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Objectives To test the hypothesis that photographs (in addition to self-reported data) can be collected daily by patients with 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 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 Twenty-five patients with SSc-related digital lesions consented, of whom 19 completed the 30-day study, with evaluable data from 27 lesions. Mean (s. d.) baseline Pain score was 5.7 (2.4) and HDISS-DU 2.2 (0.9), indicating high lesion- and disease-related morbidity. A total of 506 images were used in the analysis [mean number of used images per lesion 18.7 (s. d. 8.3)]. Mean (s. d.) manual and automated lesion areas at day 1 were 11.6 (16.0) and 13.9 (16.7) mm2, respectively. Manual area decreased by 0.08 mm2 per day (2.4 mm2 over 30 days) and automated area by 0.1 mm2 (3.0 mm2 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 ones, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Localised scleroderma and systemic sclerosis are rare chronic fibrosing disorders seen in children, and are collectively referred to as Juvenile Scleroderma. Histopathology of the two forms is non-distinct but they differ in terms of vasculopathy, internal organ involvement, morbidity and mortality. Raynaud's phenomenon with digital tip ulcers is considered hallmark of systemic sclerosis. Quality of life gets greatly affected by these diseases. Early identification in the inflammatory phase of the disease, effective treatment and strict surveillance remain crucial for better outcomes. Emerging vascular and immunosuppressive strategies, coupled with efforts from scientific community to develop better biomarkers and monitoring tools, help constantly to improve survival rates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To explore the characteristics of systemic sclerosis with acro-ulceration (SSc-DUs) and its association with organ involvement and autoantibodies in order to improve the understanding of the disease. Methods The clinical data of 70 patients with SSc-DUs were analyzed retrospectively, and the sites of ulcer and organ involvement were also analyzed. The clinical data of 155 patients with systemic sclerosis without acroulcers (SSc-No-DUs) were used as controls to assess the association between SSc-DUs and organ involvement and autoantibodies. Results The most common sites of ulcers were the fingertips (51.43%), interphalangeal joints (22.86%) and toes (15.71%), while the involvements of the heel, elbow and ankle joints were relatively rare. The rates of heart failure (31.42%) and esophageal involvement (65.71%) in SSc-DUs group were higher than those in SSc-No-DUs group (both P0.05). Conclusions The ulcers in patients with SSc-DUs are more common in the fingertips and interphalangeal joints. SSc-DUs patients are more likely to have esophageal involvement and a higher incidence of heart failure. Anti-Scl-70 antibody (+), anti-SSA antibody (+), and anti-Ro-52 antibody (+) may be danger signs of the development of ulcers.

Objective: Unusual clinical course Background: Vascular Behçet's disease (VBD) is a rare but potentially life-threatening subtype of Behçet's disease that is characterized by multisystemic vasculitis. It primarily affects males with ancestry traced back to regions along the ancient Silk Road. Both arteries and veins, regardless of size, may exhibit complications, including aneurysmal degeneration or occlusion. While venous involvement is observed in two-thirds of VBD cases, arterial complications are notably the most severe and lethal. Arterial aneurysmal degeneration is more common than occlusive complications, with larger arteries being predominantly affected in VBD. Data regarding isolated small-vessel arterial occlusive disease in VBD are limited. Given the rarity of this presentation in this patient population, it becomes mandatory to thoroughly evaluate such patients to differentiate small-vessel vasculitis from other similar diseases, such as Raynaud's phenomenon, which has a different etiology and management and generally has a more benign course. Here, we delineate the concept of isolated small-vessel vasculitis as a cause of blue toe syndrome in patients with VBD. Case Report: This report describes a distinctive case of vascular Behçet's disease in a 51-year-old man who initially exhibited unilateral blue toe syndrome, which swiftly progressed to dry gangrene of the toes. Despite reports of large-vessel involvement, there is a paucity of data on isolated small-vessel vasculitis-induced digital ischemia in VBD. Conclusions: This atypical case underscores the necessity of clinical discernment in differentiating inflammatory microvascular occlusive disease from vasospastic Raynaud's syndrome, both of which can complicate Behçet's disease. [ABSTRACT FROM AUTHOR]

