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Systemic sclerosis (SSc) is an autoimmune disease characterised by microvasculopathy, immune dysregulation, and skin and visceral organ fibrosis. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published in the scientific community.In this review we report an overview of some of the most relevant contributions published in 2021.

Resume La sclerodermie systemique (ScS) est une maladie du tissu conjonctif caracterisee par une microangiopathie diffuse et un dereglement immunitaire qui aboutissent, a terme, a une fibrose generalisee touchant la peau et les organes internes. Si les criteres de 2013 de l’EULAR/ACR ont effectivement ameliore la sensibilite pour le diagnostic de la ScS, il s’avere que la sous-classification traditionnelle en formes cutanees limitee et diffuse ne suffit pas a couvrir l’ensemble des phenotypes du spectre de la sclerodermie. A cet egard, une vaste etude recente fondee sur des analyses typologiques et d’autres projets en cours tentent d’affiner la stratification des patients atteints de ScS car l’evolution de cette maladie est a ce jour encore tres difficile a prevoir. Des etudes precliniques et des essais comparatifs randomises recents ont obtenu des resultats encourageants avec de nouveaux medicaments ciblant les voies de signalisation inflammatoires/immunologiques et fibrotiques. L’un des principaux besoins non satisfaits dans la ScS est l’identification precoce des patients a haut risque de mortalite, pour lesquels il convient de definir et de nuancer l’agressivite des traitements en fonction du pronostic. Par ailleurs, l’option de transplantation pulmonaire et cardiaque peut egalement etre envisagee pour certains patients soigneusement selectionnes. Bien que le pronostic de la ScS reste mediocre, une meilleure stratification des patients, associee aux avancees therapeutiques recentes et en cours, pourrait influencer considerablement l’evolution de la maladie dans un avenir proche. Enfin, la necessite de developper des therapies combinees devrait s’intensifier prochainement dans le but de combattre plus efficacement cette maladie complexe. Dans cette revue, nous presentons de nouvelles informations relatives aux atteintes d’organes et aux options therapeutiques.

Objectives Pregnancy in SSc is burdened with an increased risk of obstetric complications. Little is known about the underlying placental alterations. This study aimed to better understand pathological changes and the role of inflammation in SSc placentas. Leucocyte infiltration, inflammatory mediators and atypical chemokine receptor 2 (ACKR2) expression in SSc placentas were compared with those in other rheumatic diseases (ORD) and healthy controls (HC). Methods A case–control study was conducted on eight pregnant SSc patients compared with 16 patients with ORD and 16 HC matched for gestational age. Clinical data were collected. Placentas were obtained for histopathological analysis and immunohistochemistry (CD3, CD20, CD11c, CD68, ACKR2). Samples from four SSc, eight ORD and eight HC were analysed by qPCR for ACKR2 expression and by multiplex assay for cytokines, chemokines and growth factors involved in angiogenesis and inflammation. Results The number of placental CD3, CD68 and CD11 cells was significantly higher in patients affected by rheumatic diseases (SSc+ORD) compared with HC. Hepatocyte growth factor was significantly increased in the group of rheumatic diseases patients (SSc+ORD) compared with HC, while chemokine (C-C motif) ligand 5 (CCL5) was significantly higher in SSc patients compared with ORD and HC. CCL5 levels directly correlated with the number of all local inflammatory cells and higher levels were associated with histological villitis. Conclusions Inflammatory alterations characterize placentas from rheumatic disease patients and could predispose to obstetric complications in these subjects.

To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc).Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests.Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p0.03 and p0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p0.05) and on morning stiffness at 6 and 12 months (p0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p0.05). No changes in lung or gastrointestinal involvement were found.ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Background: Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking. Aims: To describe the systemic sclerosis–primary biliary cholangitis phenotype, including baseline characteristics and outcomes. Methods: We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis–specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit. Results: A total of 261 patients were enrolled (115 primary biliary cholangitis–systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis–primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies ( p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis–systemic sclerosis patients ( p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension ( p Conclusion: Our data show that systemic sclerosis–primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.

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.

© Copyright Clinical and Experimental Rheumatology 2022., Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

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.

