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Background: We evaluated the prevalence of myocardial involvement by native T1 and T2 mapping, the diagnostic performance of mapping in addition to conventional Lake Louise Criteria (LLC), as well as correlations between mapping findings and clinical or conventional cardiovascular magnetic resonance (CMR) parameters in systemic sclerosis (SSc) patients. Methods: Fifty-five SSc patients (52.31 ± 13.24 years, 81.8% female) and 55 age- and sex-matched healthy subjects underwent clinical, bio-humoral assessment, and CMR. The imaging protocol included: T2-weighted, early post-contrast cine sequences, native T1 and T2 mapping by a segmental approach, and late gadolinium enhancement (LGE) technique. Results: Global myocardial T1 and T2 values were significantly higher in SSc patients than in healthy subjects. An increase in native T1 and/or T2 was present in the 62.1% of patients with normal conventional CMR techniques (negative LGE and T2-weighted images). Respectively, 13.5% and 59.6% of patients fulfilled original and updated LLC (overall agreement = 53.9%). Compared with patients with normal native T1, patients with increased T1 (40.0%) featured significantly higher left ventricular end-diastolic volume index and cardiac index, biventricular stroke volume indexes, and global heart T2 values, and more frequently had a history of digital ulcers. Biochemical and functional CMR parameters were comparable between patients with normal and increased T2 (61.8%). Conclusion: T1 and T2 mapping are sensitive parameters that should be included in the routine clinical assessment of SSc patients for detecting early/subclinical myocardial involvement.

Background and Objectives: Digital ulcers (DUs) are the most common complication in patients with Systemic Sclerosis (SSc). They cause pain with hand dysfunction and negatively impact activities of daily and working life. Our study aims to evaluate the efficacy of a combined treatment of manual therapy and ultrasound therapy in SSc patients with ischemic DU (IDU) compared to manual therapy alone. Materials and Methods: We conducted a before-and-after study (non-randomized study). We enrolled a consecutive series of IDU patients undergoing rehabilitation treatment and divided them into two groups: a treatment group consisting of patients undergoing a combination of manual therapy and US water immersion and a standard care group consisting of patients subjected to manual therapy alone. At the time of the first visit (T0) and at the end of the 4-week rehabilitation period (T1), we evaluated functional capacity, pain intensity, ulcer evolution, and quality of life. Results: In the treatment group, we observed a statistically significant improvement in the functional capacity of the hand (DHI: 28.15 ± 11.0 vs. 19.05 ± 8.83; p < 0.05), pain (NRS: 5.55 ± 1.2 vs. 2.9 ± 1.09; p < 0.05), and PSST score (24.4 ± 4.0 vs. 16.2 ± 2.36; p < 0.05). In the standard care group, we observed a statistically significant improvement only for the functional capacity of the hand (DHI: 28.85 ± 9.72 vs. 22.7 ± 7.68; p < 0.05). Finally, from the comparison between the treatment group and the standard care group, we observed statistically significant improvements in pain (2.9 ± 1.09 vs. 4.5 ± 1.07; p < 0.05) and in the PSST scale (16.2 ± 2.36 vs. 20.4 ± 4.02; p < 0.05). Furthermore, at the end of treatment in the treatment group, 15 ulcers (62.5%) were completely healed, while in the standard care group, only 3 ulcers were completely healed (14.3%). Conclusions: Combined treatment with manual therapy and ultrasound therapy appears to be useful in the management of IDU in patients with scleroderma.

PURPOSE: Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension (PH), a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. METHODS: 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. RESULTS: Our pooled cohort analysis revealed reduced global RVLSS at rest (−16.2 ± 3.9%) with normal basal contractility (−25.6 ± 7.7%) and relative hypokinesis of the midventricular (−14.1 ± 6.0%) and apical (−8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p=0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. CONCLUSION: Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone.

