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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. 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. 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. In SSc patients, MaR1 is reduced compared to HC and it is a predictive marker of new DUs. • Maresin1 was significantly lower in scleroderma patients than in healthy controls. • Maresin1 was higher in scleroderma patients with new digital ulcers. • Maresin1 is a predictive marker of new digital ulcers in scleroderma patients. [ABSTRACT FROM AUTHOR]

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. 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. 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. IL33 and sST2 are increased in SSc patients and ST2 might be a marker of microvascular damage. • SSc patients had higher serum level of IL33 and sST2 than HC. • sST2 was higher in SSc patient with DUs, late NVC pattern and increased RRI • ST2 might be a marker of microvascular damage of skin and kidney in SSc patients [ABSTRACT FROM AUTHOR]

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease ( PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon ( RP), digital ulcers ( DU) in systemic sclerosis ( SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis ( AO) and interstitial lung disease ( ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness ( IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO. [ABSTRACT FROM AUTHOR]

Objective To describe the CT angiographic findings of arterial vasculopathy in the major vessels as well as medium and micro vascular affection of the whole upper limbs arterial tree in patients with systemic sclerosis (SSc) with and without digital ulceration. Methods Twenty-two cases with systemic sclerosis (12 limited and 10 diffuse) were recruited for the study. All patients fulfilled the American Rheumatism Association (ACR) criteria for the classification of SSc. For all patients routine laboratory investigations were performed including complete lipid profile. Computed tomography angiography (CTA) studies for the whole upper limb arterial tree were performed for both upper limbs in all cases. Results CTA studies showed involvement of subclavian arteries in 3 cases and axillary artery was involved in five cases. Brachial artery was affected in 5 cases. In the forearm the radial artery was affected in 4 cases with bilateral involvement in two cases (6 vessels), while ulnar artery was affected in five cases. Unilateral non visualization of the superficial palmar arch was observed in two cases with limited disease, while thinning out of the vessel wall with poor distal run off in 18 cases. A higher number of arterial vasculopathy was significantly associated with systolic pulmonary artery pressure ( P = 0.001). Conclusions Macrovascular arterial vasculopathy of upper limbs may occur in SSc irrespective of the disease pattern. Major arteries can be affected in association with other medium sized arteries of the forearms and microvascular arterial branches of the hands. [ABSTRACT FROM AUTHOR]

Patients with systemic sclerosis ( SSc) usually develop Raynaud's phenomenon, persistent digital ischemia and sometimes develop digital ulcers ( DU). Several studies have reported an association of carotid artery atherosclerosis with SSc by evaluating carotid intima-media thickness ( IMT) in SSc patients. However, none of those studies analyzed the association between DU and carotid artery atherosclerosis in SSc patients. We examined the association of carotid artery atherosclerosis with digital ulcers by comparing SSc patients with ( n = 48, 29.5%) and without ( n = 206, 70.5%) DU. The demographic and clinical features of the SSc patients showed that young age, male sex, anti-topoisomerase I antibody positivity, severe skin sclerosis, interstitial lung disease complication and cardiac involvements were significantly prevalent in patients with DU. In addition, diffuse cutaneous type, anti- RNA polymerase III antibody positivity and severe skin sclerosis are more frequent in SSc patients with DU at the extensor surface of joints than SSc patients with DU at the digital tip. There were no differences in serum lipid level, carotid IMT or plaque score between SSc patients with and without DU, suggesting that atherosclerotic changes are not primarily involved in the development of DU. [ABSTRACT FROM AUTHOR]