Although antisynthetase antibodies (ARS) are the established markers of the so-called antisynthetase syndrome (ASSD), in these patients the concomitant positivity of anti-Ro52 antibodies, reported in up to the 50% of cases, is not rare. Several studies focused on the effect of different ARS specificities on the evolution of ASSD, the most recent showing no effects. On the contrary, the role of co-occurring anti-Ro52 antibodies in ASSD is still debated. We investigated the potential of anti-Ro52 antibodies in identifying a clinical phenotype of ASSD or influencing prognosis, irrespectively to the underlying ARS specificity.Retrospective analysis of clinical, imaging and laboratory characteristics, therapeutic approaches and outcome at baseline and at last follow-up, of 60 ASSD patients progressively enrolled at our Hospital.We identified 34 anti-Ro+ and 26 anti-Ro- ASSD patients. Classic triad prevalence at baseline was similar between the two groups, whereas interstitial lung disease (ILD) (p value=0.01) and myositis (p value=0.03) were significantly more prevalent in anti-Ro52+ and in anti-Ro52- patients at last follow up, respectively. No differences in therapeutic approaches, oxygen need and ILD patterns were observed. Overall mortality was 25% (15 subjects). No differences in mortality, overall and disease related, between anti-Ro52+ and anti-Ro52- patients were observed (p value=0.764), despite the more frequent ILD occurrence in anti-Ro52+ patients. Survival curves were not different at any time point (Log-rank test, p value 0.98).Anti-Ro52 antibodies affect time course and clinical characteristics of ASSD. Although ILD is significantly more associated to anti-Ro52 antibodies, no difference in mortality was observed compared to anti-Ro52 negative patients.

ObjectivesTocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.MethodsPatients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.ResultsNinety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.ConclusionAlthough this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by the positivity of autoantibodies against different aminoacyl transfer RNA (tRNA) synthetases. Morbidity and mortality of this disease are highly affected by interstitial lung disease (ILD) which is present in about 80% of patients. In this study, we investigated possible differences in 84 immune-related circulating miRNAs between ASSD patients with and without ILD; we enrolled 15 ASSD patients, 11 with ILD (ILD+) and 4 without ILD (ILD-), and 5 patients with idiopathic pulmonary fibrosis (IPF) as an additional control group. All patients were at disease onset and not on therapy at the time of inclusion. Differentially expressed miRNAs were identified in plasma-derived exosomes, using an miRNA PCR array (MIHS-111ZG, Qiagen, Hilden, Germany); miR-30a-5p and miR-29c-3p were upregulated in ASSD-ILD patients compared to patients without lung involvement (adjusted p-value < 0.05). IPF patients showed higher miR-29c-3p expression levels with respect to both ASSD and ASSD-ILD (p = 0.0005), whereas levels of miR-30a-5p were not different. miR-29c-3p and miR-30a-5p are overexpressed in ASSD-ILD+ patients compared with ILD?. These miRNAs are involved in the regulation of inflammation and fibrosis through their action on NF-?B and TGF-?1. Although the mechanistic role of these miRNAs in ASSD-ILD development has to be elucidated, we suggest that their exosome levels could be useful in identifying patients at risk of ILD. Funding: This research was supported by the Ministry of Health IRCCS Foundation Policlinico San Matteo Grant [grant number 948-rcr2019i2-46].

International audience; Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.