Objective To explore the characteristics of systemic sclerosis with acro-ulceration (SSc-DUs) and its association with organ involvement and autoantibodies in order to improve the understanding of the disease. Methods The clinical data of 70 patients with SSc-DUs were analyzed retrospectively, and the sites of ulcer and organ involvement were also analyzed. The clinical data of 155 patients with systemic sclerosis without acroulcers ( SSc-No-DUs) were used as controls to assess the association between SSc-DUs and organ involvement and autoantibodies. Results The most common sites of ulcers were the fingertips (51.43%), interphalangeal joints (22. 86% ) and toes (15. 71% ), while the involvements of the heel, elbow and ankle joints were relatively rare. The rates of heart failure (31. 42% ) and esophageal involvement (65. 71% ) in SSc-DUs group were higher than those in SSc-No-DUs group (both P <0. 05). The positive rates of anti-SCL-70 antibody (80.00%), anti-SSA antibody (38.57%) and anti-Ro-52 antibody (22. 86% ) in SSc-DUs group were higher than those in SSc-No-DUs group (all P <0. 05) . There were no significant differences in the incidence of the lung, kidney and thyroid diseases, positive titer of anti-nuclear antibody, typing of anti-nuclear antibody, immunoglobulin and complement levels between the two groups (all P >0. 05). Conclusions The ulcers in patients with SSc-DUs are more common in the fingertips and interphalangeal joints. SSc-DUs patients are more likely to have esophageal involvement and a higher incidence of heart failure. Anti-Scl-70 antibody ( + ), anti-SSA antibody ( + ), and anti-Ro-52 antibody ( + ) may be danger signs of the development of ulcers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. Methods: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Results: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 nonpharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. Conclusion: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment of RP and/or DUs, emphasising the need for further studies to evaluate efficacy and safety aspects. [ABSTRACT FROM AUTHOR]

Carmen Bobeica,1,&ast; Elena Niculet,2,3,&ast; Carmina Liana Musat,2,&ast; Lina Iancu,4 Mihaela Craescu,2,3 Andreea Mioara Luca,5 Bogdan Ioan Stefanescu,6 Emma Gheorghe,7 Mihaela Debita,8 Claudiu-Ionut Vasile,8 Gabriela Balan,8– 10 Camelia Busila,8 Alin Laurentiu Tatu3,8,11 1Medical Department, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, 800008, Romania; 2Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, 800008, Romania; 3Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR (Centrul Integrat Multidisciplinar de Cercetare de Interfata Dermatologica - CIM-CID), “Dun&abreve;rea de Jos” University, Galați, Romania; 4Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, 800008, Romania; 5Department of Plastic Surgery, “Sf. Ioan” Clinical Emergency Hospital for Children, Galați, 800487, Romania; 6Clinical Surgical Department, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, Romania; 7Department No. 1 (Preclinical), Faculty of Medicine and Pharmacy, “Ovidius” University, Constanța, 900527, Romania; 8Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University, Galați, 800008, Romania; 9Department of Gastroenterology, “Sf. Apostol Andrei” County Emergency Clinical Hospital, Gala&tcedil;i, 800578, Romania; 10Research Center in the Field of Medical and Pharmaceutical Sciences, “Dun&abreve;rea de Jos” University, Gala&tcedil;i, 800008, Romania; 11Dermatology Department, “Sf. Cuvioasa Parascheva” Clinical Hospital of Infectious Diseases, Galați, 800179, Romania&ast;These authors contributed equally to this workCorrespondence: Elena Niculet; Carmina Liana Musat, Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dun&abreve;rea de Jos” University of Galați, 35 Alexandru Ioan Cuza Street, Galați, 800216, Romania, Tel +40741398895 ; +40723338438, Email helena_badiu@yahoo.com; carmina.musat@ugal.roPurpose: Systemic sclerosis (SSc) is a relatively rare collagenosis manifested as microvasculopathy, excessive cutaneous and visceral fibrosis in a background of autoimmune alteration. Autoimmune vasculopathy in SSc occurs early and begins with endothelial cell activation followed by blood vessel intimal proliferation in a context of defective angiogenesis. The alteration of peripheral micro and macrocirculation in SSc is evident through vascular lesions, such as Raynaud’s phenomenon, telangiectasias, acrocyanosis, digital ulcers, gangrene, peripheral pulse deficiency. Our paper details the results of the study on the association between telangiectasias and other types of immune-mediated peripheral vascular lesions that can be identified in SSc. The presence of these peripheral vascular lesions can provide information about the magnitude of the peripheral vasculopathy.Patients and Methods: A total of 37 patients diagnosed with SSc, recruited from a university clinic in Bucharest between February 2019 and March 2020, were enrolled in an observational study. We evaluated the presence of telangiectasias, as a stigma of autoimmune microvasculopathy, and their association with other immune-mediated peripheral vascular lesions that may be present in SSc.Results: The presence of telangiectasias was identified in the absence, but especially in the presence of acrocyanosis and digital ulcerations, and patients with peripheral pulse deficiency almost always had telangiectasias. Less than a quarter of the patients with digital ulcers progressed unfavorably to gangrene, and only one required amputation, telangiectasias being present not only in the patient with amputation but in all patients with gangrene.Conclusion: We appreciate that telangiectasias may be the clinical expression of peripheral vasculopathy characteristic of SSc, they can often be present in association with other peripheral vascular lesions and may represent a valuable indicator for the gangrene risk of digital ulcerations in SSc.Keywords: systemic sclerosis, vascular lesions, phenomenon Raynaud’s, telangiectasias, acrocianosis, digital ulcers