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.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

Background Systemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vasculopathy, cellular inflammation, fibrosis of the skin associated with multiple internal organs involvement. Ischaemic digital ulcers (IDU) of the hands commonly occur in patients with SSc adversely affecting functional independence. Purpose Aim of the study is to investigate the effectiveness of a rehabilitation protocol based on the combined use of ultrasound (US) therapy and therapeutic exercise in terms of ulcers healing, pain relief, and hand functioning in patients affected by SSc with IDUs. Moreover, we also investigated the safety of the proposed intervention. Study design Prospective before-after study. Methods We included 20 patients with IDUs secondary to SSc. All patients were treated with US combined with manual therapy, including McMennel joint manipulation, pompage mobilization technique and connective tissue massage, for 10 sessions. We evaluated softness, dyschromia, pain, and hand mobility using the Pressure Sore Status Tool (PSST), the Numerical Rating Scale (NRS), and the Duruoz Hand Index (DHI) at T0 and at the end of the treatment (T1). Results Treatment with US combined with manual therapy significantly reduced ulcers depth, improved ulcers margins, and reduced periwound skin damage (median PSST score 16 at T1, ppp Conclusion Therapeutic US combined with manual therapy should be used as additional intervention to manage IDUs in SSc patients.

This book aims to summarize the latest advances in the rheumatic diseases, particularly regarding their pathophysiology and targeted therapy, with a focus on the recent efforts of vascular and pulmonary manifestations in order to anticipate new and future directions of these research topics. Rheumatic diseases represent a heterogeneous group of severe autoimmune disorders. The present Special Issue aims to provide an overview of the diversity and complexity of vascular and pulmonary manifestations of rheumatic diseases and to highlight gaps in our knowledge of how to effectively manage them. Despite their significant morbidity, we have a limited understanding of their pathogenesis. The eleven published articles reported here underline the complexity of rheumatic diseases and the difficulty of managing them. The manuscripts provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools that assist with diagnosis, risk stratification, and therapy. A significant number of articles have reported innovative and effective treatments for the most frequent and debilitating complications of rheumatic diseases. The book emphasizes the importance of multidisciplinary teams using the skills of laboratory researchers, clinicians, radiologists, and pathologists. Furthermore, recent findings are presented and discussed, highlighting strategies to combat worsening symptoms of rheumatic diseases. The research described in this book provide an extremely useful example of the results achieved in the field of anti-rheumatic drug development. Detailed information on new breakthroughs can be found in this book. We strongly encourage a wide group of readers to explore the book that we are presenting for inspiration to develop new approaches to the diagnosis and treatment of rheumatic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8±52.68, 370.8±41.92, and 1527±74.16SD BAU/mL, respectively; p&nbsp

Background: In clinical practice, the striking similarities observed at computed tomography (CT) between the diseases make it difficult to distinguish a COVID-19 pneumonia from a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc). The aim of the present study was to identify the main CT features that may help distinguishing SSc-ILD from COVID-19 pneumonia. Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. Findings: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p

BackgroundIn this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc).MethodsIn SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses.ResultsThe final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21–24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21–24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (pConclusionThe data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.

Myocardial deformation imaging is a very attractive clinical tool for the assessment of right ventricular (RV) systolic performance, providing incremental diagnostic and prognostic information over the traditional indices of RV function. Among various imaging modalities, echocardiography is currently the method of choice for clinical assessment of RV longitudinal strain (RVLS). The methodology of 2D speckle-tracking echocardiography to obtain RVLS has been recently standardized and demonstrated to be feasible, accurate, and robust for clinical use. Inter-technique and inter-vendor comparability and reliability of RVLS are improving. RVLS is advantageous because it is more sensitive to subtle changes in myocardial function than conventional parameters used to assess RV function (i.e. tricuspid annular plane systolic excursion, tissue Doppler systolic velocity, fractional area change, or RV ejection fraction) representing a sensitive tool for the long-term follow-up of patients. Proper interpretation of measurements requires a deep understanding of RV mechanics and pathologic tissue characteristics in different cardiovascular conditions, as well as the influence of loading conditions, image properties, and tracking algorithms on RVLS measurements.