despite the absence of specific guidelines, the treatment with intravenous immunoglobulins (IvIg) is considered effective in patients with refractory idiopathic inflammatory myopathies (IIM). The aim of our study is to evaluate the effectiveness and the safety of IvIg and define the possible profile of IIM patients candidate to IvIg treatment.we performed a retrospective study of IIM pts. treated with IvIg (2 g/kg/month). We collected demographic, epidemiological, laboratory and clinical data. Additionally, to evaluate the toxicity, the adverse events occurred during the treatment were collected.123 patients with IIM were included in the study. The main indications for the prescription of IvIg were muscle (83.7% of patients) and esophageal involvement (45.5% of patients). IvIg were started mainly for refractory disease. At the end of treatment (mean duration 14 months), muscular necrosis enzymes decreased significantly and dysphagia VAS decreased significantly (p 0.001), while MMT value increased (104.6 ± 24.2 vs. 127.0 ± 22.2 p 0.001). Ninety-six pts. (78%) responded to IvIg. They had a shorter disease duration (p 0.001), higher creatine kinase levels (p 0.001), and higher prevalence of myalgias at the baseline (p = 0.023) compared to non-responders. The presence of Raynaud's phenomenon (p = 0.023-odds ratio 0.28 [0.11-0.72]) and skin involvement (p = 0.004, odds ratio 0.18 [0.06-0.55]), were associated to a worse response. Adverse events were mostly mild and transitory.Despite their high cost, IvIg confirmed their effectiveness in refractory IIM pts., particularly in muscular and esophageal manifestations. Specific clinical characteristics at the baseline may identify the patients with higher probability of response to the treatment.

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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To date, scleroderma renal crisis (SRC) remains a life-threatening complication in patients affected by systemic sclerosis (SSc), with high morbidity and mortality. In the last few years, some studies have tried to more precisely identify predictors of SRC and clarify the role of previous drug exposure-in particular, angiotensin-converting enzyme (ACE) inhibitors and corticosteroids-in patients with SSc presenting other well-known risk factors for SRC. Different from the findings of previous reports, more recent findings suggest that the presence of chronic kidney disease, systemic arterial hypertension, and proteinuria might all be predictors of SRC. Moreover, because about 40 to 50% of SRC cases can present signs of microangiopathy, a recent study has proposed SSc thrombotic microangiopathy (SSc-TMA) as a clinically and pathophysiologically different entity from narrowly defined SRC. Even though such clear distinction may not always be applicable/feasible in clinical practice, it highlights that complement pathway dysregulation may play a key pathogenetic role in SRC presenting as TMA. Thus, plasma exchange may be considered in severe refractory cases. Nevertheless, ACE inhibitors and prompt achievement of blood pressure control (to rapidly improve ongoing renal ischemia) remain to date the cornerstone of SRC treatment. Here, we report the cases of three SSc patients with SRC followed at our rheumatology units. While describing these patients' risk factors, clinical presentation, and therapy, we aim to discuss the state of the art in SRC and highlight critical issues.

We thank Dr Santos-Moreno et al 1 for their interest in our paper2 and for sharing their experience on telemedicine use in patients with rheumatoid arthritis (RA). We agree on the fact that a preliminary consultation is necessary to assess the willingness of the patients to be evaluated by telemedicine and, possibly, to explain them how the platform works. However, given the different setting in which we applied telemedicine—a connective tissue diseases (CTDs) outpatient clinic—our approach was slightly different. In fact, unlike inflammatory arthritis, in which disease flares are in most cases symptomatic and impacting on patients’ quality of life and functionality, CTDs like systemic lupus erythematosus (SLE) or systemic sclerosis may give rise to more insidious manifestations. In our …

Systemic sclerosis (SSc) is a connective tissue disease characterised by diffuse microangiopathy and immune dysregulation which ultimately results in widespread fibrosis of the skin and internal organs. This complex autoimmune disease is characterised by heterogeneous clinical manifestations and variable disease course in which the severity of pathology dictates the disease prognosis and course. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published last year, with the aim of helping the clinician in the understanding and management of SSc patients.

We thank Lopez-Medina et al 1 for their comment on our paper and for sharing their experience with phone consultations.2 Telemedicine, in the past years, has been progressively implemented into medical practice. However, it has not been able to fully take root into routine medical care yet. The COVID-19 pandemic provided the opportunity to take a further step towards the integration between virtual and traditional medical assistance in many medical specialties including rheumatology. The restriction rules, taken over by numerous countries, together with the necessity of assuring a proper continuity of care, have forced us to adopt telemedicine tools in our routine involving chronic patients. To overcome legal matters of privacy and data protection, we have recently set up a …

