Systemic sclerosis sine scleroderma is more aggressive in children than in adults.

OBJECTIVES: To compare the clinical and laboratory features of paediatric SSc sine scleroderma (ssJSSc) with adult-onset ssSSc. METHODS: Demographic, clinical and laboratory data of ssJSSc, retrospectively retrieved from our hospital medical records, case reports from the literature and from the Pediatric Rheumatology European Society JSSc registry, were compared with the Padua cohort of adult patients with ssSSc. Patients were defined as having ssSSc if they never had skin involvement but all the following features: (i) RP and/or digital vasculopathy, (ii) positive ANA, (iii) internal organs involvement typical of scleroderma and (iv) no other defined CTD. RESULTS: Eighteen juvenile and 38 adult-onset ssSSc patients, mean disease duration 5.8 and 9.7 years, respectively, entered the study. The frequency of females affected was significantly lower in ssJSSc (38.9% vs 89.5%, P < 0.0001). When compared with adults, ssJSSc displayed fewer SSc-specific capillaroscopy abnormalities (68.8% vs 94.7%, P = 0.02) while having significantly higher vascular (digital pitting scars, ulcers 35.3% vs 10.5%, P = 0.042), respiratory (50.0% vs 23.7%, P = 0.02) and cardiac (50.0% vs 2.6%, P < 0.0001) involvement. The outcome was significantly worse in ssJSSc as six patients (33%) died (n = 3) or reached an end-stage organ failure (n = 3) in comparison with only two deaths (5.3%) in the adult cohort. ACA were significantly lower in children (20.0% vs 68.4%, P = 0.001) while no difference was noted for other SSc-specific autoantibodies. CONCLUSION: Compared with adults where ssSSc generally has an indolent course, children present with aggressive disease that heralds a worse prognosis characterized by high cardiorespiratory morbidity and mortality.

Development of a measuring app for systemic sclerosis-related digital ulceration (SALVE: Scleroderma App for Lesion VErification).

OBJECTIVES: To test the hypothesis that photographs (in addition to self-reported data) can be collected daily by patients with systemic sclerosis (SSc) using a smartphone app designed specifically for digital lesions, and could provide an objective outcome measure for use in clinical trials. METHODS: An app was developed to collect images and patient reported outcome measures (PROMS) including Pain score and the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU) questionnaire. Participants photographed their lesion(s) each day for 30 days and uploaded images to a secure repository. Lesions were analysed both manually and automatically, using a machine learning approach. RESULTS: 25 patients with SSc-related digital lesions consented of whom 19 completed the 30-day study, with evaluable data from 27 lesions. Mean (standard deviation [SD]) baseline Pain score was 5.7 (2.4) and HDISS-DU 2.2 (0.9), indicating high lesion and disease-related morbidity. 506 images were used in the analysis (mean number of used images per lesion 18.7, SD 8.3). Mean (SD) manual and automated lesion areas at day 1 were 11.6 (16.0) and 13.9 (16.7) mm2 respectively. Manual area decreased by 0.08mm2 per day (2.4mm2 over 30 days) and automated area by 0.1mm2 (3.0mm2 over 30 days). Average gradients of manual and automated measurements over 30 days correlated strongly (r = 0.81). Manual measurements were on average 40% lower than automated, with wide limits of agreement. CONCLUSION: Even patients with significant hand disability were able to use the app. Automated measurement of finger lesions could be valuable as an outcome measure in clinical trials.

Patients' unmet needs and treatment preferences concerning digital ulcers in systemic sclerosis.

INTRODUCTION: Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs. MATERIALS: SSc patients were invited through international patient associations and social media to participate in an online survey. RESULTS: 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment. CONCLUSIONS: Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management.

Thymic stromal lymphopoietin and digital microvascular damage in systemic sclerosis patients: A pilot study.