Angiopoietin-like protein 3 (ANGPTL3), which is part of a family of secreted glycoproteins that are structurally similar to angiopoietins, is principally expressed in the liver and is involved in lipid metabolism and angiogenesis. The aim of this study was to determine the clinical significance of serum ANGPTL3 levels, measured with a specific enzyme-linked immunosorbent assay, in patients with systemic sclerosis. Serum ANGPTL3 levels correlated positively with skin score in diffuse cutaneous systemic sclerosis with a disease duration ≤ 6 years. Furthermore, the prevalence of digital ulcers was significantly higher in patients with elevated serum ANGPTL3 levels than in other patients. Moreover, among patients excluding diffuse cutaneous systemic sclerosis with disease duration ≤ 6 years, serum ANGPTL3 levels correlated positively with estimated right ventricular systolic pressure. In conclusion, ANGPTL3 may contribute to the development of progressive skin sclerosis and proliferative obliterative vasculopathy, such as digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, in systemic sclerosis. [ABSTRACT FROM AUTHOR]

Raynaud's phenomenon (RP) is an episodic peripheral circulatory disorder characterized by local artery spams in subjects exposed to cold or emotional stress. It is not well-established whether RP patients show an altered rheological profile, mostly due to patient classification and clinical severity. We aimed to compare the hemorheological profile in patients with primary and secondary RP with a healthy control group. Eighteen primary RP, 22 secondary RP and 22 healthy controls, were included in the study. RP patients were also divided according to the presence of digital ulcers (7 with, 33 without). Biochemical and hemorheological variables were analyzed, including glucose, triglycerides, total-cholesterol, immunoglobulins, fibrinogen, plasma viscosity, erythrocyte aggregation, erythrocyte deformability and blood viscosity. Age was higher in secondary RP as compared with primary (p = 0.049), while glucose, triglycerides IgA, IgG and plasma viscosity were higher in secondary RP than in healthy subjects (p < 0.05). RP patients with digital ulcers presented higher IgA (p = 0.012), lower erythrocyte aggregation time (p = 0.008) and a trend for higher fibrinogen levels and plasma viscosity (p = 0.064, p = 0.069, respectively). The results of the present study indicate that secondary RP patients show a mild impairment of the rheological profile that aggravates with microangiopathy severity. [ABSTRACT FROM AUTHOR]

The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). Methods Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. Results Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients ( r = −0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). Conclusion The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud's phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies.

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., Competing Interests: Conflicts of interest Dr Nikpour has received research grant support from Actelion, BMS, GSK, Janssen, and UCB and honoraria from Actelion, Boehringer Ingelheim, Janssen, Eli Lilly, Pfizer, and UCB. Dr Krieg has received speaking fees from Actelion. Dr Denton reports personal fees or research grants to his institution from GlaxoSmithKline, Galapagos, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Horizon, and Arxx Therapeutics outside the submitted work. Dr Saracino has received speaking fees from UCB. Dr Jerjen has no conflict of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

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.

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). 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. 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. 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. • Proximal-distal gradient finger perfusion is reduced/absent in systemic sclerosis. • We defined a generalizable proximal-distal gradient formula. • Proximal-distal gradient can identify subclinical microangiopathic impairment. • Laser speckle contrast analysis is the best for peripheral perfusion evaluation. [ABSTRACT FROM AUTHOR]

Background. Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascualar dysfunction, considered to be a key element in the pathogenesis of SSc and its complications. Digital ulcers (DUs) are a manifestation of the underlying vasculopathy and fibrosis that characterizes SSc. Aim. Our objective was to establish the correlations between digital ulcers and subsets of SSc, videocapillaroscopic pattern and inflammatory syndrome. Methods. The study included a total of 35 patients with SSc, 23 patients with limited cutaneous systemic sclerosis (lcSSc) and 12 with diffuse cutaneous systemic sclerosis (dcSSc). Digital ulcers were analyzed in comparison to the two subsets of SSc, modified Rodnan skin score (mRSS), capillary nailfold changes and inflammatory syndrome. Results. DUs were more frequent in dcSSc (58,33%) than in lcSSc (26,09%). In 76,92% of the patients with digital ulcers, an active type scleroderma like pattern was observed, which is characterized by the presence of frequent giant capillaries, hemorrhages, and avascular areas. A late type scleroderma like pattern was found in 7.69% of the patients with digital ulcers. In patients with DUs, ESR and CRP are not significantly higher than those in patients without ulcers. Conclusions. Digital ulcers are a frequent manifestation of systemic sclerosis, often causing persistent and recurrent pain, severe complications such as tissue loss, infections, gangrene, autoamputation or even septicemia. [ABSTRACT FROM AUTHOR]

