including analgesia and botulinum toxin injections are also discussed. To inform the review, the MEDLINE database was searched for English-language papers published between 1946 and December 2022 using search terms: 'systemic sclerosis (scleroderma)' and 'digital ulcer' or 'finger ulcer' or 'digital vasculopathy.' EXPERT OPINION: The key challenges to preventing and treating DUs are to develop and validate reliable, sensitive outcome measures to facilitate clinical trials, and then to undertake trials of emerging new approaches to treatment, including topical therapies and (in early disease) vascular remodeling therapies.

Domain reporting in systemic sclerosis-related Raynaud's phenomenon: An OMERACT scoping review.

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.

Domain reporting in Systemic Sclerosis-Related Digital Ulcers: An OMERACT Scoping Review.

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.

Treatment of Vascular Complications in Systemic Sclerosis: What Is the Best Approach to Diagnosis and Management of Renal Crisis and Digital Ulcers?

Vasculopathy as exemplified by scleroderma renal crisis (SRC) and digital ulcers (DUs) is a cardinal feature of systemic sclerosis (SSc) and is associated with significant morbidity, including in patients with early disease. Prompt recognition and management is required to alleviate potentially irreversible damage from SSc-associated vasculopathy. Both SRC and DUs share many etiopathogenic drivers which inform the therapeutic strategy. The aim of our review was to describe the diagnosis and management of SRC and DUs in SSc, and to discuss unmet needs for future research.

A deep learning system for quantitative assessment of microvascular abnormalities in nailfold capillary images.

OBJECTIVES: Nailfold capillaroscopy is key to timely diagnosis of SSc, but is often not used in rheumatology clinics because the images are difficult to interpret. We aimed to develop and validate a fully automated image analysis system to fill this gap. METHODS: We mimicked the image interpretation strategies of SSc experts, using deep learning networks to detect each capillary in the distal row of vessels and make morphological measurements. We combined measurements from multiple fingers to give a subject-level probability of SSc.We trained the system using high-resolution images from 111 subjects (group A) and tested on images from subjects not in the training set: 132 imaged at high-resolution (group B); 66 imaged with a low-cost digital microscope (group C). Roughly half of each group had confirmed SSc, and half were healthy controls or had primary RP ('normal'). We also estimated the performance of SSc experts. RESULTS: We compared automated SSc probabilities with the known clinical status of patients (SSc versus 'normal'), generating receiver operating characteristic curves (ROCs). For group B, the area under the ROC (AUC) was 97% (94-99%) [median (90% CI)], with equal sensitivity/specificity 91% (86-95%). For group C, the AUC was 95% (88-99%), with equal sensitivity/specificity 89% (82-95%). SSc expert consensus achieved sensitivity 82% and specificity 73%. CONCLUSION: Fully automated analysis using deep learning can achieve diagnostic performance at least as good as SSc experts, and is sufficiently robust to work with low-cost digital microscope images.

A Phase II randomized controlled trial of oral prednisolone in early diffuse cutaneous systemic sclerosis (PRedSS).

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.

A phase 2 trial investigating the effects of the angiotensin II type 2 receptor agonist C21 in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. METHODS: This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3-7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. RESULTS: For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20 046°C*s vs 19 558°C*s), but not significantly (P = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P = 0.036). C21 was well tolerated. CONCLUSION: Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04388176.