BACKGROUND: Systemic sclerosis (SSc) is a complex autoimmune connective-tissue disease, characterised by vasculopathy and fibrosis of the skin and internal organs. Activation of microvascular endothelial cells (ECs) causes the intimal hyperplasia that characterises the vascular remodelling in SSc. The most frequent complication of SSc is the development of digital ulcers (DUs). Thymic stromal lymphopoietin (TSLP) may trigger fibrosis and sustain vascular damage. Aim of this study was to evaluate the correlation between serum level of TSLP and DUs. METHODS: 75 consecutive SSc patients were enrolled and serum TSLP levels were measured. The presence of history of DUs (HDU) was evaluated. Recurrent new DUs were defined as the presence of at least 3 episodes of DUs in a 12-months follow up period. The risk of developing new DUs was calculated by applying the capillaroscopic skin ulcer risk index (CSURI). RESULTS: The median value of TSLP was higher in patients with HDU than patients without HDU [181.67 pg/ml (IQR 144.67; 265.66) vs 154.67 pg/ml (IQR 110.67; 171.33), p < 0.01]. The median value of TSLP was higher in patients with an increased CSURI index than patients without an increased CSURI [188 pg/ml (IQR 171.33; 246.33) vs 159.33 pg/ml (IQR 128.67; 218), p < 0.01]. Kaplan-Meier curves demonstrated that free survival from new DUs was significantly (p < 0.01) lower in SSc patients with increased TSLP serum levels. CONCLUSION: TSLP might have a key role in digital microvascular damage of SSc patients.

Long-Term Data on Efficacy and Safety of Selexipag for Digital Systemic Sclerosis Vasculopathy.

OBJECTIVE: Raynaud phenomenon (RP) and digital ulcers (DUs) are the main signs of digital vasculopathy in systemic sclerosis (SSc). Selexipag is an oral prostacyclin agonist approved for SSc-related pulmonary arterial hypertension. Following our previous preliminary short-course report, we herein present long-term data on selexipag safety and efficacy in the treatment of SSc digital vasculopathy. METHODS: Selexipag was administered to patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies. Each subject was assessed at baseline and after 3, 6, and 12 months. Clinical outcomes related to RP and DUs were evaluated along with modified Rodnan skin score of the fingers. Digital perfusion was assessed by laser speckle contrast analysis (LASCA). Nailfold videocapillaroscopy (NVC) was also performed. RESULTS: Eight patients with SSc (63% female, mean age 50.1 years) received selexipag. After 12 months of treatment, RP was reported to significantly decrease in the number of daily episodes and mean duration (P < 0.001 and P = 0.01, respectively). All patients achieved a complete healing of their DUs (P = 0.03) within 6 months. A progressive reduction of fingers skin score was observed (P = 0.03). No structural changes of capillaries were noted on NVC. Conversely, LASCA revealed an important increase in total digital perfusion (P = 0.004) despite seasonal variability. The safety profile was consistent with that reported in the literature. CONCLUSION: We observed a sustained efficacy of selexipag on SSc digital vasculopathy during 1 year of administration. Our promising results encourage the design of a new randomized controlled trial to evaluate the effect of selexipag on SSc digital vasculopathy.

Associations of Digital Ulcers in Patients with Systemic Sclerosis: An 8-Year Retrospective Study.

INTRODUCTION: This study aimed to investigate the associations of digital ulcers (DUs) in patients with systemic sclerosis (SSc). METHODS: This retrospective study investigated the demographic characteristics, specific autoantibodies, organ involvement, and laboratory tests in patients with SSc from our hospital. RESULTS: This study enrolled 144 patients with SSc. The DU+ group consisted of 15 (10.4%) patients. Patients with SSc having DUs have longer disease duration, higher fibrinogen, higher fibrin degradation product, and lower cholesterol. None of the patients used cholesterol-lowering drugs before onset of DUs. The study also demonstrated a higher prevalence of anti-dsDNA and anti-histone antibodies in patients with SSc with DUs. Anti-dsDNA antibody is a specific antibody for SLE with a specificity of 96-99%. A total of 86.1% (124/144) of patients suffered from diffuse cutaneous SSc, and 28.5% (41/144) of patients suffered from overlap syndrome. CONCLUSION: Our study indicated that patients with SSc with fibrinogen of >2.895 g/L (p = 0.043) and cholesterol of <3.340 mmol/L (p = 0.036), which is equal to 129.258 mg/dL, are at high risk of developing DUs.

