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Davide Mohammad Reza Beigi, Greta Pellegrino, Marius Cadar, Ilaria Bisconti, Francesca Romana Di Ciommo, Katia Stefanantoni, Fabrizio Conti, Valeria Riccieri Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, ItalyCorrespondence: Davide Mohammad Reza Beigi, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, Italy, Tel +393496300710, Email davidemrb@gmail.comObjective: This work aims to evaluate the prevalence of anxiety and COVID-19-related fear in systemic sclerosis (SSc) patients during the second and third waves of the SARS-CoV-2 pandemic in Italy and their possible associated factors.Methods: A cohort study was carried out on 114 SSc patients referred to our Scleroderma Clinic, matched for sex and age. Twenty-eight of them had missed scheduled examinations during the October 2020–March 2021 period and 86 has attended regular outpatient visits during the same period. Both groups were administered (by telephone for cases and in-person for controls) the Generalized Anxiety Disorder Scale-7 (GAD-7) questionnaire and the validated on SSc patients COVID-19 Fears Questionnaire for Chronic Medical Conditions (COVID-19 Fears). Concurrent factors related to higher scores were investigated in patients who did not have an outpatient follow-up.Results: The missing group had significantly more patients scoring ≥ 8 on the GAD-7 questionnaire [22 (78.6%) vs 16 (18.6%), p < 0.0001] and significantly higher scores on the COVID-19 Fears questionnaire (median [quartiles] 31.5 [26.25;37.25] vs 20 [13.75;28], p < 0.0001) than the attending group. Multivariate analysis performed on the missing patients group showed a significant association of the lack of work and ongoing therapy for anxiety/depression with GAD-7 (p = 0.0275 and p = 0.0188) and COVID-19 Fears score (p = 0.0016 and p = 0.0099).Conclusion: Anxiety disorder and COVID-19-related fear were greater in SSc patients who missed regular follow-ups and are associated with a lack of work activity. These findings aim to identify a subgroup deserving attention regarding risk factors for missed periodic controls.Keywords: systemic sclerosis, anxiety, COVID-19 fear

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.

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.

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

Since the onset of the COVID-19 outbreak, concern has been raised about reliability of SARS-CoV-2 serological tests in people with serum positivity for rheumatoid factor (RF), due to its ability to interfere during tests carried out with immunoassay techniques, leading to false positive results. The aim of this study was to analyse, on sera from RF seropositive rheumatoid arthritis (RA) patients, the interference between RF IgM and anti-S1 RBD IgM.The study was conducted on consecutive patients affected by RF seropositive RA and, as control group, COVID-19 patients with SARS-CoV-2 pneumonia hospitalised at Sapienza University of Rome from April 2020 and April 2021. Serum samples from COVID-19 patients during their hospitalisation were collected, while RA subjects' samples were harvested prior to the onset of the COVID-19 pandemic. All samples were tested for RF IgM using nephelometry and ELIA, and for anti-S1 RBD IgM by ELISA.Forty RF seropositive RA and 42 COVID-19 patients were enrolled. In all RA patients, both nephelometric assay and ELIA showed RF IgM positivity, while only one patient of the control group tested positive for RF IgM by nephelometric assay and ELIA. IgM directed to S1 RBD were not detected in sera of RA patients, while all COVID-19 patients presented anti-S1 RBD IgM (median anti-S1 RBD IgM COVID-19 vs. RA: 368.5 IU/mL, IQR 654 IU/mL vs. 18.45 IU/mL, IQR 20 IU/mL; p0.0001).This study confirmed the lack of cross-reactivity between RF and anti-S1 RBD IgM, offering to clinicians a valuable tool for a better management of RA patients undergoing SARSCoV-2 serological tests.

SARS-CoV-2 vaccines appear to be the most promising strategy for fighting the virus and protecting also those who might be at higher risk of severe COVID-19, such as patients with rheumatic and musculoskeletal diseases (RMDs). However, vaccine hesitancy might greatly impair the possibility to reach herd immunity and curtail the virus.1 2 As underlined by some studies performed before vaccine availability, a non-negligible proportion of subjects among the general population would have refused vaccination against COVID-19.3 4 During the first weeks of the ongoing vaccination campaign, we proposed an online survey to adult patients with RMDs residing in the Lazio region followed up at our tertiary referral centre in Rome, Italy. Healthy controls (HCs) were recruited using the ‘best friend’ system. Participants had to report on eight different domains with two possible answers: ‘yes’ or ‘no’ (table 1). View this table: Table 1 Multivariable models predicting willingness to receive COVID-19 vaccination and other SARS-CoV-2 and/or vaccine-related outcomes in patients with RMDs and healthy controls Only for the item ‘Willingness to receive COVID-19 vaccination’, answers were ‘yes’ or ‘no/don’t know’, with the possibility to give an explanation in case …

Background: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations. Objective: This study aims to investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic. Methods: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of the pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in the absence of a swab testing). Results: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to the Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed a significantly lower rate of Covid-19 compared to those without (p=0.003). Conclusion: The higher prevalence of Covid-19 in ASD patients, along with the significant correlations with important clinical features and therapeutic regimens, suggests the need to develop targeted prevention/management strategies during the current pandemic wave.