Skin ulcers are very frequent in scleroderma (SSc), often complicated by local infection; the latter may be responsible for osteomyelitis (OM) of underlying bone. We retrospectively investigate the prevalence of OM in our SSc patients. The study included 248 SSc patients (M/F 21/227, mean age 61 ± 13.5 SD years) followed at our Rheumatology Unit for a mean time period of 60.8 ± 20.9 SD months. Patients with infected skin ulcers were carefully evaluated for complicating OM, which was diagnosed on the basis of typical clinical symptoms, laboratory, and radiological alterations. Skin ulcers were observed in 119/248 (48 %) SSc patients, more frequently digital ulcers (110/119, 92 %). These patients presented a significantly lower mean age (59 ± 14.5 SD vs. 64 ± 12.2 SD years; p = 0.005) and a lower percentage of anticentromere antibodies (40/119, 33.6 %, vs. 66/129, 51.2 %; p = 0.007) compared with those without ulcers. The prevalence of OM in the entire SSc patients' series was 7.7 % (19/248); it was invariably found in the setting of patients with infected digital ulcers, showing a surprisingly high percentage of underlying bone involvement (19/45, 42 %). The OM was localized at the hands in 14 patients and feet in 5; moreover, the most frequently isolated pathogens from infected digital ulcers were Staphylococcus aureus and Escherichia coli. Finally, patients with OM presented a significantly lower mean age ( p < 0.016) and higher percentage of anti-Scl70 autoantibodies ( p < 0.0128) compared to those without. We firstly demonstrated, in a large cohort of SSc patients, high prevalence of OM, invariably associated to infected digital ulcers, which represent the main predisposing condition for the development of such a harmful complication. [ABSTRACT FROM AUTHOR]

Digital ulcers (DU) are one of the most common and debilitating manifestations of vasculopathy in systemic sclerosis (SSc). Their prevention is important in order to improve patients' outcome and as a result of the economic impact they have on society. Randomised controlled studies have demonstrated that bosentan, an endothelin receptor antagonist, reduces the appearance of new DU. The aim of this retrospective study was to evaluate the occurrence of DU in a group of patients receiving long-term bosentan treatment for pulmonary arterial hypertension associated with SSc (PAH-SSc). Patients with PAH-SSc and treated with bosentan for at least 6 months ( n = 30) were evaluated. Thirty patients with SSc not treated with bosentan, but matched for sex, age, disease duration and cutaneous form of SSc, were considered as a control group. The occurrence of DU, defined as loss of tissue of varying degrees in the epidermis, dermis and subcutaneous tissue, was determined in the bosentan-treated and untreated groups. Mean duration of bosentan treatment was 3.6 years. DU were detected in six patients in the bosentan-treated group (20.0 %) and 16 patients (53.3 %) in the untreated group ( p = 0.0015). There were no significant differences in demographic or clinical characteristics between patients with or without DU at study end. The occurrence of DU in patients with PAH-SSc receiving long-term bosentan treatment was significantly lower than in untreated patients. The results from this long-term observational study provide valuable information on management of patients with PAH-SSc. [ABSTRACT FROM AUTHOR]

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers. [ABSTRACT FROM AUTHOR]

Objective. To assess patients with SSc who present without circulating ANAs or RP.Methods. Five thousand three hundred and ninety patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials and Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire.Results. Five thousand three hundred and seventy-eight (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve (0.2%) patients lacked both circulating ANA and RP. Details of the medical history could be obtained for seven patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema and one had bladder carcinoma. There was no temporal relationship between the onset of skin fibrosis and that of the tumour. Although no patient with confirmed nephrogenic systemic fibrosis was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of nephrogenic systemic fibrosis other than for the absence of chronic kidney disease or of known prior gadolinium exposure.Conclusion. We have identified a very small subgroup of SSc patients who lack both circulating ANA and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution and outcome of such patients. [ABSTRACT FROM AUTHOR]