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

Laser speckle contrast analysis (LASCA) is a non-contact technique able to quantify peripheral blood perfusion (PBP) over large skin areas. LASCA has been used to study hand PBP in several clinical conditions. These include systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) and LASCA showed that PBP was significantly lower in these conditions than in healthy subjects (HS). Moreover, it has been demonstrated that LASCA is a safe technique also able to monitor digital ulcer perfusion and their evolution in SSc patients, during systemic and local treatment. The use of LASCA, coupled with reactivity tests is commonplace in the field of microvascular function research. Post-occlusive hyperemia reactivity (POHR) and local thermal hyperemia, associated with laser techniques are reliable tests in the evaluation of perfusion in SSc patients. Other studies used laser speckled techniques, together with acetylcholine and sodium nitroprusside iontophoresis, as specific tests of endothelium function. In conclusion, LASCA is a safe, non-contact reliable instrument for the quantification of PBP at skin level and can also be associated with reactivity tests to monitor disease progression and response to treatment in different connective tissue diseases.

Objectives Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis. Whether IL-25, an IL-17 family member regulating many epidermal functions, takes part in skin fibrosis is unknown. Here we address the role of IL-25 in skin fibrosis. Methods The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and seven healthy donor (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EEs was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (Col-I), and fibronectin production by fibroblasts was assessed by ELISA. Results SSc epidermis expressed lower levels of IL-25 compared with HDs. In EEs, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix remodelling. Compared with control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6 and IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. Conclusions These results show that IL-25 participates in skin homeostasis, and its decreased expression in SSc may contribute to skin fibrosis by favouring extracellular matrix deposition over degradation.

Systemic sclerosis (SSc)-related Raynaud’s phenomenon (RP) and digital ulcers (DU) can impair health-related quality of life (HRQoL). The aim of our study was to estimate HRQoL in SSc patients treated with two different intravenous (IV) iloprost (ILO) regimens and in patients not treated with IV ILO. 96 consecutive SSc patients were enrolled in a pragmatic, prospective and non-randomized study, and divided into 3 groups: not requiring therapy with IV ILO (N=52), IV ILO once monthly (N=24) or IV ILO for 5 consecutive days every 3 months (N=20). Patients were followed up for three months. We assessed HRQoL using the generic preference-based questionnaire EQ-5D-5L. We conducted multiple regression analyses to estimate, in each treatment group, the mean general health (GH) and the mean utility index of the EQ-5D-5L, adjusting for possible confounders. The mean adjusted utility index and GH score, after three months’ follow-up, were not different in the three groups: IV ILO was able to make patients requiring IV ILO similar to those not requiring it. Moreover, there was no difference in this model between the two ILO regimens (1 day monthly vs 5 consecutive days every 3 months). The two different IV ILO regimens (the most appropriate regimen was decided according to patients’ characteristics and needs) were able to stabilize HRQoL in RP secondary to SSc non-adequately controlled by oral therapy.

Systemic Sclerosis (SSc) is a disease with limited therapeutic possibilities. Mesenchymal stem cells (MSCs)-therapy could be a promising therapeutic option, however the ideal MSCs source has not yet been found. To address this problem, we perform comparison between bone marrow (BM)-MSCs and adipose (A)-MSCs, by the miRs expression profile, to identify the gene modulation in these two MSCs source. MicroRNAs (miRs) are RNAs sequences, regulating gene expression and MSCs, derived from different tissues, may differently respond to the SSc microenvironment. The miRs array was used for the miRs profiling and by DIANA-mirPath tool we identified the biological functions of the dysregulated miRs. In SSc-BM-MSCs, 6 miRs were significantly down-regulated and 4 miRs up-regulated. In SSc-A-MSCs, 11 miRs were significantly down-regulated and 3 miRs up-regulated. Interestingly, in both the sources, the involved pathways included the senescence mechanisms and the pro-fibrotic behaviour. Furthermore, both the MSCs sources showed potential compensatory ability. A deeper knowledge of this miRs signature might give more information about some pathogenic steps of the disease and in the same time clarify the possible therapeutic role of autologous MSCs in the regenerative therapy in SSc.