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Background/aims A role for Helicobacter pylori in triggering systemic sclerosis (SSc) has been proposed, but data are conflicting. In previous studies, infection has been generally searched for by using serology. We designed this study to assess H. pylori prevalence in SSc patients with histology of gastric mucosa, considered the criterion standard for infection diagnosis. Methods This cross-sectional study enrolled 30 SSc patients who complained of upper gastrointestinal symptoms. All underwent upper endoscopy with gastric biopsies. Endoscopic alterations were recorded, and gastric mucosa biopsies were used for both histological examination and searching for H. pylori. The role for proton-pump inhibitor (PPI) therapy was considered. Fisher exact test was used for statistical analysis. Results Data of 28 SSc patients were available, 14 with ongoing PPI therapy. Helicobacter pylori infection at histology was detected in 14.3% patients, and it equally occurred in patients with or without PPI therapy. Erosive esophagitis/Barrett esophagus was detected in 26.6% of cases. Among patients with PPI therapy, 30% received half dose only. The prevalence of intestinal metaplasia was low (14.3%). Endoscopic esophageal alterations were significantly more frequent in those patients showing anti-Scl70 antibody positivity. Conclusions This study showed that prevalence of H. pylori is very low in SSc patients, so that it seems not having a role in triggering SSc. Management of gastroesophageal diseases in SSc patients needs to be improved, and looking to the autoimmune profile may be of help. Thus, collaboration between rheumatologist and gastroenterologist is highly recommended.

Background:SARS-CoV-2 infection poses a serious challenge for patients with rheumatic autoimmune systemic diseases (ASD), characterized by marked immune-system dysregulation and frequent visceral organ involvement.Objectives:To evaluate the impact of Covid-19 pandemic in a large series of Italian patients with ASD.Methods:Our multicenter telephone survey (8-week period, March-April 2020) included a large series of 2,994 patients (584 M, 2,410 F, mean age 58.9±13.4SD years) with ASD followed at 34 tertiary referral centers of 14 regions of northern, central, and southern Italian macro areas, characterized by different prevalence of SARS-CoV-2 infection. According to currently used criteria, Covid-19 was classified as definite Covid-19 (signs or symptoms of Covid-19 confirmed by positive oral/nasopharyngeal swabs at PCR testing) or highly suspected Covid-19 (signs or symptoms highly suggestive of Covid-19, but not confirmed by PCR testing due to limited availability of virological tests in that period). The results were analyzed performing the Odds Ratio by Java-Stat 2-way Contingency Table Analysis.Results:The main findings of the survey study revealed a significantly increased prevalence of Covid-19 in:a.the whole series of ASD patients (definite Covid-19: 22/2994, 0.73%; p=0.0007;definite Covid-19 plus highly suspected Covid-19: 74/2,994, 2.47%; phttps://www.epicentro.iss.it/en/coronavirus/sars-cov-2-national-surveillance-system).b.the subgroup of patients with connective tissue diseases or systemic vasculitis (n = 1,901) compared to the subgroup of inflammatory arthritis (n = 1,093), namely rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis (definite Covid-19: 19/1,901, 0.99%, vs 3/1,093, 0.27%; p=0.036; definite Covid-19 plus highly suspected Covid-19: 69/1,901, 3.6%, vs 5/1,093, 0.45%; pc.the subgroup of patients with pre-existing interstitial lung involvement (n = 526) compared to those without (n = 2,468) (definite Covid-19: 10/526, 1.90%, vs 12/2,468, 0.48%; p=0.0015; definite Covid-19 plus highly suspected Covid-19: 33/526, 6.27%, vs 41/2,468, 1.66%; pOf interest, the prevalence of Covid-19 did not correlate with presence/absence of different comorbidities, mainly diabetes, cardio-vascular and/or renal disorders, as well as of ongoing treatments with biological DMARDs; while patients treated with conventional DMARDs showed a significantly lower prevalence of Covid-19 compared to those without. Covid-19 was more frequently observed in the patients’ populations from northern and central compared to southern Italian macro area with lower diffusion of pandemic. Clinical manifestations of Covid-19, observed in 74 patients, were generally mild or moderate; 4/9 individuals requiring hospital admission died for severe pneumonia.Conclusion:The prevalence of Covid-19 observed in ASD patients during the first wave of pandemic was significantly higher than that observed in Italian general population; moreover, the actual prevalence of Covid-19 might be underestimated due to the high number of mild variants as well as the possible clinical overlapping between these two conditions. Patients with ASD should be invariably regarded as ‘frail patients’ during the pandemic course, considering the risk of worse outcome in the acute phase of Covid-19, as well as the potential long-term effects of viral infection.The statistically significant association of Covid-19 with connective tissue diseases/systemic vasculitis, as well as with pre-existing interstitial lung involvement, suggests the presence of distinct clinico-pathological ASD subsets, characterized by markedly different patients’ vulnerability to SARS-CoV-2 infection.Disclosure of Interests:None declared