This review focuses on new findings and developments relevant to the clinician caring for patients with primary and secondary [especially systemic sclerosis (SSc)-related] Raynaud phenomenon (RP). In the last 18 months, several clinical trials and observational studies of RP and of SSc-related digital ulceration have been published, reflecting increased awareness of disease burden and increased interest by pharmaceutical companies: new insights into pathophysiology are driving new approaches to treatment. Key developments are the increased use of phosphodiesterase type V inhibitors in severe RP, and of bosentan (an endothelin-1 receptor antagonist) for prevention of recurrent SSc-related digital ulcers. Other treatments being researched include topical glyceryl trinitrate (applied locally to the digits), botulinum toxin (for severe digital ischemia/ulceration), and several other drugs including oral prostanoids. Increased availability and interest in nailfold capillaroscopy, by facilitating early diagnosis of SSc, should pave the way for studies of early intervention and vascular protection. [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., (© 2021. The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: 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., Methods: 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., Results: 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 ( X 2 = 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)., Conclusion: 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., Competing Interests: Conflict of Interest None., (© 2022 Cherumi Silva et al., published by Sciendo.)

Background: Systemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations., Methods: We described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period., Results: In the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of -8.3 [95% confidence interval (CI), -12.03 to -4.574; p = 0.0007] and improved greater at week 24 to -11.67 (95% CI, -16.84 to -6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed., Conclusions: Our results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings., Chinese Clinical Trial Registry Number: ChiCTR2000030995., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hou, Su, Han, Xue, Chen, Chen, Wang, Yang, Liang and Ji.)

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., (Copyright © 2022 by the Journal of Rheumatology.)

Systemic sclerosis is a chronic inflammatory multiorgan disease belonging to the group of collagen-vascular disorders. With a prevalence of 10/100,000 inhabitants it may be regarded a rather rare disease. Its etiology and pathogenesis have still not been elucidated in detail, especially with regard to the differential involvement of skin and the cause of the clinically heterogeneous disease courses. Various components of the vasculature, connective tissue as well as the immune system are involved in a yet unknown sequence and significance. Patients need to be cared for in an interdisciplinary fashion depending on the individual organ involvement. Apart from the skin, the heart, kidneys and lungs are mainly affected in addition to frequent gastrointestinal and musculoskeletal symptoms. Clinically two distinct subsets may be separated, acral (also termed limited) and diffuse scleroderma, which are characterized by anti-centromere and anti-Scl-70/topoisomerase-1 antibodies, respectively. Recent data demonstrate a poor prognosis even in limited disease when pulmonary arterial hypertension develops at an early stage. In diffuse disease sudden and rapid onset will result in a sclerosis of major internal organs and early death in many cases. [ABSTRACT FROM AUTHOR]

Raynaud, digital ulcers and calcinosis are frequent manifestations of patients with systemic sclerosis. Digital ulcers are seen in more than half of the patients with scleroderma. Hospitalizations, ischemic complications and impairment of hand function are frequently observed in patients with digital ulcers, especially if treatment is delayed. Rapid and intensive treatment escalation in patients with scleroderma and refractory Raynaud's phenomenon is one of the most effective preventive action available in order to avoid the development of digital ulcers and tissue loss. [ABSTRACT FROM AUTHOR]

Digital ulcers (DU) and Raynaud's phenomenon are clinical manifestations of digital vasculopathy in patients with systemic sclerosis. They occur in about one third of patients. This is a very painful condition associated with serious complications such as infection or gangrene. Digital ulcers significantly limit the functional ability of the hand and reduce the patients' quality of life. Approximately 1-2% of patients with DU require amputation of the distal phalanx. Systemic pharmacotherapy of trophic digital ulcers is based on the use of calcium channel blockers, intravenous prostanoids, analgesics, antiplatelet agents, and antibiotics. Bosentan, a dual endothelin receptor antagonist, is the new hope for patients with DU. Bosentan significantly reduces the formation of new ulcers. It is suitable for patients who suffer from multiple recurrent digital ulcers. In this article the authors present an overview of literature data on the epidemiology, pathophysiology and treatment of digital vasculopathy in systemic sclerosis. The issue of treatment of recurrent digital ulcers in systemic sclerosis is documented by a case report. [ABSTRACT FROM AUTHOR]