Tuberculosis is the predominant infection in systemic sclerosis: thirty-year retrospective study of serious infections from a single centre.

To look for the spectrum of infections and the factors predisposing to infection in patients with systemic sclerosis (SSc). In this retrospective study, demographic, clinical features, details of infections, immunosuppressive therapy, and outcomes of patients with SSc attending clinics at department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India from 1990 to 2022 were captured. Multivariable-adjusted logistic regression was applied to identify independent predictors of infection. Data of 880 patients, mean age 35.5 ± 12 years, and female: male ratio 7.7:1, were analyzed. One hundred and fifty-three patients had at least 1 infection with a total of 233 infectious episodes. Infections were most common in lung followed by skin and soft tissue. Tuberculosis was diagnosed in 45 patients (29.4%). Klebsiella was the commonest non-tubercular organism in lung and Escherichia coli in urinary tract infections. In comparison to matched control group, patients with infection had a greater number of admissions due to active disease, odds ratio (OR) 6.27 (CI 3.23-12.18), were receiving immunosuppressive medication OR, 5.05 (CI 2.55-10.00), and had more digital ulcers OR, 2.53 (CI 1.17-5.45). Patients who had infection had more likelihood for death OR, 13.63 (CI 4.75 -39.18). Tuberculosis is the commonest infection and lung remains the major site of infection in patients with SSc. Number of hospital admissions, digital ulcers and immunosuppressive therapy are predictors of serious infection in patients with SSc. Patients with infections had more likelihood of death.

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review.

OBJECTIVE: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. METHODS: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. RESULTS: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. CONCLUSION: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.

Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model.

OBJECTIVE: To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. METHODS: We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. RESULTS: Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. CONCLUSION: The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Association between oxygen delivery and digital ulcers in systemic sclerosis.

OBJECTIVE: Tissue hypoxia due to microvasculopathy is the main cause of digital ulcers (DUs) in systemic sclerosis (SSc). Reduced oxygen delivery (DO2) to the tissues may also contribute to the development of DU. This study was conducted to investigate the association between DO2 and DUs in patients with SSc. METHODS: In all, 111 patients and 30 healthy controls were enrolled. DO2 was calculated by using the formula; DO2 = Cardiac output × arterial oxygen saturation (SpO2) × serum haemoglobin level × 1.39 × 10. Both right index finger SpO2 measurements (index-SpO2) and highest value of SpO2 (maximum SpO2) obtained among the fingers of the subjects were used for the calculations and DO2 results were adjusted both for weight and body surface area (BSA). RESULTS: Mean DO2 was lower in SSc patients as compared to controls in all 4 different calculations but the difference was only statistically significant when using index-SpO2 and adjusting for BSA (498 mL/min/m2 vs 549 mL/min/m2, p = 0.03). There was a strong positive correlation between cardiac output and DO2 calculated by using the index-SpO2 (r = 0.903; p < 0.001). Of the SSc patients, 46 (41.4 %) had DUs within the last 12 months. Patients with DUs had higher mean mRSS, lover mean FVC and more frequently diffuse disease, interstitial lung disease, anti-SCL70 antibody positivity (p < 0.05 for all). No difference was observed in DO2 among DU positive or DU negative groups by any calculation (p > 0.05 for all). CONCLUSIONS: DO2 in SSc patients seems to be lower than healthy controls. However, DO2 is similar between the patients with and without DUs. Our results suggest that the contribution of DO2 is negligible to the development of DU and support the major role of microvasculopathy in SSc patients with DUs.

Evidence and consensus-based recommendations for non-pharmacological treatment of fatigue, hand function loss, Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis.

OBJECTIVE: SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms. METHODS: A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined. RESULTS: Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force. CONCLUSIONS: These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.

Improvement with time of vascular outcomes in systemic sclerosis: a systematic review and meta-analysis study.

