BACKGROUND:Systemic sclerosis (SSc) primary heart involvement (SSc-pHI) is one of the leading causes of mortality in SSc. We aimed to evaluate risk factors for SSc-pHI and its progression and the outcomes in the EUSTAR (European Scleroderma Trials and Research) cohort. METHODS:SSc-pHI was defined according to the World Scleroderma Foundation/Heart Failure Association definition. Data from 5741 patients with SSc in the EUSTAR cohort were analyzed. Additional cardiovascular data were collected from a subcohort of 838 patients with SSc. Lasso regression was used for risk factor analyses. Kaplan-Meier estimator was used for survival analyses. Progression of SSc-pHI was evaluated by a study definition developed by rheumatology and cardiology experts. RESULTS:Risk factors for the presence of SSc-pHI comprised skeletal muscle atrophy (odds ratio [OR], 2.00 [95% CI, 1.00-2.68]), age (OR, 1.91 [95% CI, 1.73-2.03]), male sex (OR, 1.77 [95% CI, 1.42-2.05]), swollen joints (OR, 1.70 [95% CI, 1.47-1.98]), skeletal muscle weakness (OR, 1.38 [95% CI, 1.00-1.85]), and tendon friction rubs (OR, 1.46 [95% CI, 1.00-1.77]) (n=3276). Telangiectasia (OR, 2.10 [95% CI, 1.38-2.72]), intestinal symptoms (OR, 1.70 [95% CI, 1.04-2.42]), age (OR, 1.47 [95% CI, 1.21-1.62]), and antitopoisomerase I antibodies (OR, 1.37 [95% CI, 1.00-1.77]) were associated with an increased risk for new onset of SSc-pHI (n=1000). Survival rate was significantly lower in patients with SSc-pHI than in those without (P value <0.0001, n=3768). Patients with SSc-pHI had a lower survival rate than patients with interstitial lung disease (n=3365). Swollen joints were associated with an increased risk of progressive SSc-pHI (OR, 2.49 [95% CI, 1.79-3.52]) (n=595). Tendon friction rubs (OR, 1.21 [95% CI, 0.94-1.90]) increased the risk of heart failure with preserved ejection fraction in patients with SSc-pHI. CONCLUSIONS:We defined progressive SSc-pHI and identified risk factors for new onset and progression of SSc-pHI and for SSc-pHI-associated heart failure with preserved ejection fraction in the largest cohort with SSc. These findings may guide patient stratification for diagnostic workup and therapy.

Background: Patients with rheumatic diseases (RMDs) are at increased risk of herpes zoster (HZ), particularly when receiving immunosuppressive treatment. While recombinant zoster vaccine (RZV) has shown high effectiveness in the general population, evidence in rheumatologic patients remain limited due to their exclusion from pivotal trials. Objectives: To evaluate the effectiveness of RZV and to collect additional safety data in a heterogeneous cohort of rheumatologic patients, compared with a control cohort from the general population. Methods: We conducted a retrospective study including 179 adults who received two intramuscular doses of RZV between January 2021 and June 2025. The cohort included 114 patients with RMDs and 65 individuals from the general population. Effectiveness was defined as the ability to prevent HZ reactivation while safety concerns were recorded as any adverse event temporally associated with the vaccination. Results: We observed a statistically significant reduction in terms of VZV relapses following vaccination (p < 0.001). Among patients diagnosed with RMDs, only one case of HZ recurrence was observed 14 weeks after vaccination, with no significant difference compared to general care patients. One patient experienced a disease flare requiring glucocorticosteroids. RZV demonstrated a favourable safety profile, with minor adverse events (fever, injection-site reactions, headache and myalgia) reported in 17.5% of patients after the first dose and 21.5% after the second. No significant association was observed between adverse events and advanced immunosuppressive therapy. Conclusions: RZV displayed an effective and reassuring safety profile in a heterogeneous cohort of patients affected by RMDs, irrespective of the diagnosis and the ongoing therapy. This supports the broader use of RZV as a safe and valuable preventive strategy in patients with RMDs.