ObjectiveTo identify the factors potentially associated with serum gamma-glutamyltransferase (GGT) elevation in patients with rheumatoid arthritis (RA).MethodsThis is a cross-sectional monocentric study including RA patients over a 12-month period. Data on liver function, RA disease activity, and hepatotoxic and cardiovascular (CV) risk factors were systematically collected. To provide a simple tool to evaluate both joint disease activity and CV risk factors, we constructed the Disease Activity Score in 28 joints (DAS28)-GGT composite index by replacing erythrocyte sedimentation rate (ESR) with GGT.ResultsAmong the 129 included patients, 32 (25%) had isolated GGT increase. GGT correlated with age, C-reactive protein (CRP) levels, and body weight and were significantly increased in patients with alcohol intake, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome. GGT levels also gradually increased with the number of CV risk factors and correlated with the Framingham CV risk score. The composite index DAS28-GGT remained a reliable marker of RA disease activity and accurately detected patients with CV risk factors. Conversely to the DAS28 and the DAS28-CRP, the DAS28-GGT steadily increased according to the number of CV risk factors and had an increased diagnostic value compared to the DAS28 and DAS28-CRP for the presence of at least 2 CV risk factors and a Framingham CV risk score greater than 10%.ConclusionGGT may be considered as a marker of systemic inflammation and CV risk in patients with RA. Based on these findings, we herein propose an original index, the DAS28-GGT, which is able to evaluate both joint disease activity and CV risk. This index will deserve further validation in prospective cohorts.

The COVID-19 pandemic deeply affected northern-Italian regions.1 Lombardy and Emilia-Romagna had the highest cumulative incidence with 627.1 and 470.53 cases/100 000 inhabitants respectively on 16 April 2020 according to Italian ‘Istituto Superiore di Sanita’ (ISS). While a mild course has been reported in patients with chronic arthritis treated with targeted immunosuppressive agents,2 few and controversial data are available about COVID-19 in systemic lupus erythematosus (SLE).3 4 To this purpose, since 6 April 2020, given the mobility restriction imposed nationwide, we initiated a telemedicine project aimed at ensuring regular follow-up, starting from SLE patients.5 During the visit, we conducted a survey to investigate any COVID-19 related symptoms that occurred since 15 February 2020 and the results of available nasopharyngeal swabs. The survey was addressed to patients coming from Lombardy and Emilia-Romagna. We evaluated 165 patients (112 females, 84%, median age 52.5 years, range 25–81; median disease duration 13 years, range 1–53). Among them, 127 (77%) were on hydroxychloroquine …