OBJECTIVES: Vascular disease in SSc is associated with significant morbidity and mortality. Preliminary data may lead to the suggestion of a modifiable unified-vascular endophenotype. Our aim was to determine whether the prevalence, mortality and severity of SSc-vascular disease have changed over time. METHODS: We performed a systematic review and meta-analysis of the literature in PubMed 1950-2019 related to SSc-digital ulcers (DUs), pulmonary artery hypertension (PAH) and scleroderma renal crisis (SRC). We included full-text articles and extracted study characteristics and assessed risk of bias/quality. We examined the prevalence, mortality and surrogate measures of SSc-associated vascular disease severity. RESULTS: We included 55 studies in our meta-analysis. The pooled prevalence of DUs (41.0%), PAH (9.5%) and SRC (4.9%) remained largely stable over time. There was significant improvement in PAH 1-year (P = 0.001) and SRC mortality (P < 0.001), but not PAH 3-year (P = 0.312) or 5-year (P = 0.686) mortality. The prevalence of DU healing did not significantly change (P = 0.265). There was a trend (all P = ∼0.1) towards improvement in PAH surrogates: mean pulmonary artery pressure, pulmonary vascular resistance and right atrial pressure. For SRC, there was evidence that the overall frequency of dialysis (66.7%, P = 0.297) and permanent dialysis (35.4%, P = 0.036) increased over time. CONCLUSION: Despite the heterogeneity and scarcity of the disease, there have been major improvements obtained in the various vascular complications in SSc leading to benefit in survival. This is supported by a trend towards improvement in several surrogate markers and demonstrates that progress in vascular management translates into major patient benefit.

Maresin1 is a predictive marker of new digital ulcers in systemic sclerosis patients.

BACKGROUND: Digital ulcers (DUs) are one of the main causes of disability among systemic sclerosis (SSc) patients. The inflammation plays a crucial role in mediating the pathophysiological process underlying SSc. Objective of this study was to evaluate Maresin1 (MaR1) serum levels in SSc patients and in healthy controls (HC). Secondary aims were to evaluate the relationship between MaR and diseases variables and to assess the predictive role of MaR1 in the development of new digital ulcers (DUs) during 18 weeks follow-up. METHODS: MaR1 serum level was evaluated in 55 SSc patients and 24 HC. In SSc patients, clinical assessment was performed at baseline and after 18 week follow-up by the same-blinded observer on serum MaR1 levels. RESULTS: MaR1 was significantly lower in SSc patients than in HC [367 pg/ml (IQR 304-468.3 pg/ml) vs 467.7 pg/ml (IQR 422-522 pg/ml), p < 0.001]. During follow-up, six patients (10.9%) developed DUs. MaR1 was higher in SSc patients with new DUs than in patients without new DUs [518.2 pg/ml (IQR 468.2-596.5 pg/ml) vs 355 pg/ml (IQR 299.8-444.7 pg/ml), p < 0.01]. Free survival from new DUs is significantly lower in SSc patients with increased MaR1 serum level than in SSc patient with normal MaR1 serum level. In multivariate analysis, serum level of MaR1 > 393.2 pg/ml is a predictive marker for new DUs. CONCLUSION: In SSc patients, MaR1 is reduced compared to HC and it is a predictive marker of new DUs.

Definition and application of proximal-distal gradient finger perfusion in systemic sclerosis by laser speckle contrast analysis.

OBJECTIVE: In patients with systemic sclerosis (SSc) the perfusion of the fingers shows an alteration of the physiological proximal-distal gradient (PDG). The aim of this study is to provide a generalizable definition of PDG, applying it in a cohort of SSc patients and healthy controls (HC) using laser speckle contrast analysis (LASCA). METHODS: Adult consecutive SSc patients and HC were enrolled. Peripheral blood perfusion of the hands was evaluated by LASCA, subsequently obtaining 3 different regions of interest: from the distal interphalangeal joint to the fingertip (DIST), from the metacarpophalangeal joint to the distal interphalangeal joint (PROX), and of the whole finger (TOT). A PDG formula independent of both intra- and inter-personal factors was then built. The PDG formula so obtained was: [(DIST × 2.63) - PROX]/TOT. RESULTS: Ninety-four SSc patients (79.8% female, mean age 58.7 years) were enrolled. Applying the PDG formula, SSc patients revealed mean PDG values significantly lower than HC (1.82 ± 0.44 PU vs 2.70 ± 0.38 PU; p < 0.0001). Patients with a previous history of digital ulcers presented significant lower PDG values (p = 0.002). The ROC curve analysis identified in 2.28 PU the best PDG cut-off value between SSc and HC, with 86% sensibility and 90% specificity. CONCLUSION: This study provided a PDG formula generalizable to all kind of subjects, applying it in SSc with great sensibility and specificity using LASCA, the best non-invasive imaging technique for the dynamical evaluation of peripheral perfusion. LASCA-PDG appears also as a tool able to identify a subclinical microangiopathic impairment.