Background: Systemic sclerosis (SSc) a systemic fibrosing autoimmune-rheumatic disease [1]. Among all systemic rheumatic diseases, SSc is associated with the highest case-related mortality and heart involvement is one of the leading causes of death in SSc patients [2]. The prevalence of clinically manifest SSc-pHI ranges from 7% to 39% [3]. Autopsy studies, however, have demonstrated myocardial fibrosis, myocardial inflammation, or contraction band necrosis in up to 80% of SSc patients [4]. When SSc-pHI is clinically manifest, it is associated with a five-year mortality of 75%. Nevertheless, SSc-pHI is poorly understood and a consensus definition was only recently reached [5]. Objectives: Here we aimed to evaluate the risk factors for the development and progression of SSc-pHI and the outcomes of patients with SSc-pHI in the worldwide largest SSc cohort. Methods: SSc-pHI was defined according to the 2022 consensus-based WSF/HFA definition of SSc-pHI [5]. Data from 5741 SSc patients of the EUSTAR cohort were analyzed. In addition, supplementary data were collected from a sub-cohort of 496 SSc patients with in-depth cardiac phenotyping. Lasso regression was used for risk factor analyses. Kaplan-Meier estimator was used for survival analyses. Progression of SSc-pHI was evaluated by a study-definition developed by rheumatology and cardiology experts. Results: We identified muscle atrophy (OR 2.00), age (OR 1.91), male sex (OR 1.77), swollen joints (OR 1.70), muscle weakness (OR 1.38), and tendon friction rubs (OR 1.36) as risk factors for the presence of SSc-pHI (n = 3276 SSc patients). Telangiectasia (OR 2.10), intestinal symptoms (OR 1.70), age (OR 1.47), and Scl-70 antibodies (OR 1.37) were associated with an increased risk for the development of SSc-pHI (n = 1000 SSc patients). The overall survival rate of patients with SSc-pHI was significantly lower than of patients without SSc-pHI (p-value < 0.0001, n = 3768 SSc patients). Swollen joints were associated with an increased risk of progressive SSc-pHI (OR 2.49) (n = 595 SSc patients) independent of CRP levels or rheumatoid factor positivity. Conclusion: Here we proposed a multi-disciplinary definition of progressive SSc-pHI, identified risk factors for the development and progression of SSc-pHI in the worldwide largest SSc cohort so far. These findings may guide patient stratification for diagnostic work-up and therapeutic decision making. REFERENCES: [1] Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002.[2] Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76(11):1897-905.[3] Bissell LA, Md Yusof MY, Buch MH. Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group. Rheumatology (Oxford). 2017;56(6):882-95.[4] D’Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. 1969;46(3):428-40.[5] Bruni C, Buch MH, Furst DE, De Luca G, Djokovic A, Dumitru RB, et al. Primary systemic sclerosis heart involvement: A systematic literature review and preliminary data-driven, consensus-based WSF/HFA definition. J Scleroderma Relat Disord. 2022;7(1):24-32. Acknowledgements: NIL. Disclosure of Interests: None declared.

Novel progressive fibrotic phenotype has recently been proposed characterized by progressive and inexorable worsening of the disease. Krebs von den Lungen-6 (KL-6) has been proposed as fibrotic-ILD biomarker. We aimed to assess the role of KL-6 in fibrotic-ILD and the progressive phenotype in accordance with serial serum KL-6. Methods: 107 patients were enrolled in the study (median age,IQR, 65(54-71)y/o) followed at respiratory diseases and rheumatology units of University of Siena. Thirty-five had diagnoses of IPF, 18 sarcoidosis, 10 PLCH, 5 LAM, 24 fibrotic HP(fHP), 13 RA (4/13 RA-ILD) and 22 SSc (18/22 SSc-ILD). Serial serum samples were collected before therapy (t0) and 24 months later (t1) from IPF, SSc- and RA-ILD patients. Twenty-two healthy controls (HC) were enrolled. Serum samples were assayed for KL-6 concentrations (Fujirebio Europe, Gent, Belgium). Results: Higher KL-6 concentrations were reported in IPF, fHP and SSc-ILD patients than HC (p<0.0001). KL-6 cut-off value of 885 U/mL identified fibrotic-ILD patients. Logistic regression analysis indicated KL-6 (p=0.004) and smoking-habit (p=0.005) affected the ILD diagnosis. The decision tree model showed KL-6>1145 U/mL, DLco <= 60.15 %, FVC <= 86 % to classify 86 % IPF patients. Inverse correlation between T0-KL-6 and T1-FVC%(r=-0.314, p=0.046) and T1-DLco%(r=-0.327, p=0.038) in the progressive group. Conclusion: KL-6 proved to be a reliable marker for diagnosis and prognosis of fibrotic ILD patients with predictive value in progressive fibrotic patients and a useful marker to identify the new and similar progressive phenotype of IPF and SSc-ILD patients assessing the functional progression in accordance with serial serum KL-6 measurements.