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

Background: Cardiac involvement in systemic sclerosis (SSc) affects the prognosis of the disease. Echocardiography is the first line imaging tool to detect cardiac involvement, but it is not able to routinely detect myocardial fibrosis. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is the gold standard for replacement myocardial fibrosis assessment, but its availability is currently limited. Aim: We aimed to assess the clinical and instrumental parameters that would be useful for predicting the presence of LGE-CMR, to achieve a better selection of patients with SSc that could benefit from third-level CMR imaging. Methods: 344 SSc patients underwent a comprehensive echocardiogram and LGE-CMR on the same day; for 189 patients, a 24 h ECG Holter monitoring was available. Results: CMR showed non-junctional replacement myocardial fibrosis via LGE in 25.1% patients. A history of digital ulcers (OR 2.188; 95% C.I. 1.069–4.481) and ventricular arrhythmias at ECG Holter monitoring (OR 3.086; 95% C.I. 1.191–7.998) were independent predictors of replacement myocardial fibrosis. Conclusions: CMR can detect patterns of clinical and subclinical cardiac involvement, which are frequent in SSc. A history of digital ulcers and evidence of ventricular arrhythmias at ECG Holter monitoring are red flags for the presence of replacement myocardial fibrosis in CMR. The association between digital ulcers and myocardial fibrosis suggests that a similar pathological substrate of abnormal vascular function may underlie peripheral vascular and cardiac complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Digital ulcers (DUs) comprise the main manifestation of vasculopathy and are a major cause of disability in patients with systemic sclerosis (SSc). A literature search in Web of Science, PubMed and Directory of Open Access Journals was performed in December 2022 to identify articles published in the last decade regarding the management of DUs. Prostacyclin analogues, endothelin antagonists and phosphodiesterase 5 inhibitors have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. Moreover, autologous fat grafting and botulinum toxin injections, although not readily available, can be of use in recalcitrant cases. Many investigational treatments with promising results could pave the way for a paradigm shift in the treatment of DUs in the future. Despite these recent advances, challenges remain. Better-designed trials are of paramount importance to optimise DU treatment in the years to come. Key Points • DUs are a major cause of pain and reduced quality of life in patients with SSc. • Prostacyclin analogues and endothelin antagonists have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. • In the future, a combination of more powerful vasodilatory drugs, perhaps in conjunction with topical approaches, may improve outcomes. [ABSTRACT FROM AUTHOR]