Background:Tocilizumab (TCZ) showed trends for improving skin fibrosis and prevented progression of lung fibrosis in patients with systemic sclerosis (SSc) in placebo-controlled randomised clinical trials (RCTs). However, safety and effectiveness of TCZ beyond these selected and enriched clinical trial populations in SSc is still unknown.Objectives:To assess safety and effectiveness of TCZ treatment compared to standard of care in SSc patients from the large, multicentre, observational, real-life EUSTAR network/database using propensity score matching.Methods:SSc patients from the EUSTAR network/database, who fulfilled the ACR/EULAR 2013 classification criteria, with a baseline and a follow-up visit at 12±3 months, receiving TCZ or standard of care (controls), were selected. The following variables were used for the propensity score matching (1:1): age at diagnosis, gender, disease subtype, baseline modified Rodnan skin score (mRSS), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), co-therapy with immunosuppressives, disease duration, and year of treatment. Primary endpoints were mRSS and FVC at 12±3 months follow-up compared between the groups, using paired t-tests. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months follow-up according to standard definitions (1,2). Sensitivity analyses assessed pre-processing decisions (selection of most recent vs. random observation for control patients with multiple suitable time intervals), as well as the matching method (optimal vs. exact matching). Missing values were addressed with 100-fold multiple imputation using chained equations. Safety data were analysed in all patients. The study including the statistical analysis plan was pre-registered at www.drks.de (DRKS-ID: DRKS00015537).Results:We identified 93 SSc patients treated with TCZ and 2370 SSc patients with standard of care who fulfilled the inclusion criteria. Forty nine (57.7%) of the TCZ treated patients were diffuse, eight patients were not classified, disease duration was (mean±SD) 6.35±5.40 years, their baseline mRSS was 15.05±10.85, and 76 (81.7%) received immunosuppressive therapy in addition to TCZ.Through multiple imputation and propensity score matching, 100 imputed sets of 93 pairs of TCZ/controls were generated. Comparison between groups showed consistent effects of TCZ across all pre-defined primary and secondary endpoints: mRSS was lower in the TCZ group (mean difference (95% confidence interval (CI)) -1.8 (-4.79 to 1.19), p=0.24, Figure 1A). Similarly, FVC % predicted was higher in the TCZ group mean difference (2.25, 95% CI -4.57 to 9.06), p=0.51, Figure 1B). Considering secondary endpoints, the percentage of skin progressors as well as lung progressors at follow up was lower in the TCZ group (odds ratio OR 0.67 (95% CI 0.07 to 6.41), p=0.74 and OR 0.53 (95% CI 0.16 to 1.7); p=0.2, respectively. Consistently, the percentage of regressors for skin (OR 1.6 (95% CI 0.56 to 4.54), p=0.38) and for lung (OR 1.74 (95% CI 0.66 to 4.58), p=0.26) was higher in TCZ. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion:In this large, observational, controlled, real-life EUSTAR study, effectiveness of TCZ did not reach statistical significance compared to standard of care treatment but showed consistent positive effects of TCZ on skin and lung fibrosis across all pre-defined primary and secondary endpoints confirming data from recent RCTs.References:[1]Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis 2016:1743-8.[2]Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021:219-227.Disclosure of Interests:Simon Kuster: None declared, Suzana Jordan: None declared, Muriel Daniele Elhai: None declared, Ulrike Held: None declared, Klaus Steigmiller: None declared, Cosimo Bruni: None declared, Florenzo Iannone: None declared, Serena Vettori: None declared, Elise Siegert: None declared, Simona Rednic: None declared, Veronica Codullo: None declared, Paolo Airò Consultant of: Dr. Airo’ reports personal fees (consultancies) from Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Yolanda Braun-Moscovici: None declared, Nicolas Hunzelmann: None declared, Maria Joao Salvador: None declared, Valeria Riccieri: None declared, Ana Maria Gheorghiu: None declared, Juan Jose Alegre Sancho: None declared, Katarzyna Romanowska-Prochnicka: None declared, Ivan Castellví: None declared, Ina Koetter: None declared, Marie-Elise Truchetet Consultant of: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Grant/research support from: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Francisco J López-Longo: None declared, Pavel Novikov: None declared, Alessandro Giollo: None declared, Yuichiro Shirai: None declared, Laura Belloli: None declared, Elisabetta Zanatta: None declared, Eric Hachulla: None declared, Vanessa Smith: None declared, Christopher Denton: None declared, Ruxandra Ionescu: None declared, Tim Schmeiser: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold Consultant of: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape. Masataka Kuwana: None declared, Yannick Allanore: None declared, Oliver Distler Speakers bureau: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: The study was partially supported by a grant from Roche. Roche was not involved in analysis or interpretation of the results.

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

Treat to target (T2T), aiming at inactive disease (ID), has become the recommended strategy for axial-SpA (ax-SpA). Using the Ankylosing Spondylitis Disease Activity Score (ASDAS), we assessed the prevalence of ID in ax-SpA patients treated with TNFα inhibitors (TNFi).A multicentric, cross-sectional study was performed assessing disease activity status (BASDAI and ASDAS) of consecutive patients with ax-SpA on stable treatment with TNFi for at least six months. We analyzed differences with nonradiographic axSpA (nr-ax-SpA) and the influence of population characteristics and comorbidities in reaching ID. ID was defined as ASDAS-CRP1.3.A total of 218 patients were enrolled, 165 with AS and 53 with nr-ax-SpA. ASDAS-CRP ID was reached by 89 (40.8%) patients, while 163 (74.8%) of patients achieved good disease control with BASDAI. There were no significant differences between the two diagnostic groups. Multivariate logistic regression demonstrated a negative correlation of concomitant fibromyalgia, higher BASMI and current NSAIDs with the chances of reaching ASDAS-CRP ID or BASDAI4.T2T represents a new challenge in the management of ax-SpA, with recently introduced disease activity measures being significantly more stringent. The prevalence of ID was affected by concomitant fibromyalgia, decreased spine mobility and concomitant NSAIDs.