The outbreak of SARS-CoV-2 has changed the habits and lives of people worldwide. Patients affected by systemic sclerosis (SSc) experienced constant fear because of their immunocompromised status. The aim of this study was to investigate the prevalence of SARS-CoV-2 infection and to analyze the lifestyle changes in a single-center cohort of SSc patients and if these changes were more severe than in the general population. During the Italian lockdown, we supplied two surveys to our 184 SSc patients. In the first one, filled by 110 patients, we asked if SARS-CoV-2 had infected them or if they experienced signs and symptoms consistent with COVID-19. The second survey, performed by 79 SSc patients and 63 healthy subjects, included questions about the lifestyle adopted during this specific period. Among our patients, COVID-19 was diagnosed only in one case, while three other subjects reported signs and symptoms suggestive for the disease. Regarding the second survey, our patients greatly changed their lifestyle during the pandemic, adopting more restrictive isolation measures, because of their awareness of frailty. To date, we do not dispose of enough data to speculate about the risk of COVID-19 among immunocompromised patients, although in our SSc patients their frailty seems to have been their shelter. Pending more accurate epidemiological studies, it is essential to share as much data as possible to better understand the impact of COVID-19 on SSc patients' health. Key points • The lifestyle adopted by SSc patients during the first months of COVID-19 pandemic was characterized by more stringent isolation rules than general population. • The prudential behavior of patients with SSc during Italian lockdown should be considered as a possible bias when analyzing the risk of SARS-CoV-2 disease in these subjects, as well as a protective factor against infection.

Background Endothelial-to-mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation, seems to be involved in Systemic Sclerosis (SSc) pathogenesis. In this process endothelial cells lose their specific markers, and acquire a mesenchymal phenotype, thus expressing cell products such as alpha smooth muscle actin (α-SMA) (1,2). Circulating endothelial progenitors cells (EPCs) derive from bone marrow stem cells and contribute to de novo vessels formation. Several studies, although with conflicting results, have shown that EPCs in the peripheral blood of patients with SSc are impaired in their number and function (3). Objectives to assess the expression of α-SMA, possibly associated with a pro-mesenchymal switch (EndoMT) of the circulating Early (CD34+KDR+CD 133+) and Late (CD34+KDR+) EPCs in the peripheral blood of SSc patients and of patients with Very Early Diagnosis of SSc (VEDOSS) compared with healthy controls (HC) using flow cytometry. Methods we enrolled 11 patients (7 SSc and 4 VEDOSS), classified according to the classification criteria for SSc (4) and for VEDOSS not fulfilling SSc criteria (5), and 10 HC. Phenotypic characterization was performed as previously described by Vasa et al. using a FACS Calibur (BD Immunocytometry Systems). EPCs number was expressed as a percentage of cells within the lymphocyte gate. Results we found a significantly higher percentage of α-SMA positive Early EPCs (CD34+KDR+CD 133+αSMA+) in all patients respect to HC (0,06% ±0,03 vs 0,03% ± 0,01; p=0,0149) particularly in VEDOSS patients (0,07%±0,01 vs 0,03±0,01 p=0,008). Moreover, in VEDOSS patients, also the percentage of Early EPCs (CD34+KDR+CD 133+), Late EPCs (CD34+KDR+)and α-SMA positive Late EPCs (CD34+KDR+αSMA+) were significantly higher than in HC (0,05%±0,01 vs 0,03%±0,01 p=0,05; 0,07%±0,01 vs 0,04%±002 p=0,04; 0,06%±0,01 vs 0,04%±0,02 p=0,05). Besides Early EPCs and α-SMA positive Early EPCs percentages seem to be significantly reduced in patients taking iloprost (p=0,05 and p=0,01 respectively), calcium channel blockers (CCB) (p=0,05 and p=0,03) and DMARDs (p=0,017 and p=0,013). Conclusion EndoMT seems to be involved in the pathogenesis of SSc and circulating EPCs seem to be impaired in number and function in SSc patients. In our study we found higher levels of EPCs, in particular α-SMA positive Early EPCs in both groups of patients (SSc and VEDOSS) respect to HC. Thus we can hypothesize a predominant pro-mesenchymal phenotype of this kind of EPCs. This could be considered the expression of the involvement of EPCs in EndoMT process and could better explain the controversial role of EPCs in SSc pathogenesis. Very interesting is the finding of a lower percentage of Early EPCs, and in particular of α-SMA positive Early EPCs, in those patients taking iloprost, CCB and DMARDs, suggesting a potential effect of these drugs on this subgroup of EPCs. References [1] Corallo C, et al. Arthritis Res Ther2016; [2] Manetti M, et al. Ann Rheum Dis2017; [3] Del Papa N, et al. Front. Immunol2018; [4] Van den Hoogen F, et al. Ann Rheum Dis2013; [5] Avouac J, et al. Ann Rheum Dis2011. Disclosure of Interests Katia Stefanantoni Consultant for: Only 1 scientific advice for Italfarmaco in 2016, cristiana barbati: None declared, Carlotta Angelelli: None declared, Greta Pellegrino: None declared, cristiano alessandri: None declared, Guido Valesini: None declared, Valeria Riccieri: None declared