Les ulcères digitaux (UD) correspondent à une perte de substance de l'épiderme et du derme profond d'évolution chronique au niveau des doigts. Il s'agit d'une complication sévère et fréquente de la sclérodermie systémique. La physiopathologie des UD est complexe et peut dépendre de différents mécanismes, au sein desquels la vasculopathie joue toujours un rôle dominant. Les UD cicatrisent lentement, peuvent se compliquer et surtout récidiver. Le retentissement fonctionnel et douloureux est majeur pour les patients, d'où la nécessité d'un dépistage et d'un traitement précoces. Ils entraînent en outre un impact économique majeur et sont responsables d'une grande partie de l'invalidité liée à la sclérodermie systémique. Il est capital de cibler la population à risque d'UD pour favoriser la prévention et un traitement précoce. Pour prendre en charge un ulcère digital chez un patient sclérodermique il faut d'abord en préciser le mécanisme puis proposer la prise en charge la plus adaptée selon les circonstances. Les mesures non spécifiques peuvent être prophylactiques (limiter les traitements vasoconstricteurs, les toxiques, les traumatismes, lutter contre le froid, favoriser la rééducation), ou curatives (antalgiques et soins locaux). Plus spécifiquement, les traitements des ulcères cherchent à favoriser la vasodilatation périphérique. Différents types de médicaments seront discutés dans cette revue (inhibiteurs calciques, dérivés de la prostacycline, bosentan, sildénafil). Le traitement doit toujours être adapté au mécanisme dominant et ajusté à la tolérance et à l'évolution du patient. Il doit s'accompagner d'un suivi rapproché et multidisciplinaire. Digital ulcers (DU) are a chronically progressive loss of epidermal and deep dermal tissue in the fingers. It is a severe and frequent complication of systemic sclerosis. The pathophysiology of DU is complex and may depend on different mechanisms, in which vasculopathy always plays a dominant role. DUs heal slowly, can become complicated and above all can have recurrences. The functional and painful repercussions are major for patients, hence the need for early detection and treatment. They also have a major economic impact and are responsible for much of the disability associated with systemic sclerosis. Targeting the population at risk of DU is crucial for prevention and early treatment. The management of a digital ulcer in a scleroderma patient requires first clarifying the mechanism and then suggesting the most appropriate management according to the circumstances. Non-specific measures can be prophylactic (limit vasoconstrictor treatments, toxic substances, trauma, fight against cold, favor rehabilitation), or curative (analgesics and local care). More specifically, ulcer treatments seek to promote peripheral vasodilation. Different types of drugs will be discussed in this review (calcium channel blockers, prostacyclin derivatives, bosentan, sildenafil). Treatment must always be adapted to the dominant mechanism and adjusted to the patient's tolerance. Patients must be accompanied by close multidisciplinary monitoring. [ABSTRACT FROM AUTHOR]

Abstract Introduction Systemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body’s response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis. Methods Blood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits. Results The results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042 ng/ml [2.295–7.749]) compared to the control group (1.969 ng/ml [1.531–2.903] p

Magdalena Maciejewska,1 Albert Stec,2 Micha&lstrok; Zaremba,2 Cezary Maciejewski,3 Lidia Rudnicka,2 Mariusz Sikora4 1Department of Dermatology, Doctoral School of Medical University of Warsaw, Warsaw, Poland; 2Department of Dermatology, Medical University of Warsaw, Warsaw, Poland; 3 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland; 4National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, PolandCorrespondence: Mariusz Sikora, National Institute of Geriatrics, Rheumatology and Rehabilitation, Sparta&nacute;ska 1, Warsaw, 02-637, Poland, Email drmariuszsikora@gmail.comBackground: Systemic sclerosis is a connective tissue disease characterized by vasculopathy and progressive fibrosis, leading to multiorgan dysfunction. Given the complex and not fully elucidated pathogenesis, biomarkers of rapid disease progression and therapeutic response are lacking. Copeptin, which reflects vasopressin activity in serum, is used in diagnosing or prognosing different cardiometabolic conditions.Objective: The aim of study was to investigate the concentration of copeptin in patients with systemic sclerosis and correlate it with specific clinical symptoms.Patients and Methods: Serum copeptin was measured in patients with systemic sclerosis (34 women and 3 men; mean age 57.6 years) and in healthy individuals (n=30) using commercially available ELISA kits. According to the criteria of LeRoy our systemic sclerosis cohort consisted of 17 patients with limited cutaneous systemic sclerosis (45.9%) and 20 diffuse cutaneous systemic sclerosis patients (54.1%). According to the criteria of LeRoy our systemic sclerosis cohort consisted of 17 patients with limited cutaneous systemic sclerosis (45.9%) and 20 diffuse cutaneous systemic sclerosis patients (54.1%). The median duration of the disease was 10 [4– 14] years.Results: We found significantly higher copeptin concentration in patients with systemic sclerosis (4.21 pmol/L [3.04– 5.42]) in comparison to control group (3.40 pmol/L [2.38– 3.76], p< 0.01). Copeptin significantly correlated with Raynaud’s condition score (r=0.801, p< 0.05). Patients with “late” capillaroscopic patterns had higher copeptin concentrations (5.37 pmol/L [4.29– 8.06]) than patients with “early” (2.43 pmol/L [2.25– 3.20], p< 0.05) and “active” patterns (3.93 pmol/L [2.92– 5.16], p< 0.05]). Copeptin was found to be significantly higher in SSc patients with DUs (5.71 pmol/L [IQR 4.85– 8.06]) when compared to SSc patients without DUs (3.31 pmol/L, [2.28– 4.30], p< 0.05). Additionally, copeptin concentration had good diagnostic accuracy in discriminating between patients with and without digital ulcers (AUC=0.863). Alprostadil decreased copeptin concentration from 4.96 [4.02– 6.01] to 3.86 pmol/L [3.17– 4.63] (p< 0.01) after 4– 6 cycles of administration.Conclusion: Our findings suggest that copeptin may be a promising biomarker of microcirculation alterations in systemic sclerosis.Keywords: serum biomarkers, vasculopathy, endothelial dysfunction, digital ulcers, systemic sclerosis