Objective Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. Methods Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. Results 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9–51) and 40 (24%) developed new accompanying features after 19months median (IQR 6–56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68–9.21, p=0.002). Conclusion Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.

Interstitial lung disease (ILD) encompasses a wide range of parenchymal lung pathologies with different clinical, histological, radiological, and serological features. Follow-up, treatment, and prognosis are strongly influenced by the underlying pathogenesis. Considering that an ILD may complicate the course of any connective tissue disease (CTD) and that CTD's signs are not always easily identifiable, it could be useful to screen every ILD patient for a possible CTD. The recent definition of interstitial pneumonia with autoimmune features is a further confirmation of the close relationship between CTD and ILD. In this context, the multidisciplinary approach is assuming a growing and accepted role in the correct diagnosis and follow-up, to as early as possible define the best therapeutic strategy. However, despite clinical advantages, until now, the pathways of the multidisciplinary approach in ILD patients are largely heterogeneous across different centers and the best strategy to apply is still to be established and validated. Aims of this article are to describe the organization of our multidisciplinary group for ILD, which is mainly focused on the early identification and management of CTD in patients with ILD and to show our results in a 1 year period of observation. We found that 15% of patients referred for ILD had an underlying CTD, 33% had interstitial pneumonia with autoimmune feature, and 52% had ILD without detectable CTD. Furthermore, we demonstrated that the adoption of a standardized strategy consisting of a screening questionnaire, specific laboratory tests, and nailfold videocapillaroscopy in all incident ILD proved useful in making the right diagnosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse microangiopathy and immune dysregulation which ultimately result in widespread fibrosis of skin and internal organs. Although the 2013 EULAR/ACR criteria have allowed to improve the sensitivity for SSc diagnosis, it has recently come to light that the traditional subclassification into limited and diffuse cutaneous forms does not appear to fully capture the different phenotypes of the scleroderma spectrum. In this regard, a recent large cluster analysis-based study and other ongoing projects are trying to achieve a better stratification of SSc patients, as the disease course remains largely unpredictable to date. Recent preclinical studies and randomized controlled trials have yielded encouraging results with new drugs targeting inflammatory/immunological and fibrotic pathways. One of the main unmet needs in SSc remains the early identification of patients at high mortality risk, for whom aggressiveness of therapies ought to be determined and weighed against disease prognosis. Furthermore, lung and cardiac transplantation may also be taken into account in some carefully selected patients. Though the prognosis of SSc remains poor, an optimized stratification of patients along with the recent and ongoing advances in therapies could greatly impact the natural course of the disease in the near future. Moreover, it is envisioned that there will be an increasing need in the future to further develop combination therapies to better fight against this complex disease. In this review we discussed new insights into organ involvements and therapeutic options.

The diagnostic assessment of patients with Interstitial Lung Disease (ILD) can be challenging due to the large number of possible causes. Moreover, the diagnostic approach can be limited by the severity of the disease, which may not allow invasive exams. To overcome this issue, the referral centers for ILD organized Multidisciplinary Teams (MDTs), including physicians and experts in complementary discipline, to discuss the management of doubtful cases of ILD. MDT is currently considered the gold standard for ILD diagnosis, but it is not often simple to organize and, furthermore, rheumatologists are still not always included. In fact, even if rheumatologic conditions represent a common cause of ILD, they are sometimes difficult to recognize, considering the variegated clinical features and their association with all possible radiographic patterns of ILD. The first objective of this review is to describe the clinical, laboratory, and instrumental tests that can drive a diagnosis toward a possible rheumatic disease. The secondary objective is to propose a set of first-line tests to perform in all patients in order to recognize any possible rheumatic conditions underlying ILD.