Background: an increased risk of malignancies (1.5-5 times) was found in Systemic Sclerosis (SSc). Well recognized risk factors are the diffuse form, advanced age and (1), more recently, the positivity for anti-RNA Polimerase III antibodies (aRNAP3) has assumed considerable importance (2). Objectives: the aim of this study was to evaluate the frequency of neoplasms and precancerous conditions, as well as the main risk factors, in our cohort of patients with SSc. Methods: we enrolled 312 consecutive patients (288/92% females and 24/8% males, mean age 62.3 years, average disease duration 108 months) afferent at our department from 2000 to 2018, with a diagnosis of SSc confirmed according to the 2013 aCR/EULAR criteria (3). All patients underwent clinical, instrumental and laboratory evaluation. In 93 patients, negative for anti-topoisomerase I antibodies (aScl70) and anti-centromere antibodies (ACA), the presence of aRNAP3 antibodies was evaluated by an ELISA method (QUANTA LiteTM RNA Pol III). Results: we found a limited form of disease in 229 patients (73.4%) and a diffuse form in 83 (26.6%). Eighty eight (28.2%) patients were positive for aScl70, 112 (35.9%) for aCA and 17 (5.4%) for aRNAP3. In the whole group, 44 (14%) patients had a positive familiar history for neoplasm while 105 (33.65%) had a history of neoplasms and/or precancerous conditions. Among these 105 cases, 44 (41.9%) were malignant, 50 (47.6%) benign and 11 (10.5%) had precancerous conditions. The most frequent neoplasms were breast carcinomas (14 cases/14.9%), thyroid (7 cases/7.4%), lung and kidney (3 cases/3.1%), melanomas (5 cases/5.3%). The most frequent precancerous condition was Barrett’s esophagus (7 cases/63.3%). Regarding the antibody profile, 5 (4.8%) patients were positive for anti-RNAP3 and only 2 (1.9%) of these patients presented a malignant neoplasm, breast cancer in both cases. In 30 cases (28.6%) these neoplastic/precancerous conditions had arisen in the close period (± 36 months) at the SSc diagnosis and only 3 of them were anti-RNAP3 positive. Among the evaluated risk factors. Only familiarity was significantly associated with the development of neoplasia (p = 0.003), confirmed at the multivariate analysis (OR 2.9, IC95% [1,5-5,7]; p=0,002). Conclusion: our study evaluated not only malignant neoplasms, but also benign neoplasms and precancerous conditions and identified familiarity as the only significant risk factor. In our cohort we did’nt find any relationship between the presence of anti-RNAP3 antibodies and the development of neoplasms, not even stratifying for the type of neoplasm. However, to better define our data, we should analyze anti-RNAP3 also in the double negative (antiScl70 and aCA) cases, in light of the recent evidence of double antibody positivity, as well as other newly investigated rare autoantibodies, associated with neoplasm in many connective tissue diseases, including SSc. References [1] Szekanecz E, et al. (2012) autoimmun Rev11, 852; [2] Shaha aAet al(2017) J Scleroderma Relat Disord. 2, 153; [3] Van den Hoogen F, et al. (2013) ann Rheum Dis72, 1747–55. Disclosure of interests: Katia Stefanantoni Consultant for: only 1 scientific advice for Italfarmaco in 2016, Natalia Di Tommaso: None declared, Nicoletta Iannace: None declared, Iliana Sciarra: None declared, Carlotta angelelli: None declared, Elena Marafioti: None declared, Greta Pellegrino: None declared, massimiliano vasile: None declared, Guido Valesini: None declared, Valeria Riccieri: None declared