Introduction: Systemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body's response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis. Methods: Blood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits. Results: The results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042 ng/ml [2.295–7.749]) compared to the control group (1.969 ng/ml [1.531–2.903] p < 0.01). Patients with diffuse cutaneous SSc (2.803 ng/ml, IQR 2.221–8.799) and limited cutaneous SSc (3.231 ng/ml, IQR 2.566–5.502) exhibited elevated serum HIF-1α levels compared to the control group (p < 0.01). We found a notable increase in HIF-1α plasma concentration in patients with an "active" pattern (6.625 ng/ml, IQR 2.488–11.480) compared to those with either an "early" pattern (2.739, IQR 2.165–3.282, p < 0.05) or a "late" pattern (2.983 ng/ml, IQR 2.229–3.386, p < 0.05). Patients with no history of digital ulcers had significantly higher levels of HIF-1α (4.367 ng/ml, IQR 2.488–9.462) compared to patients with either active digital ulcers (2.832 ng/ml, IQR 2.630–3.094, p < 0.05) or healed digital ulcers (2.668 ng/ml, IQR 2.074–2.983, p < 0.05). Conclusions: Our results indicate that HIF-1α may serve as a biomarker in assessing microcirculatory changes in individuals with systemic sclerosis. [ABSTRACT FROM AUTHOR]

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. 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.' 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. [ABSTRACT FROM AUTHOR]

Patients with systemic sclerosis (SSc) develop various vascular disorders, including digital ulcers (DUs), which are sometimes intractable. Bosentan is a dual endothelin receptor antagonist expected to suppress the development of new DUs. The objective of this study was to analyze retrospectively Japanese SSc patients treated with bosentan and investigate its efficacy and safety. We analyzed 40 patients who visited our department from 2009 to 2022 and were treated with bosentan. Of the 25 patients who were able to continue bosentan, 64% (16 patients) were cured by 16 weeks. New DUs occurred in 5.9% (2/34) of patients and the number of new DUs per person was 0.1. Adverse events occurred in 45% (18/40), and hepatic dysfunction was occurred most frequently at 32.5% (13/40). In univariate analysis, hepatic dysfunction was significantly high in patients with low modified Rodnan total skin thickness score. Antimitochondria‐antibody‐positive patients were more likely to develop liver dysfunction. Hepatic dysfunction was improved without the reduction or discontinuation, dose reduction, discontinuation, or concomitant use of ursodeoxycholic acid. These results suggest that bosentan can be selected as an additional treatment for DU, which is difficult to treat with existing therapies, while carefully monitoring hepatic function. [ABSTRACT FROM AUTHOR]

Background. Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. Predictors of the outcomes of ILD in SSc are under investigation.Objective – to assess association of the digital ulcers with dynamics of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) in patients with SSc-ILD.Methods. It was a longitudinal study involving 77 pts with SSc-ILD (mean age was 46±13.2; 69% have limited subset of the disease; 93% were female). The mean duration of follow up was 58.9±11.3 months. At the end of the study a number of pts with digital ulcers (DUs) was 27 (35%). Additionally 77 pts with SSc-ILD were investigated with HRCT and were divided into 3 groups; The group 1 (16 pts) with improvement; group 2 (39 pts) without any changes and group 3 (22 pts) with worsening of fibrosis. PFT (measurement of forced vital capacity (FVC) and diffusion lung capacity (DLco)) were made.Results. 27 (35%) pts with SSc-ILD had DUs at the end of the study. The most pts with DUs was in groups 2 and 3 (14 and 9) accordingly at the end of the study. After 5 years of follow up FVC increased significantly in all pts without DUs (n=54) from 88.5±19 to 96±23% (p0.05). The mean value of FVC in all pts with DUs didn’t change (88±14 and 86±16%; p>0.05) with tendency to decreasing in group 3 (from 83±12.5 to 74±13%; p>0.05). After 5 years of follow up DLco declined significantly in all pts with or without DUs, however in the 1st group decline of DLco wasn’t significant. The decreasing of DLCO was more prominent in group 3 than in group 2. Therefore, in group 2 in patient without DU (n=24) – from 65±16 to 60±11% (p˂ 0.05) and in patients with DU (n=14) DLCO changed from 61±15 to 57±14% (p 0.05). In group 3 in patients without DU (n=13) DLCO decreased from 55±15 to 48±15% (p˂ 0.05) and in patients with DU (n=9) – from 50±20 to 44.5±15% (p˂ 0.05).Conclusions. In patients without DUs significant increasing of FVC during 5 years long follow up was observed. The worsening of fibrosis on HRCT in pts with DUs was associated with the lowest value of FVC and DLco at the entry and at the end of the study.