None

Systemic sclerosis (SSc) is an autoimmune disease, characterized by the presence of generalized vasculopathy and tissue fibrosis. Collagen vascular disorder in SSc is due to fibroblast and endothelial cell dysfunctions. This leads to collagen overproduction, vascular impairment and immune system abnormalities and, in the last stage, multi-organ damage. Thus, to avoid organ damage, which has a poor prognosis, all patients should be carefully evaluated and followed. This is particularly important in the initial disease phase, so as to facilitate early identification of any organ involvement and to allow for appropriate therapy. Pulmonary disease in SSc mainly involves interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). High-resolution computed tomography (HRCT) and pulmonary function tests (PFT) have been proposed to monitor parenchymal damage. Although transthoracic echocardiography is the most commonly used screening tool for PAH in SSc patients, definitive diagnosis necessitates confirmation by right heart catheterization (RHC). Moreover, some studies have demonstrated that nailfold videocapillaroscopy (NVC) provides an accurate evaluation of the microvascular damage in SSc and is able to predict internal organ involvement, such as lung impairment. This review provides an overview of the correlation between lung damage and microvascular involvement in SSc patients.

‘Resilience’ can be defined as ‘the psychological phenomenon representing the capacity of individuals to cope successfully with significant change, adversity or risk’ (1). Intrigued by the impact o...

Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.

International audience; Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients.

Objectives To investigate subclinical and clinical abnormalities in retinal and choroidal vascular plexuses in patients with SSc by means of optical coherence tomography angiography (OCT-A). Methods A total of 20 consecutive SSc patients were recruited and compared with 20 healthy subjects. Quantitative analysis of vessel density (VD), choriocapillaris plexus flow index (CCP-FI) and choroidal vascularity index were performed on OCT-A images in the superficial capillary plexus (SCP), deep capillary plexus (DCP) and CCP for all patients. Images were further reviewed by two independent readers for the assessment of qualitative abnormalities, including tortuosity, rarefaction areas, megacapillaries and macular-foveal capillaries. Results The DCP-VD in the whole scan and in the perifoveal, superior, inferior, nasal and temporal regions was significantly lower in the SSc group. The CCP-FI was significantly higher in SSc patients. When comparing SSc patients with and without digital ulcers, significantly decreased SCP-VD was demonstrated in the whole, perifoveal, superior, inferior, temporal and nasal regions. No difference in any of the OCT-A parameters was observed when comparing patients with and without interstitial lung disease. Qualitative analysis of OCT-A revealed at least one abnormality in 95% of patients. Conclusion We showed the ability of OCT-A to disclose early ocular vascular abnormalities in patients with SSc. Our results may represent a hypothesis-generating basis for exploring the potential role of OCT-A in diagnosis, monitoring and prognosis stratification in SSc.

The objective of this study was to determine the correlation between functional and radiological longitudinal change in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), and to test the OMERACT definition of clinically meaningful progression of pulmonary function tests (PFTs) for the prediction of ILD radiological evolution. We retrospectively retrieved high-resolution computed tomography (HRCT) studies and PFTs including DLco, both available at two time-points and performed within 6 months of each other, in SSc patients. A subset of patients was selected using a 12-24-month clinically oriented interval (n = 58). The extent of ILD at HRCT was scored according to a visual semi-quantitative method (SQCT). The correlation of absolute change (Δ) in the SQCT score with change in FVC and DLco was examined using Pearson's correlation coefficient. The concordance between the OMERACT criteria (≥ 10% FVC relative decline; or 5-10% FVC and ≥ 15% DLco relative decline) and SQCT categorical change (5% and 10%) was investigated. A total of 129 patients were enrolled. During 12-24-month follow-up, ΔSQCT was negatively correlated with ΔFVC (r = - 0.487, p = 0.0001) and ΔDLco (r = - 0.298, p = 0.023). Ten patients demonstrated CT progression ΔSQCT > 5%, among whom 5 with ΔSQCT > 10%. OMERACT criteria identified 25 patients with progressive SSc-ILD, of whom only 5 presented ΔSQCT > 5 and 3 presented ΔSQCT > 10%. In conclusion, change in radiological extent of SSc-ILD was correlated to functional decline in a limited time-frame. Repeated HRCT after 12-24 months may be useful for the longitudinal characterization of ILD evolution in patients with stable pulmonary function. Conversely, functional changes are suggestive of a concurrent radiological progression only after this interval. Key Points • In SSc patients, chest HRCT performed every 12-24 months can detect minimal but significant changes in ILD extent, even in subjects with stable pulmonary function. • PFT changes in 12-24 months are related to the radiological ILD progression. • OMERACT criteria might overlook patients with radiological progression. • Repeated chest HRCT may be useful for monitoring SSc-ILD when performed within 12 to 24 months from baseline in order to promptly detect progression and possibly impact on prognosis.