Autoimmune rheumatic diseases as a group are characterized by common features such as multisystem involvement, polypharmacy, and the presence of comorbidities. Recent large epidemiological studies shed light on their role as risk factors for thromboembolic complications. The pathogenic factors are now better understood. The proposed mechanisms for this increased risk include increased hypercoagulability, lack of inhibitors, and other factors. The group of vasculitis which includes Behcet’s disease, giant cell vasculitis, Takayasu’s arteritis, and ANCA-associated vasculitis deserves special attention. However other diseases such as systemic lupus erythematosus, Sjogren syndrome, scleroderma, rheumatoid and psoriatic arthritis, myositis, and sarcoidosis are also associated with significantly increased risk of thrombosis.

Background Patients with systemic sclerosis (SSc) are at risk of developing pulmonary arterial hypertension (PAH), which is often diagnosed late when the benefits of vasoactive therapies are limited. The concept of exercise pulmonary hypertension as a possible transitional phase anticipating resting PAH has been assessed in several pathologies, but has not been endorsed by the latest European Guidelines, because not supported by sufficient data. Purpose To evaluate whether PASP values at rest and at peak exercise, estimated at echocardiography, could be predictors of further development of PAH. Methods Four hundred and twenty-nine SSc patients without a previous diagnosis of PAH, enrolled at 4 referral Centres, underwent standard exercise Doppler echocardiography with PASP estimation at rest and at peak stress. Patients were then followed-up to assess the development of PAH, as diagnosed by a complete diagnostic work-up including right heart catheterization. PAH was defined by pre-capillary pulmonary hypertension (mean pulmonary artery pressure ≥25 mmHg with pulmonary arterial wedge pressure ≤15 mmHg), without significant interstitial lung disease and/or left heart disease. Results During the median follow-up of 75 months (IQR 29–114), 16 patients developed PAH. A combined cut-off of ≥24 mmHg as resting PASP and ≥40 as peak PASP was identified as the best predictor of further development of PAH (see Figure). Both resting PASP and peak PASP were predictors of PAH at univariate analysis (resting PASP OR 1.13, 95% C.I. 1.07–1.19, p Kaplan-Meier curves Conclusions Exercise increase in PASP is an independent predictor of later development of PAH in SSc. An increase in exercise PASP is frequent and is not necessarily associated with a later development of PAH, whereas the very high negative predictive value of a normal PASP both at rest and at peak exercise can be used in the clinical practice to confidently rule out about one third of patients. Acknowledgement/Funding Italian Ministry of Health (Ricerca Finalizzata 2011-2012)

Background: Clinical evolution and optimal management of IPAF are still undefined and need prospective assessment. Objectives: to define the characteristics and evolution of IPAF patients in a multidisciplinary setting. Methods: IPAF pts referring to multidisciplinary Rheumatology/Pneumology outpatient clinic. We excluded patients with diagnosis of Anti-synthetase Sd. Data were retrospectively collected. Results: we analyzed the first 25 pts (19 F, 76%, 6 M, 24%), with a median onset age of 67 years (IQR, 59-74) and follow-up of 32 months (IQR 22-69). ANA test was positive in 23 (92%) cases (cytoplasmic+ in 17:68%). Anti-ENA screen was + in 9: 36% pts. One pt was + for anti-PM-Scl, one for for anti-Mi2 and one for anti-Ku Ab. Pts had mainly a NSIP pattern (19, 76%, cases; with concomitant OP, in 3). Three patients had UIP-like and 3 OP pattern. The majority of patients (15, 60%) satysfied only the morphological and serological domains. Clinical domains satisfied were: arthritis (4) Raynaud’s ph. (5) palmar teleangectasias (2) mechanic’s hands (1) and Hikers feet (1). Clinical spectrum time course was variable in 5 pts: 3 pts developed arthritis after ILD, and 2 developed ILD respectively after arthritis and inflammatory miopathy. Three pts were admitted in ICU for Rapidly Progressive (RP) ILD and 2 died. All pts received low dose steroids in combination mainly with Azathioprine, Mycophenolate, Cyclosporin, Hydroxychloroquine. 92% of patients were alive at FU. Conclusions: A multidisciplinary approach is useful in the diagnosis and the management of IPAF. RP-ILD was common, prognosis of IPAF was highly variable.