Purpose: The efficacy of adjunctive ambrisentan treatment in patients with systemic sclerosis (SSc) suffering from digital ulcers (DUs) was investigated. Material and methods: Patients (4 males, 7 females) diagnosed with SSc at our hospital between 2017 and 2022 were enrolled. Ten of them had diffuse SSc, while one had limited SSc. These patients received daily 5 mg doses of ambrisentan in addition to their regular SSc treatment for 16 weeks. Parameters including the total number and size of existing and new DUs, Visual Analog Score (VAS), frequency of Raynaud's phenomenon (RP) attacks, and any adverse effects were assessed. Results: At baseline, the median number and size of DUs was 3.0 (interquartile range (IQR): 2.0–4.0 cm) and 0.4 cm (IQR: 0.3–0.5 cm), respectively. Following the intervention, seven patients with a median of 2.0 DUs and a size of 0.35 cm (IQR: 0.15–0.45 cm) at baseline achieved complete healing. Significant improvements were also observed in other patients. VAS scores decreased from a baseline median of 5.0–0.0 (IQR: 0.0–1.0), and both the frequency and duration of RP attacks notably reduced. Conclusion: Adjunctive ambrisentan therapy proved effective in promoting DU healing and preventing new DUs in SSc patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective. Systemic sclerosis (SSc) is burdened by Raynaud phenomenon (RP) and digital ulcers (DUs), and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy. Methods. Patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag. RP- and DU-related clinical outcomes were evaluated, and digital perfusion was assessed by laser speckle contrast analysis (LASCA), all at baseline and after 3 months. Results. Selexipag was administered to 9 patients with SSc (66.6% female, mean age 52.3 [SD 16.6] yrs). One patient had to stop the drug because of adverse effects. After 3 months of selexipag administration, there was a significant reduction in RP daily episodes (P = 0.01) and RP mean duration (P = 0.04). The number of DUs decreased from 10 to 4 without reaching statistical significance. A significant improvement in mean perfusion of the fingers (P = 0.02) was observed with LASCA. Conclusion. Selexipag showed good potential for the treatment of SSc digital vasculopathy. Our results are certainly preliminary, yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc digital vasculopathy are needed. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a systemic disease characterized by autoimmune responses, vasculopathy and tissue fibrosis. The pathogenic mechanisms involve a wide range of cells and soluble factors. The complexity of interactions leads to heterogeneous clinical features in terms of the extent, severity, and rate of progression of skin fibrosis and internal organ involvement. Available disease-modifying drugs have only modest effects on halting disease progression and may be associated with significant side effects. Therefore, cellular therapies have been developed aiming at the restoration of immunologic self-tolerance in order to provide durable remissions or to foster tissue regeneration. Currently, SSc is recommended as the 'standard indication' for autologous hematopoietic stem cell transplantation by the European Society for Blood and Marrow Transplantation. This review provides an overview on cellular therapies in SSc, from pre-clinical models to clinical applications, opening towards more advanced cellular therapies, such as mesenchymal stem cells, regulatory T cells and potentially CAR-T-cell therapies. [ABSTRACT FROM AUTHOR]

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 β 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. [ABSTRACT FROM AUTHOR]