Objectives: Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries. Methods: Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison. Results: Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042). Conclusions: UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients.

Introduction Based on ACR/EULAR classification criteria, minor salivary glands biopsy (MSGB) is a useful diagnostic tool for the diagnosis of primary Sjögren’s syndrome (SS). The main objective of our study was to evaluate the diagnostic role of MSGB, as well as to highlight correlations between histological findings and autoimmune profiles. Material and methods We retrospectively evaluated histological and autoimmunity data from patients who underwent MSGB in our department in cases of suspected SS, from March 2011 to December 2018. Salivary gland samples were evaluated using Chisholm and Mason (CM) grading and the focus score (FS). Results A total of 1,264 patients (108 males, 1,156 females) were included. The median age was 55.22 ±13.51 years (range: 15–87). In univariate binary logistic regression, CM ≥ 3 and FS ≥ 1 were significantly predicted by antinuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-Ro/SSA titer as well as anti-La/SSB, anti-Ro/SSA, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) positivity. In multivariate analysis, CM ≥ 3 and MSGB positivity were significantly associated with ANA titer; FS ≥ 1 was not associated with laboratory findings. A positive biopsy was associated with laboratory findings, as ANA and ENA titers, anti-Ro/SSA, anti-La/SSB, RF and ACPA positivity may discriminate patients with SS-related histological findings. Conclusions Minor salivary glands biopsy is a useful tool to diagnose SS in cases of highly suggestive clinical symptoms but in the absence of a specific autoimmunity.

We herein report the case of a 40-years-old female patient with unremarkable medical history who presented to the emergency department complaining of recent onset of fever and symmetrical ankle arthritis. On the suspicion of reactive arthritis, treatment with antibiotics and prednisone was promptly started. Ten days later, the patient experienced a relapse of the symptoms associated with an increase of acute phase reactants. Physical examination showed bilateral knee and ankles swelling, together with localized small papular and painful lesions on her left shoulder in correspondence of an old black small tattoo. A complete ophthalmological examination did not show signs of ocular involvement. In the suspicion of a tattoo-promoted sarcoid reaction, a punch biopsy of the skin was performed, confirming the diagnosis of systemic sarcoidosis with cutaneous and articular involvement (Figure 1A-1B). Serum level of angiotensin-converting enzyme and lysozyme were normal, and a chest X-ray showed no abnormalities. A treatment with steroids and methotrexate (MTX) was started leading to a complete remission of the disease within 6 months. Tattoo associated sarcoidosis, has been reported since 1939 (1). It may have a systemic or localized involvement and diagnosis, besides clinical features, primarily relies on histopathology. After biopsy confirmation, a systemic check-up should be performed (1). The incidence of tattoo-induced sarcoid arthritis is unknown, but up to 25% of patients with sarcoidosis have an associated acute or chronic arthritis. Ankles are the most frequently involved joints occurring in 75–100% of the patients (2). Corticosteroids and disease-modifying antirheumatic drugs including MTX and hydroxychloroquine proved effective on systemic features (3,4). Furthermore, ocular uveitis might be present in about 40% of the cases and must be kept in consideration in the clinical assessment of tattoo associated systemic sarcoidosis (5). This case shows how tattoo induced sarcoidosis may occur decades after tattooing and even monochromatic small tattoos are able to induce systemic inflammatory reaction, in contrast to what previously reported (3).