IL33 and sST2 serum level in systemic sclerosis microvascular involvement.

AIM: Endothelial dysfunction and microvascular damage are hallmarks of systemic sclerosis (SSc). Objective of this study was to evaluate IL33 and ST2 serum levels in SSc patients and healthy controls (HC). Secondary aim was to evaluate the IL33 axis in the SSc microvascular manifestation. METHODS: IL33 and sST2 have been assessed in 46 SSc patients and 24 HC matched for sex and age. Main clinimetric indexes were assessed. Skin perfusion of hands was evaluated by Laser Speckle Contrast Analysis (LASCA) and echocolordoppler ultrasound of renal arteries was performed to evaluate subclinical renal involvement. RESULTS: SSc patients had higher serum level of IL33 and sST2 than HC. IL33 and sST2 were significantly higher in SSc patient with digital ulcers (DUs) compared to SSc patients without DUs. SSc patients with late nailfold videocapillaroscopy (NVC) pattern had higher serum levels of sST2 than SSc patients with active NVC pattern. SSc patients without proximal-distal gradient (PDG) at LASCA had significantly higher sST2 serum level compared to SSc patients with PDG. SSc patients with renal resistive index (RRI) ≥ 0.70 had higher serum levels of sST2 than SSc patients with RRI < 0.70. A positive linear correlation was shown between sST2 and RRI, between sST2 and intrarenal S/D and between sST2 and PI. Kaplan-Meier curves show a significantly reduced free survival from DUs in patients with increased sST2 (p = 0.025). In multivariate analysis, sST2 is associated with the development of new DUs. CONCLUSION: IL33 and sST2 are increased in SSc patients and ST2 might be a marker of microvascular damage.

Systemic sclerosis in adults. Part II: management and therapeutics.

The management of systemic sclerosis (SSc) is complex, evolving, and requires a multidisciplinary approach. At diagnosis and throughout the disease course, clinical assessment and monitoring of skin involvement is vital using the modified Rodnan Skin Score, patient-reported outcomes, and new global composite scores (such as the Combined Response Index for Systemic Sclerosis, which also considers lung function). Immunomodulation is the mainstay of skin fibrosis treatment, with mycophenolate mofetil considered first line. Meanwhile vasculopathy-related manifestations (Raynaud's phenomenon, digital ulcers) and calcinosis, require general measures combined with specific pharmacologic (calcium-channel blockers, phosphodiesterase type 5 inhibitors, and prostanoids), nonpharmacologic (digital sympathectomy and botulinum toxin injections), and often multifaceted, management approaches. Patients should be screened at the time of diagnosis specifically for systemic manifestations and then regularly thereafter, with appropriate treatment. Numerous targeted therapeutic options for SSc, including skin fibrosis, are emerging and include B-cell depletion, anti-interleukin 6, Janus kinase, and transforming growth factor ß inhibition. This second article in the continuing medical education series discusses these key aspects of SSc assessment and treatment, with particular focus on skin involvement. It is vital that dermatologists play a key role in the multidisciplinary approach to SSc management.

CD21low B cells are predictive markers of new digital ulcers in systemic sclerosis.

The objective of this study was to evaluate the predictive role of CD21low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12-month follow-up. After a 12-month follow-up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3-13.6) versus 4.8 (3.5-7.4); p < 0.01]. The 10% cut-off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587-0.878; P = 0.01]. Kaplan-Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients.

Laser speckle contrast analysis predicts major vascular complications and mortality of patients with systemic sclerosis.