Objective Clinical trials assessing systemic sclerosis (SSc)-related digital ulcers have been hampered by a lack of reliable outcome measures of healing. Our objective was to assess the feasibility of patients collecting high-quality mobile phone images of their digital lesions as a first step in developing a smartphone-based outcome measure. Methods Patients with SSc-related digital (finger) lesions photographed one or more lesions each day for 30 days using their smartphone and uploaded the images to a secure Dropbox folder. Image quality was assessed using six criteria: blurriness, shadow, uniformity of lighting, dot location, dot angle and central positioning of the lesion. Patients completed a feedback questionnaire. Results Twelve patients returned 332 photographs of 18 lesions. Each patient sent a median of 29.5 photographs [interquartile range (IQR) 15–33.5], with a median of 15 photographs per lesion (IQR 6–32). Twenty-two photographs were duplicates. Of the remaining 310 images, 256 (77%) were sufficiently in focus; 268 (81%) had some shadow; lighting was even in 56 (17%); dot location was acceptable in 233 (70%); dot angle was ideal in 107 (32%); and the lesion was centred in 255 (77%). Patient feedback suggested that 6 of 10 would be willing to record images daily in future studies, and 9 of 10 at least one to three times per week. Conclusion Taking smartphone photographs of digital lesions was feasible for most patients, with most lesions in focus and central in the image. These promising results will inform the next research phase (to develop a smartphone monitoring application incorporating photographs and symptom tracking). [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is autoimmune disease characterized by endothelial dysfunction and microvascular damage. Resistin has been implied in microvascular dysfunction. Objective of this study is to evaluate the association between baseline resistin and development of new digital ulcers (DUs) in SSc patients. At baseline, serum resistin has been assessed in 70 female SSc patients and 26 healthy controls (HC). In SSc patients, clinical assessment was performed at baseline and after a 52-weeks follow-up. Serum resistin level was increased in SSc patients compared to HC [5.89 ng/ml (2.5 ng/ml–8.1 ng/ml) vs 2.3 ng/ml (0.4 ng/ml–2.4 ng/ml), p = 0.0004)]. Resistin was lower (p = 0.005) in SSc patients with early capillaroscopic pattern than patients with active or late capillaroscopic pattern [2.49 ng/ml (0.89 ng/ml–5.81 ng/ml) vs 7.11 ng/ml (3.48 ng/ml–11.35 ng/ml) and 6.49 ng/ml (3.35 ng/ml–8.87 ng/ml), respectively]. After a 52-weeks follow-up, 34 (48.6%) patients developed new DUs. Median serum resistin was significantly higher in patients with new DUs than in patients without new DUs [6.54 ng/ml (3.35 ng/ml–11.02 ng/ml) vs 4.78 ng/ml (1.06 ng/ml–7.6 ng/ml), p = 0.019]. Kaplan–Meier curves show a significantly reduced free survival from DUs in patients with increased resistin (p = 0.002). In multivariate analysis, resistin is associated with the development of new DUs. Increased serum resistin level is a predictive marker of new DUs in SSc. [ABSTRACT FROM AUTHOR]

Although systemic sclerosis (SSc) is currently incurable, there have been recent advances in treatment. This review article begins by providing a brief background to SSc in terms of disease subtyping and autoantibodies, because both predict disease trajectory and help clinicians to select appropriate monitoring and treatment protocols. Broad principles of management are then described: 'disease-modifying' therapies and therapies directed at reducing disease burden and/or progression of SSc-related digital vascular disease and of internal organ involvement. Next, advances in the management of digital vasculopathy, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and early diffuse cutaneous SSc are discussed in turn, for example: (a) increased use of phosphodiesterase inhibitors and endothelin receptor antagonists for digital vasculopathy; (b) early recognition and treatment of PAH, including with combination therapies; (c) increased use of mycophenolate mofetil and of nintedanib in ILD; and (d) immunosuppression now as standard practice in early diffuse cutaneous SSc, and autologous haematopoietic stem cell transplantation for highly selected patients with progressive diffuse disease. Finally, future challenges are discussed, including ensuring that all patients with SSc are monitored and treated according to best practice guidelines, and whenever possible giving patients the opportunity to participate in clinical trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Barbara Ruaro,1 Tania Santiago,2,3 Michael Hughes,4 Gemma Lepri,5 Gabriele Poillucci,6 Elisa Baratella,6 Francesco Salton,1 Marco Confalonieri1 1Unit of Pulmonology, University Hospital of Trieste, Trieste, Italy; 2Department of Rheumatology, Centro Hospitalare Universitário de Coimbra, Coimbra, Portugal; 3Medicine Faculty, University of Coimbra, Coimbra, Portugal; 4Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 5Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Firenze, Florence, Italy; 6Department of Radiology, Department of Medicine, Surgery and Health Science, University of Trieste, Trieste, ItalyCorrespondence: Barbara RuaroUnit of Pulmonology, University Hospital of Trieste, Trieste, ItalyTel +39 3470502394Email barbara.ruaro@yahoo.itAbstract: Systemic sclerosis (SSc), an autoimmune connective tissue disease, characterized by skin fibrosis, increased dermal thickness and microvascular involvement. Fibroblasts and myofibroblasts deposit excessive amounts of collagenous and non-collagenous extracellular matrix components in the skin. This leads to microvascular abnormalities and Raynaud’s phenomenon, with painful digital ulcers (DU) at the fingertips adding to patient discomfort. The skin involvement and severity in SSc was evaluated by the Modified Rodnan skin score (mRSS). Although high-frequency ultrasound (HUS) has been widely researched in the study of skin thickness and DU in SSc, its adoption into clinical practice is not yet common. However, novel insights into the still relatively unknown disease pathogenesis in SSc and its evaluation may be provided by HUS, including early (pre-clinical) skin involvement. It may also be useful in both the evaluation and follow-up of DU. Indeed, it is a non-invasive, safe, inexpensive and reproducible method able to assess not only SSc patients’ cutaneous structural changes, but also their vascular system changes. Moreover, several recent studies have reported that elastosonography (ES) is of use when investigating skin involvement in systemic sclerosis. This review aims at providing information as to role HUS and ES play in research advancements and the clinical perspectives in the evaluation of skin thickness and DU in SSc patients.Keywords: systemic sclerosis, ultrasound, elastosonography, skin, skin thickness, digital ulcers