This Research Topic collection entitled “Osteoporosis in Rheumatic Diseases, What’s New?”, compiled by authors from various countries, confirms that patients with rheumatic diseases are frequently also affected by osteoporosis (OP). All the articles included reported that OP is a major comorbidity in rheumatic patients due to factors like, chronic treatment, inflammation, immobility, low body mass index (BMI), and low vitamin D serum concentrations.

Ultrasound has been widely explored in systemic sclerosis in the clinical and research settings. Ultrasound allows a non-invasive and ionising radiation-free ‘window’ into this complex disease and is well-suited to repeated examinations. Ultrasound provides novel insights into the pathogenesis and measurement of disease in systemic sclerosis, including early (preclinical) internal organ involvement. The purpose of this review is to describe the role of ultrasound to foster clinical and research advancements in systemic sclerosis relating to (1) musculoskeletal, (2) digital ulcer, (3) lung disease and (4) skin disease. We also highlight unmet needs which much be addressed for ultrasound to assume a central role in systemic sclerosis clinical care and research.

Background Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc), associated with a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. Due to unspecific symptoms, the diagnosis of PAH is often delayed. On this basis, it is of great value to improve current diagnostic methods and develop new strategies for evaluating patients with suspected PAH. Interleukin-32 (IL-32) is a proinflammatory cytokine expressed in damaged vascular cells, and the present study aimed to assess if this cytokine could be a new biomarker of PAH during SSc. Methods The IL-32 expression was evaluated in the sera and skin samples of 18 SSc-PAH patients, 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH) and 14 healthy controls (HCs), by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Receiver-operating characteristic (ROC) curves were performed to evaluate the cut-off of IL-32 in identifying patients with PAH. Furthermore, in SSc patients, correlation analyses were performed between IL-32 sera levels and mean pulmonary artery pressure (mPAP) evaluated by right heart catheterization (RHC) and systolic pulmonary artery pressure (sPAP), obtained by echocardiography. Additionally, the number of skin IL-32+ cells was correlated with modified Rodnan skin score (mRSS). Results In SSc-PAH patients, IL-32 sera levels were significantly higher when compared with SSc patients without PAH and patients affected by iPAH. The analysis of ROC curve showed that IL-32 sera levels above 11.12 pg/ml were able to predict patients with PAH (sensitivity = 90%, specificity = 100%). Furthermore, the IL-32 sera levels of patients with SSc correlated with both mPAP and sPAP. In the skin derived from SSc-PAH patients, the number of IL-32+ cells was significantly increased when compared with the skin derived from SSc patients without PAH, correlating with the mRSS. Conclusion Our study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc.