Background:The ScS approach has changed considerably in recent years especially concerning the very early diagnosis of the disease (VEDOSS) at the time when the patient is still in an undifferentiated form (UCTD) at risk of developing SSc (1, 2). Of great value are different clinical, instrumental and laboratory findings, such as specific autoantibodies and Nailfold VideoCapillaroscopy (NVC), able to identify those cases progressing into overt SSc. IL-33 cytokine is known to exert pro-fibrotic effects through its membrane receptor ST2 on immune cells and myofibroblasts and recent studies suggest that it can be released following endothelial cell activation at the onset of SSc (3, 4).Objectives:Our aim has been to evaluate IL-33 serum levels in a monocentric cohort of VEDOSS patients, looking for the possible association with clinical phenotype and disease progression, focusing on the microvascular capillaroscopic changes.Methods:Fourty-seven VEDOSS patients underwent a complete clinical, instrumental and laboratory evaluation, including NVC and specific SSc autoantibodies. At baseline serum IL-33 levels were measured using an ELISA assay. In 32 of them we also had a second serum sample at a follow-up time of at least 24 months (range 24 to 96 months).Results:During the follow-up time, 17 patients were subsequently reclassified as having ScS whereas 30 remained VEDOSS. The “progressor” subjects positively correlated with the presence of anti-Topoisomerase I antibodies (p>0,004). IL-33 concentrations had a median value of 427.2 pg/ml (IQR 967.9 pg/ml) at baseline and of 130.4 pg/ml (IQR 399 pg/ml) at the follow up, showing a statistically significant difference independently from the progression of the disease (p=0.03). Besides significantly higher levels were detected in those patients with more severe NVC changes, defined as “active” pattern (pConclusion:The analysis of our data confirms previous report (5) on higher IL-33 serum levels in the very early stages of UCTD patients at risk for SSc, regardless of their progression in established SSc, although related to more severe microvascular NVC involvement. The lowering of IL-33 serum levels that we detected in the follow up of our patients, may be linked to the well-known endothelial changes during the progression of the SSc and seems also to be partially affected by treatments. Investigation on a greater number of patients are needed to better understand our findings.References:[1]J. Avouac et al. Ann Rheum Dis 2011[2]G Valentini et al. Clin Exp Med 2017[3]Manetti M, et al. Ann Rheum Dis 2010[4]Terras S et al. Ann Rheum Dis 2013[5]Vettori S, et al. J Clin Immunol 2014Disclosure of Interests:None declared