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. 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). 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. TSLP might have a key role in digital microvascular damage of SSc patients. • SSc patients with history of DUs have higher serum level of TSLP. • TSLP is higher in SSc patient with recurrent new DUs. • TSLP is higher in SSc patient with CSURI≥2.96. • Free survival from new DUs is significantly lower in SSc patients with increased TSLP. [ABSTRACT FROM AUTHOR]

Objective: To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease.Methods: We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored.Results: Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs.Conclusion: Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a heterogeneous complex autoimmune connective tissue disease with variable presentation as a consequence of multisystem involvement. One of the key features of SSc is Raynaud's phenomenon along with vascular endothelial dysfunction that leads to digital ulcers (DUs). Raynaud's tends to be triggered by decreasing thermal gradient exposure, while stress and smoking also play a role. DUs arising as a consequence of severe Raynaud's and vasculopathy are a major cause of morbidity and disability in SSc. We set out to determine the relationship between smoking, Raynaud's phenomenon, DUs, and skin thickness in our Waikato Systemic Sclerosis cohort. The Waikato Systemic Sclerosis (SSc) database was used to extract data. Variables collected included demographics, age of diagnosis, SSc subtypes, age at first non-Raynaud's phenomenon, medications used for treatment of Raynaud's phenomenon or ulcers, and maximal modified Rodnan skin score (mRSS). Raynaud's phenomenon and finger DUs (severity for each over the past week and since diagnosis) and a Scleroderma Health Assessment Questionnaire (SHAQ) visual analog 10 cm scale were collected. The lead rheumatologist completed a physician's assessment of Raynaud's and the disease severity questionnaire. Of the cohort of 143 patients, 100 patients were eligible to complete the questionnaires. Seventy-five patients returned completed questionnaires. Of these, the majority were female (88%), 52 (69.3%) had limited cutaneous systemic sclerosis (lcSSc), 17 (22.7%) had diffuse cutaneous systemic sclerosis (dcSSc), and 6 (8%) had an overlap syndrome. Thirty-six (48%) had a smoking history (in the time frame of collection of serial data). Mean ± standard deviation (SD) pack-years smoked were 17.11 ± 15.29 years. Thirty-five participants had a history of DUs, with a median of 4 DU (range 1–20). Of 17 patients with dcSSc, 12 (70.6%) had ulcers in comparison with 17 of 52 (32.7%) patients with lcSSc. There was a significant relationship between SSc subtype and the number with ulcers (X2 = 10.1, P = 0.007). There was also a significant relationship between physician severity of Raynaud's and presence of ulcers (t = 6.1, P < 0.001), which was not evident between patients' severity of Raynaud's and presence of ulcers (t = 1.9, P = 0.06). On the SHAQ score, smokers had significantly worse Raynaud's phenomenon over the prior week (t = 3.08, P = 0.03) and were more likely to note DUs over the preceding week, although the latter was not statistically significant (t = 1.95, P = 0.055). There was no association between smoking and skin thickness as measured by mRSS (r = 0.23, P = 0.19). Our study demonstrates that smokers have had worse Raynaud's phenomenon over the past week and they were also more likely to note DUs with a trend toward significance but not statistically significant most likely due to our small sample size. Our study also demonstrated that patients with dcSSc had more ulcers in comparison with lcSSc. This study justifies physicians strongly recommending smoking cessation in patients with SSc. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]