BACKGROUND:Krebs von den Lungen-6 (KL-6) is a high-molecular-weight (200kDa) glycoprotein proposed as a diagnostic biomarker for differentiating interstitial lung disease (ILD). Systemic sclerosis (SSc) is a rare immune-mediated disorder, and ILD is the leading cause of morbidity and mortality. Pleuroparenchymal fibroelastosis (PPFE) has been described to have a poor prognosis in SSc-ILD patients. This study undertook to compare serial changes in KL-6 in SSc-ILD patients with and without PPFE, to verify its prognostic value as a disease biomarker.MATERIALS AND METHODS:Twenty-five SSc-ILD patients (median IQR, 62 (56-58); 20% males) were retrospectively enrolled. 12 SSc-ILD patients (48%) had also a radiological diagnosis of PPFE. Serum KL-6 concentrations were measured by KL-6 reagent assay (Fujirebio Europe, Ghent, Belgium).RESULTS:Serum KL-6 measurements were increased in SSc-ILD patients with and without PPFE compared with healthy controls (P < .0001). Comparative analysis of the rate of variation of KL-6 over the 6 years of follow-up was performed by serial two-yearly KL-6 measurements: Δ1(t1-t0), Δ2(t2-t1) and Δ3(t3-t2). In SSc-ILD patients with PPFE pattern, Δ3 was significantly different than those without PPFE pattern (P = .0020). Serum KL-6 levels were significantly different (P = .0455) either at Δ2 and Δ3 in the PPFE group. In SSc-ILD patients with PPFE, at t3 serum KL-6 concentrations were inversely correlated with FEV1 (r = -.76; P = .037) and FVC percentages (r = -.79; P = .028).CONCLUSION:These results suggest that serial measurements of KL-6 in the follow-up of these patients may help to monitor disease progression. In real life, in SSc-ILD patients PPFE should be always evaluated at CT and when present should suggest a tight follow-up to monitor its evolution.

Background: Together with autoimmune-inflammation and fibrosis, microvasculopathy is a hallmark of SSc. However, also macrovascular changes may occur including peripheral proliferative vasculopathy. Whether this changes may represent a specific SSc marker with a predictive value remains a matter of debate.[1,2,3] Objectives: To study peripheral macrovascular involvement by color doppler ultrasound (CDUS) with spectral wave analysis (SWA) in a cohort of 40 SSc patients as compared to healthy controls. To further analyze any differences among the SSc population. Methods: Forty SSc patients and 36 healthy controls were examined by CDUS with SWA of both hands. Macrovascular involvement was assessed by measuring the resistivity index (RI) of distal ulnar and radial arteries. Examinations were performed with an Esaote MyLab Twice machine equipped with a linear 10-22 MHz probe. Ultrasound examination was carried out by two independent rheumatologists blinded to clinical conditions of the patients. Statistical analysis was performed by using MaxStat software. Results: The RI index resulted increased in the SSc cohort as compared with healthy controls (left ulnar RI 0.977 vs 0.715; right ulnar RI 0.996 vs 0.699; left radial RI 0.988 vs 0.706; right radial RI 0.999 vs 0.688; p<0.001). SSc patients with an increased RI in one artery were more probable to have an increased RI in the other vessels too (r 2 = 0.35; p<0.01). In addition, 8 out of 40 SSc patients presented left ulnar artery occlusion (UAO) and 7 out of 40 SSc patients presented right UAO, of which 6 presented bilateral UAO. Awaiting to enlarge the cohort for further analysis, descriptive data regarding increased RI at CDUS/SWA and clinical features, including years from onset of the disease, subtype of SSc, mRSS, history of digital ulcers, interstitial lung disease and PAH are described in Table 1. Conclusion: Peripheral macrovascular involvement was observed in SSc patients as compared with healthy controls. Further studies will determine whether this feature may have specificity for diagnosis/prognosis in SSc. References: [1]Lescoat A, Yelnik CM, Coiffier G et al. Ulnar Artery Occlusion and Severity Markers of Vasculopathy in Systemic Sclerosis: A Multicenter Cross-Sectional Study. Arthritis Rheumatol. 2019;71:983-990. [2]Lescoat A, Coiffier G, Rouil A et al. Vascular Evaluation of the Hand by Power Doppler Ultrasonography and New Predictive Markers of Ischemic Digital Ulcers in Systemic Sclerosis: Results of a Prospective Pilot Study. Arthritis Care Res (Hoboken). 2017;69:543-551. [3]Schioppo T, Orenti A, Boracchi P, De Lucia O, Murgo A, Ingegnoli F. Evidence of macro- and micro-angiopathy in scleroderma: An integrated approach combining 22-MHz power Doppler ultrasonography and video-capillaroscopy. Microvasc Res. 2019;122:125-130. Table 1. Main clinical features of the SSc cohort (n=40) studied by CDUS for macrovascular involvement. SSc cohort (n = 40) Years from onset range (35 y – 0 y) mean = 10.5 y Autoantibodies ACA 13/40 Anti-TopoI 14/40 Other 13/40 mRSS range (0 -30) mean = 3 ILD 17/40 PAH 7/40 Capillaroscopy pattern Early 10/40 Active 11/40 Late 6/40 History of digital ulcers 16/40 Left ulnar IR 0.977 Left radial IR 0.988 Right ulnar IR 0.996 Right radial IR 0.999 Disclosure of Interests: None declared.