Background:Social distancing due to COVID-19 pandemic had a major impact on the mental health of general population, with a high prevalence of post-traumatic stress disorder (PTSD) related symptoms1, 2. Psychological repercussions were notably found in people with chronic diseases, including systemic sclerosis (SSc) patients, where an increasing of anxiety symptoms, related also to low financial resources, emerged3.Objectives:To evaluate the impact of COVID-19 lockdown on the onset of PTSD in patients with SSc, firstly during the total confinement period (March-April 2020) and then at the time of less restrictive government measures, following the RT index lowering (June-July 2020)4.Methods:We carried out a case-control study on 57 SSc patients, according to the ACR/EULAR 2013 criteria, and on 57 healthy subjects as control group (HC), matched by sex and age. At T0 (March-April) and T1 (June-July) both populations received the “Impact of Event Scale Revised” questionnaire (IES-R) by e-mail, with a cut-off of ≥ 33 defining probable diagnosis of PTSD5. A multivariate analysis of possible factors influencing IES-R score, such as age, number of cohabitating people and weekly outings count, was performed in SSc patients at both times of the survey.Results:At T0 we found a significantly greater number of SSc patients with IES-R score ≥ 33 compared to HC (26/45.6% vs 13/22.8%; median value [quartiles] 31 [19.5;42.5] vs 24 [15.5; 32]; p-value 0.046). At T1, we obtained data from 44 SSc patients and 35 HC but no significant difference was noticed (18 / 40.9% vs 8 / 23.5%; 26 [15.25; 38] vs 26.5 [20.75; 32.5]; p> 0.05). SSc patients also had significantly fewer weekly outings than HC, both at T0 (p Conclusion:We found a significantly higher prevalence of PTSD in SSc patients compared to HC at the strictest lockdown time, turning into comparable when government measures were less restrictive, due to the minimum RT index values recorded in Italy. Older age and lower count of weekly outings were associated with PTSD in SSc patients during the lockdown, whereas the count of weekly outings was lower than in HC during both the examined periods. The results of this study indicate that COVID-19 lockdown had a worse impact in SSc patients, where the fewer weekly outings may depend on their clinical condition and on a greater concern about their health6. These findings strengthen the World Scleroderma Foundation recommendations regarding care to the psychological frailty of SSc patients7.References:[1]Wang C, Brain Behav Immun. 2020.[2]Dubey S, Psychiatr Pol. 2020.[3]Thombs BD, J Psychosom Res. 2020 Dec.[4]https://covid19.infn.it/grafici/?chart=italia,rt,covidstat[5]Weiss, D. S., & Marmar, C. R. (1996). The Impact of Event Scale - Revised, Assessing. psychological trauma and PTSD (pp. 399-411).[6]Orlandi M, Clin Rheumatol. 2020[7]Matucci-Cerinic M, Ann Rheum Dis. 2020Table 1.Descriptive analysis of study population: T0 (Time 0), T1 (Time 1), SD (Standard Deviation), IES-R (Impact of Event Scale-Revised).SSc patient groupHS groupFemale:male ratio at T046:746:7Mean age ± SD at T059±12.851±8.7IES-R ≥33 score n°/% at T026/45.6%*13/22.8%IES-R ≥33 score n°/% at T118/40.9%8/23.5%IES-R score at T0, median value [quartiles]31 [19.5;42.5]24 [15.5;32]IES-R score at T1, median value [quartiles]26 [15.25; 38]26.5 [20.75; 32.5]N° of weekly outings at T0, median value [quartiles]2 [1;3.5]4 [2;10]**N° of weekly outings at T1, median value [quartiles]5 [3;6]14 [6.75;15]***pDisclosure of Interests:None declared.

Background:Systemic sclerosis (SSc) is a rare and progressive autoimmune disease, whose diagnosis is difficult in the early stages because of the lack of specific signs and symptoms. Criteria for a Very Early Diagnosis of SSc (VEDOSS) have been proposed to identify those patients affected by undifferentiated connective tissue disease (UCTD) at risk to develop SSc [1]. For the diagnosis of SSc a strict clinical and laboratory follow up is mandatory [2]. CXCL4 chemokine recently proved to be higher in early SSc [3][4][5].Objectives:Aim of our study was to evaluate at baseline the main clinical-demographic and laboratory parameters in a group of VEDOSS patients, comparing these features during the follow-up, to detect any difference between progressors (P) and non-progressors (NP) into SSc. Furthermore, we dosed plasma levels of CXCL4.Methods:We included 27 VEDOSS patients, defined by EUSTAR 2011 Criteria and not fulfilling the 2013 ACR/EULAR classification criteria of SSc, attending the Rheumatology Unit of Policlinico Umberto I in Rome from 2009 to 2020. Demographic, laboratory and instrumental features were analyzed, and, after a mean follow-up of 5.7±1,7 years, we compared the P to NP patients. Having obtained written informed consent, blood samples were taken at baseline to measure plasma levels of CXCL4 chemokine using an ELISA assay.Results:At baseline the 27 VEDOSS patients (mean age 53.2±13.5 years, all females) had ANA positivity in 25 (93%) cases and Raynaud’s phenomenon in 25 (93%) cases. In a mean follow-up time of 43.5 ± 23.1 weeks from the first clinical examination, 15 (55%) patients were classified as P into SSc. These P patients showed a significant association with SSc specific antibodies such as anti-Centromere, anti-Scl70 and anti-RNAPIII (p=0.014) as well as with a specific “Scleroderma pattern” at the nailfold capillaroscopy (p=0.022) respect to those NP into SSc. A group of 6 P patients evolved in less than 24 months (mean 19,6 ± 6,8 weeks) and were defined “Fast Progressor”. They were also significantly associated with those autoantibodies considered as having a worse prognosis such as anti-Scl70 and anti-RNAPIII (p=0.005), and had a shorter duration of RP (88 vs 189.3 months) and a younger mean age (49.5 vs 55.4 years) respect to “Slow Progressor” (SSc evolving in >24 months). At baseline we detected significantly higher median plasma levels of CXCL4 in the 27 VEDOSS patients compared to 10 healthy subjects (9024±10559 pg/ml versus 348,5±684,3 pg/ml; p=0.0047). We also noticed a trend for lower CXCL4 levels in the “Fast Progressor” than in the “Slow Progressor” (3303 ± 6065 pg/ml vs 13300 ± 10308 pg/ml; p=0.052) without reaching a significant value, due probably to the low number of cases.Conclusion:Our study confirms that the presence of specific autoantibodies and capillaroscopic abnormalities correlate to an increased risk of developing SSc in patients with UCTD [6]. Beside we found significantly higher levels of CXCL4 in our 27 VEDOSS patients respect to controls, in agreement with other authors showing the association of this chemokine with early stages and specific organ involvement [4][5][7]. The finding of CXCL4 lower levels in “fast progressor” cases is consistent with our recent report of anti-CXCL4 antibodies in patients with early SSc, determining lower levels of this antigen [7]. We need deeper investigations to better evaluate the role of CXCL4 in the different stages of SSc.References:[1]J. Avouac et al., Ann. Rheum. Dis., 2011.[2]F. van den Hoogen et al., Ann. Rheum. Dis., 2013.[3]G. Valentini et al., Clin. Exp. Med., 2017.[4]R. Lande et al., Nat. Commun., 2019.[5]L. van Bon et al., N. Engl. J. Med., 2014.[6]M. Vasile et al., Clin. Exp. Rheumatol., 2018.[7]R. Lande et al., Int. J. Mol. Sci., 2020.Disclosure of Interests:None declared