Background: In systemic sclerosis (SSc) patients, dry eye syndrome (DES) is the most frequent ocular feature. The aim of this study was to investigate ocular DES-related SSc patients and to establish any correlation with the severity of the disease. Methods: Retrospectively, data from 60 patients with SSc underwent ophthalmic examination, where non-invasive film tear break-up time (NIF-TBUT), tear film lipid layer thickness (LLT), anesthetic-free Schirmer test I, tear osmolarity measurement (TearLab System), and modified Rodnan skin score (mRSS) data were collected. The visual analog scale (VAS) and Symptom Assessment in Dry Eye (SANDE) methods were utilized. The results were correlated with mRSS and the duration of SSc. Results: Severe DES occurred in 84% of cases, and was more severe in women. The eyelids were involved in 86.6%, secondary to meibomian gland disease (MGD). A direct correlation was found between the tear osmolarity (mean 328.51 &plusmn, 23.8 SD) and skin score (mRSS) (r = 0.79, p &lt, 0.01). Significantly reduced NIF-TBUT, LLT, and Schirmer test I values were observed in the case of severe skin involvement. Conclusions: SSc patients show lipid tear dysfunction related to the severity and duration of the disease due to inflammation and the subsequent atrophy of the meibomian glands.

Systemic sclerosis (SSc) is a connective tissue disease, characterized by vascular damage and progressive fibrosis, affecting the skin and internal organs. The vascular changes include functional and structural abnormalities in the microcirculation, which play a central role not only in diagnosis but also in the prognosis and follow-up of systemic sclerosis patients. Nailfold videocapillaroscopy (NVC) is a safe, validated, noninvasive, inexpensive, reliable, and reproducible method that allows for the evaluation of structural changes in scleroderma microangiopathy. However, capillary blood flow/perfusion cannot be measured by NVC under standard conditions and, consequently, must rely on various laser techniques and thermography for the assessment and quantification of cutaneous blood perfusion. Other emerging technologies, such as optical Doppler tomography and spectroscopy, may be used to evaluate the skin flow. This review updates current knowledge on the use of microvascular evaluation techniques in SSc, including complications such as digital ulcers and pulmonary arterial hypertension.

Objectives Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. Methods SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. Results The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. Conclusion Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

Objectives: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). Methods: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. Results: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. Conclusions: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

ObjectiveTo prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function.MethodsSeventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% ResultsAbsolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%).ConclusionsChest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed.

Digital ulcers (DUs) represent a severe and common complication occurring in patients affected by Systemic Sclerosis (SSc), with a consistent impact on the quality of life and often resulting in longer hospitalization than unaffected patients. Conventional treatment of SSc ulcers consists of both topical and systemic (oral or intravenous) pharmacological therapies. Several surgical options are also available, but there is overall a lack of official guidelines or recommendations. The aim of this study was to evaluate the efficacy of a novel local therapy based on polyurethane foam dressings, namely the Highly Hydrophilic Polyurethane Foam (HPF), in addition to the conventional pharmacological treatment, in a cohort of 41 SSc patients with at least one active ulcer. Our results showed that the addition of HPF to the conventional treatment based on systemic drugs induced i) a significant reduction in the number of active DUs (p=0.0034); ii) a significant reduction of the mean duration of ulcer-related hospitalization as compared with standard therapy (p=0.0001); iii) a significant improvement of patients’ Quality of Life, as evaluated through the Scleroderma Health Assessment Questionnaire (SHAQ) (p=0.00011). Therefore, in our experience, the combined management of DUs can improve both the onset of new DUs and DU’s healing thus leading to a better outcome.

The aim of this research was to determine any correlations between Dickkopf-1 serum levels (Dkk-1, a natural inhibitor of the Wnt signaling pathway promoting osteoclastogenesis) and the Trabecular Bone Score (TBS), in systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. It also aimed at determining any difference in Dkk-1 serum levels between SSc and RA patients and a control group (CNT) of healthy subjects. A prospective study was carried out in 60 SSc and 60 RA patients and 60 CNT. Dkk-1 serum levels were evaluated by the ELISA method (Quantikine Human Dkk-1 Immunoassay, R&D System, Minneapolis, USA). The severity of microvascular damage was evaluated by nailfold videocapillaroscopy (NVC patterns: “Early,” “Active,” “Late”), in the SSc patients. TBS analysis and bone mineral density (BMD, g/cm2) were measured in all patients/subjects. The SSc patients showed higher Dkk-1 serum levels than RA (p