OBJECTIVES: The aim of study was to evaluate peripheral blood perfusion and the proximal-distal gradient (PDG) of the hands as biomarkers of SSc major vascular complications (digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis) and mortality by laser speckle contrast analysis. METHODS: In this retrospective observational study, 176 SSc patients [158 female, median age 53 (51-57) years] and 142 healthy controls [115 female, median age 53 (48-55) years] were enrolled. Clinical data were collected at baseline and annually through 5 years of follow-up. Hand dorsum perfusion images were divided into three regions of interest (ROI): ROI1 included the second, third, and fourth fingers distal to the proximal interphalangeal finger joint; ROI2 included the area between the proximal interphalangeal finger joint and the metacarpophalangeal joint; ROI3 included the hand dorsum. PDG was identified when the perfusion mean difference between ROI1 and ROI2 was >30 perfusion units. RESULTS: Median peripheral blood perfusion was significantly lower for SSc patients than healthy controls. PDG was present in 51.5% of SSc patients and in 98.6% of healthy controls. Using the final multivariate model, nailfold videocapillaroscopy (NVC) pattern [hazard ratio (HR) 0.065 (0.015-0.283), P <0.0001] and PDG [HR 0.376 (0.194-0.727), P <0.01] were found to be risk factors for major vascular complications. By multivariate analysis, age [HR 1.051 (1.014-1.088), P <0.01), NVC pattern [HR 0.001 (0.000-3.111), P >0.05], and PDG [HR 0.207 (0.073-0.589), P <0.01] were found to be risk factors for 5-year SSc mortality. CONCLUSION: PDG predicts major vascular complication and 5-year mortality of SSc patients.

Color Doppler Ultrasonography of digital arteries and digital ulcers development in systemic sclerosis.

BACKGROUND: The aim of this study was to evaluate the role of Color Doppler Ultrasonography (CDUS) of proper palmar digital arteries (PPDA) as predictive marker of new digital ulcers (DUs) in systemic sclerosis (SSc) patients during 5 years follow-up. METHODS: 36 SSc patients were examined using nailfold videocapillaroscopy (NVC) and CDUS of PPDA. RESULTS: Fourteen (38.9%) patients had chronic or acute occlusions (C and D pattern) on CDUS evaluation. Using a cut-off of 0.70, 21 (58.3%) patients had a Resistive Index (RI) ≥0.70. Nineteen (52.8%) patients developed new DUs during the follow-up. The median value of RI was higher in SSc patients with DUs than in SSc patients without DUs [0.73 (IQR 0.70-0.81) vs 0.67 (IQR 0.57-0.70), p < 0.0001]. The Kaplan-Meier analysis showed a free survival from new DUs higher (p < 0.01) in SSc patients with Pattern A and B than SSc patients with Pattern C and D. The Kaplan-Meier curves showed that free survival from new DUs is lower (p < 0.001) in SSc patients with increased RI (≥0.70) than in SSc patients with normal RI. In multivariate analysis with two co-variates, RI ≥ 0.70 [HR 5.197 (1.471-18.359), p < 0.01] and NVC late scleroderma pattern [HR 7.087 (1.989-25.246), p < 0.01] were predictive markers of new DUs. CONCLUSIONS: RI of PPDA in association with NVC could be used to evaluate SSc patients with increased risk of new DUs development.

Locoregional Treatments for Digital Ulcers in Systemic Sclerosis: A Systematic Review.

The management of digital ulcers in systemic sclerosis is difficult. While the 2017 European League Against Rheumatism (EULAR) guidelines clearly defined the use of systemic therapies for digital ulcers, little is known about the efficacy of locoregional treatments. The aim of this review is to systematically assess the spectrum of published locoregional therapies for digital ulcers. A total of 58 studies were included. Among the different locoregional treatment strategies described, injections of fat-derived cells and botulinum toxin showed promising results in the reduction of pain and the number of digital ulcers. By contrast, this review found that sympathectomy yielded disappointing results, with low rates of effectiveness and frequent recurrence. For other treatments, such as hyperbaric oxygen therapy, phototherapy (ultraviolet A), low-level light therapy, intermittent compression, Waon therapy, extracorporeal shockwave, vitamin E gel, and topical dimethyl sulphoxide, the conflicting results or limited published data reflected the low level of evidence. Larger randomized clinical trials are required to confirm the validity of promising techniques.