Background:Electrocardiographic (ECG) abnormalities are described in 25-75% Systemic Sclerosis (SSc) cases and they are associated with other systemic manifestations as well as with a worse prognosis. There is an increasing need for clinical and laboratory biomarkers to ameliorate the diagnostic and therapeutic approaches to patients with ECG abnormalities, due to their actual low sensitivity and specificity. Adipokines are circulating proteins that appear dysregulated in SSc and leptin in particular is synthesized in response to inflammatory conditions and seems to play a proinflammatory and pro-fibrotic action in SSc. Interesting, many studies in the last years have underlined its role in the cardiac remodeling mechanisms and in the development of cardiac fibrosis in other chronic diseases.Objectives:Aim of our study is to evaluate the role of leptin in the development of cardiac rhythm disorders (CRD) during SSc. Furthermore, by the analysis of the clinical and demographical parameters of our SSc patients, we tried to define other possible features associated with increased serum leptin concentration.Methods:We included eighty-five SSc patients, fulfilling the 2013 ACR/EULAR classification criteria, attending the Regional Rare Disease Center of Policlinico Umberto I of Rome. Fifty presented significant CRD at non-invasive diagnostic techniques (12 Lead ECG, 24-hour Holter ECG). Demographic, clinical, conventional cardiovascular risk factors were examined; instrumental and laboratory assessments were obtained, together with ECG recordings. Thirty-five SSc patients without pathologic finding at ECG traces, matched for demographic and clinical features, were recruited as the control group. In all cases, after obtaining written informed consent, blood samples were taken to measure serum levels of leptin using an ELISA assay (Life Technologies-Italia).Results:The fifty SSc patients with CRD (mean age 51±15 years; F:M 41:9) had pulmonary fibrosis (PF) in 32 cases (64%) and a BMI >25Kg/m2in 22 (44%) while in the control group of thirty-five SSc patients (mean age 49±16 years; F:M 33:2) PF was found in 15 (43%) and a BMI >25Kg/m2in 9 (35%); We detected significantly higher median values of serum leptin in SSc patients with CRD compared to the control group (12027 pg/ml IQR 12314 versus 6392 pg/ml IQR 7103;p 0,0009). Additionally, SSc patients with a BMI> 25 kg/m2(31 cases) as well as those with PF (47 cases) showed a significantly higher median serum leptin levels compared to those with BMI 2(13161 pg/ml IQR 13610 versus 8187 pg/ml IQR 8255;p 0,0008) and those without PF (11740 pg/ml IQR 11940 versus 7616 pg/ml IQR 7855;p 0,0079).Conclusion:To our knowledge this is the first report on high serum levels of leptin in SSc patients with CRD that also confirms its increase in those cases with a BMI >25 kg/m2and with PF, according to scientific literature data. The role of leptin in the pathogenesis of SSc remains unclear although it is already known its involvement in the development of cardiac fibrosis during other chronic diseases. On the basis of these results we speculate on leptin involvement in the pathogenesis of CRD during SSc, although further studies are needed with larger cohort of patients.References:[1]Vacca A et al. Rheumatology, 2014[2]Tyndall AJ et al. Ann Rheum Dis, 2010[3]Muresan L et al. Iran J Pub Health, 2017[4]Sanna T et al. Indian Pacing Electrophysiol J, 2009[5]Riccieri V et al. Clin Exp Rheumatol, 2011[6]Żółkiewicz J et al. Arch Dermatol Res, 2019[7]Huby AC et al. Circulation, 2015[8]Shulze PC et al. Clin Chim Acta, 2005[9]Van de Hoogen F et al. Arthritis Rheum, 2013[10]Gui X et al. Biochem Biophys Res Commun, 2018Disclosure of Interests:Greta Pellegrino: None declared, Katia Stefanantoni Consultant of: ItalfarmacoBoehringer Ingelheim, Fausta Facioni: None declared, Carlotta Angelelli: None declared, Antonietta Gigante: None declared, Roberto Badagliacca: None declared, Carmine Dario Vizza: None declared, Sergio Morelli: None declared, Edoardo Rosato: None declared, Valeria Riccieri: None declared