Background Systemic sclerosis is a systemic connective tissue disease characterized by endothelium damage, fibrosis, and subsequent atrophy of the skin. Perioral fibrosis produces a characteristic microstomia together with microcheilia, both of which cause severe difficulties and affects patients’ daily life, such as eating and oral hygiene. Since there are no effective and specific therapies, we have aimed at evaluating the response to filler injections of hyaluronic acid together with platelet-rich plasma. Methods Ten female patients aged between 18 and 70 were included in this study. Each patient was treated with three filler injections of hyaluronic acid and platelet-rich plasma at an interval of 15 to 20 days. Follow-up check-ups were recorded 1, 3, and 24 months after the end of the treatment. During the therapy and the subsequent follow-up, we evaluated the mouth’s opening, freedom of movement of the lips, and skin elasticity. Results After the treatment, patients had achieved good results already after the first injection and the improvement was maintained in the following months, up to 2 years. In particular, 8 (80%) patients showed a greater mouth’s opening and increased upper lip’s thickness during 1-month follow-up and maintained these results after 2 years (maximum mouth’s opening T0 47.61; T3 49.23; T4 48.60 p p p p p Conclusions Our study demonstrates that filler injections of hyaluronic acid and platelet-rich plasma represent an efficient local therapeutic alternative for patients affected by scleroderma. The treatment has significantly improved patients’ quality of living.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a major cause of morbidity and mortality, mostly presenting as non-specific interstitial pneumonia. Little is known about the prevalence of pleuroparenchymal fibroelastosis (PPFE), a specific entity affecting the visceral pleura and subpleural parenchyma. We set out to estimate PPFE prevalence in two large cohorts of SSc patients and to assess its impact on survival and functional decline.A total of 359 SSc patients, derived from two referral centres in two different countries (UK and Italy), were included. The first available high-resolution computed tomography scan was independently evaluated by two radiologists blind to clinical information, to quantify ILD extent, freestanding bronchial abnormalities, and lobar percentage involvement of PPFE on a four-point categorical scale. Discordant scores were adjudicated by a third scorer. PPFE extent was further classified as limited (≤2/18) or extensive (>2/18). Results were evaluated against functional decline and mortality.The overall prevalence of PPFE in the combined SSc population was 18% (11% with extensive PPFE), with no substantial difference between the two cohorts. PPFE was significantly linked to free-standing bronchial abnormalities (61% versus 25% in PPFE versus no PPFE; pIn the current study, we provide an exhaustive description of PPFE prevalence and clinical impact in the largest cohort of SSc subjects published so far. PPFE presence should be carefully considered, due to its significant prognostic implications.

Background: Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. Methods: Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3rd culture passage and then either maintained in normal growth medium (untreated cells) or independently treated with different concentrations of selexipag (from 30 mu M to 0.3 mu M) or ACT-333679 (from 10 mu M to 0.1 mu M) for 48 h. Protein and gene expressions of a-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (S100A4), COL-1, and FN were investigated by western blotting and quantitative real-time PCR. Erk1/2 and Akt phosphorylation was investigated in untreated and ACT-333679-treated cells by western botting. Results: Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of a-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts. Conclusions: Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules.

Among all possible systemic sclerosis internal organ complications, kidney involvement is frequently neglected or underestimated, except for the life-threatening scleroderma renal crisis. Fortunately, this severe clinical presentation is nowadays better controlled with available treatments, in particular angiotensin-converting enzyme inhibitors, and this has led to a reduction in its short- and longer-term mortality. Pathogenetic determinants are not well understood and many different other kidney involvements are possible in systemic sclerosis, including proteinuria, albuminuria, reduction of renal filtration, autoantibodies-related glomerulonephritis, and drug-related side effects. Different serological and radiological methods of evaluations are nowadays available, some representing promising diagnostic tool and prognostic outcome measure. Except for angiotensin-converting enzyme inhibitors in scleroderma renal crisis, no other treatment is currently recommended for treatment of kidney involvement in systemic sclerosis. For this reason, further studies are necessary to investigate its prognostic impact, in particular in combination with other systemic sclerosis–related internal organ manifestations. This review summarizes current available literature on kidney involvement in systemic sclerosis.