Raynaud's syndrome (or Raynaud's phenomenon, RP) is an episodic disorder caused by vasospasm of peripheral arterioles. Exposure to cold temperatures or emotional stress is the most common underlying cause. The clinical manifestations include a sudden change in the colour of the fingers (less often of the toes), edema, paresthesia, and during a severe course of the disease, atrophy may occur in the involved tissues with ulcers or gangrene. The primary Raynaud's phenomenon (Raynaud's disease) that is characterized by an increased tendency to vasospasms due to an increased tone of sympaticus, can often be successfully treated with a change of lifestyle and the disease can completely remit. Secondary Raynaud's phenomenon (Raynaud's syndrome) is caused by an underlying systemic disease (mostly systemic sclerosis), or by various types of involvement of the arterial system (vasculitis, etc.). The diagnosis is based on a typical clinical picture. Laboratory and functional tests aim to establish the actual disorder of blood circulation (using Doppler ultrasonography, capillaroscopy etc.) and especially to exclude a systemic disease. Basic laboratory tests include determination of the activity of inflammation - C-reactive protein, rheumatoid factor, erythrocyte sedimentation rate, blood counts and antinuclear antibodies. The patient should be monitored by an angiologist to exclude concurrent macroangiopathy, or by a rheumatologist to monitor the patient for the development of any manifestations of autoimmune rheumatic diseases over time. Pharmacotherapy of RP is based on calcium channel blockers, as the drugs of first choice. However, their use is limited in some patients with RP due to tendency to hypotension. Endothelin receptor antagonists (especially bosentan) and phosphodiesterase-5 inhibitors (such as sildenafil, or longer-acting tadalafil) are the new available drugs that were introduced in the prevention of vasospasm and formation of ulcers in systemic sclerosis. The most severe cases with prolonged vasospasms leading to acral ulcerations can be treated with local or intravenous prostaglandin E1 and pharmacological or surgical sympathectomy should be considered. [ABSTRACT FROM AUTHOR]

Objectives. To assess the prevalence and risk factors of ulnar artery occlusion (UAO) in an unselected SSc patient cohort and to determine whether UAO is associated with digital ulcers (DUs).Methods. A total of 79 SSc patients and 40 ‘healthy’ controls underwent colour duplex sonography of the radial and ulnar artery to compare blood flow velocity, resistive indices (RIs) and presence of occlusion and were followed for a mean of 53 months.Results. In both, radial and ulnar arteries, peak systolic velocity (PSV) and end-diastolic velocity (EDV) were significantly lower and RI higher in SSc patients compared with controls (PSVrad: 40.1 vs 48.6 cm/s; PSVuln 38.2 vs 56.6 cm/s; EDVrad 3.8 vs 10.4 cm/s; EDVuln 3.0 vs 13.0 cm/s; RIrad 0.91 vs 0.82; RIuln 0.92 vs 0.80; all P < 0.01). Seventeen (21.5%) SSc patients had UAO (11 patients bilateral) compared with none in the control subjects. Patients with UAO had a significantly longer disease duration (170 vs 66 months, P < 0.001). At baseline, the prevalence of DU was not different in upper extremities with UAO [8/28 (28.6%)] compared with upper extremities without UAO [36/129 (27.9%)]. However, during follow-up new or recurrent DU occurred more often in upper extremities with UAO than in those without UAO [14/28 (50%) vs 24/113 (21.2%); relative risk (RR) = 2.4; 95% CI 1.4, 3.7; P = 0.002].Conclusion. Blood flow is significantly decreased in radial and ulnar arteries in SSc. UAO is frequent and an important risk factor for the development of DUs in patients with SSc. [ABSTRACT FROM PUBLISHER]