Background:Endothelial-to-mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation, seems to be involved in Systemic Sclerosis (SSc) pathogenesis. In this process endothelial cells lose their specific markers, and acquire a mesenchymal phenotype, thus expressing cell products such as alpha smooth muscle actin (α-SMA) (1,2).Circulating endothelial progenitors cells (EPCs) derive from bone marrow stem cells and contribute tode novovessels formation. Several studies, although with conflicting results, have shown that EPCs in the peripheral blood of patients with SSc are impaired in their number and function (3).Objectives:to assess phenotypic characteristics of EPCs fromSSc patients and from patients with Very Early Diagnosis of SSc (VEDOSS) compared with healthy controls (HC). In particular we want to evaluate the expression of α-SMA, as marker of a pro-mesenchymal switch (EndoMT) in:Circulating Early (CD34+KDR+CD 133+) and Late EPCs(CD34+KDR+) in the peripheral blood using flow cytometryCultured EPCs using Western blot analysisMethods:we enrolled 11 patients (6 SSc and 5 VEDOSS), classified according to the classification criteria for SSc (4) and for VEDOSS not fulfilling SSc criteria (5), and 5 HC. Phenotypic characterization was performed as previously described by Vasa et al. using a FACS Calibur (BD Immunocytometry Systems). EPCs number was expressed as a percentage of cells within the lymphocyte gate. 5*106 PBMCs were plated on human fibronectin-precoated (10 μg/ml Sigma-Aldrich) 6-well plates and cultured for 7-12 days to obtain EPCs. PBMCs from one HC were also cultured with 20% SSc patient serum. Collected EPCs were lysed and a Western blot analysis for α-SMA detection was performed.Results:we found a significant higher percentage of α-SMA positive Early EPCs in all patients respect to HC (0,06% ±0,03 vs 0,03% ± 0,01; p=0,0149) particularly in VEDOSS patients (0,07%±0,01 vs 0,03%±0,01 p=0,008). Similarly we found a significant higher expression of α-SMA protein in all patients and VEDOSS patients respect to HC (0,1895±0,16 vs 0,07± 0,06 p= 0,0342; 0,3075 ± 0,14 vs 0,07± 0,06 p=0,0159). After the incubation of HC PBMCs with SSc serum, the α-SMA protein expression seems to be increased respect to its expression in thePBMCs of the same HC cultured without SSc serum (0,33 vs 0,1).Conclusion:we found higher percentage of Early α-SMA positive EPCs and a higher expression of α-SMA protein in cultured EPCs in patients group (SSc and VEDOSS) than in HC. So we hypothesized a predominant pro-mesenchymal phenotype of this kind of EPCs. This could be considered the expression of the involvement of EPCs in the EndoMT process and it better explain the controversial role of EPCs in SSc pathogenesis. Moreover the modified expression of α-SMA in HC EPCs co-cultured with 20% SSc serum could suggest the presence of a factor inducing the EndoMT process in the disease.References:[1]Corallo C et al Arthritis Res Ther 2016;[2]Manetti M et al AnnRheumDis 2017;[3]Del Papa N et al Front. Immunol 2018;[4]Van den Hoogen F et al AnnRheumDis 2013.[5]Avouac J et al Ann Rheum Dis 2011;Disclosure of Interests:Katia Stefanantoni Consultant of: ItalfarmacoBoehringer Ingelheim, cristiana barbati: None declared, Tania Colasanti: None declared, Carlotta Angelelli: None declared, Greta Pellegrino: None declared, cristiano alessandri Grant/research support from: Pfizer, Guido Valesini: None declared, Valeria Riccieri: None declared