Objectives Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in SF. Recently, the production of neutrophil extracellular traps (NETs) embedding MSU crystals has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in SFs during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyse activation of necroptosis pathway in SF from crystal-induced arthritis. Methods SF samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in SF by nucleic acid stain and by quantification of human neutrophil elastase. Activation of phosphorylated MLKL was assessed by western blot. Results We observed that SF neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in SF and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway. Conclusions Our findings suggest that a role of NETs in crystal-induced arthritis is to 'trap extracellular particles', including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition, and may have implications for disease evolution rather than for spontaneous resolution of the acute attack.

Background Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions. Results The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6–37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17–2.35), congestive heart failure (HR = 2.76, CI 95% 1.80–4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21–4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06–2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008–2017 period. Conclusions The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.

Haemolysis and methaemoglobinaemia (MetHb) are rare metabolic complications that can occur in Alkaptonuria (AKU), for which there is no curative treatment. Presented is a case of a man who had AKU, and serves as a reminder of life-threatening complications that can occur with haemolysis and MetHb. This case presents an opportunity to revisit important considerations relating to the investigation and treatment of haemolysis and MetHb with a view to raising awareness, and in doing so hopefully reducing the uniformly fatal outcome. Additionally it is proposed that treatment of haemolysis and MetHb with nitisinone is considered as a potentially lifesaving treatment as it is believed that reducing the concentration of circulating homogentisic acid will reduce oxidative stress.

BackgroundRheumatoid arthritis (RA) is a chronic systemic inflammatory disease. In this disease, interstitial lung diseases (ILD) is associated with high risk of mortality. Rituximab, a monoclonal antibody directed against CD20, is effective in the treatment of articular manifestations in RA while controversial results have been reported on rituximab efficacy in RA-ILD patients. AimsTo describe the clinical and radiological characteristics of 28 patients with RA-ILD and analyse the efficacy of anti-CD20 therapy in 14 RA-ILD patients treated with this drug for more than 1 year. ResultsIn our population, high resolution computed tomography features revealed usual interstitial pneumonia (UIP) in 15/28 (54%) of patients, non-specific interstitial pneumonia in 8/28 (29%) patients, other patients presented fibroelastosis and nodular fibrotic patterns. Higher mortality rate was observed in RA patients with radiological UIP pattern compared to those with different radiological patterns, although our patients with RA associated with radiological UIP pattern had a longer survival (7 years from ILD diagnosis) compared with literature data (3-5 years from ILD diagnosis). Half of our patients were treated with rituximab and they had a progressive reduction of lung function parameters. After 6 and 12 months of anti-CD20 therapy, our patients presented a stabilisation of lung function parameters. ConclusionOur study supported the theory that patients with RA and radiological UIP pattern at computed tomography scan presented the worst survival; rituximab therapy seems to be effective stabilising ILD involvement and lung function deterioration.

BACKGROUND:Baricitinib is a JAK inhibitor that blocks intracellular signalling pathways of inflammatory cytokines recommended for Rheumatoid arthritis (RA) patients not responding to initial treatment. Among RA extrareticular features, interstitial lung involvement is primarly characterized by fibrotic evolution. The aim of the present study was to analyse the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment. MATERIALS AND METHODS:15 patients (median (IQR) 65 (55-66); 13% males and 74% smokers) treated with baricitinib were enrolled. 4 patients (27%) were classified as RA-ILD before baricitinib therapy. Our study is the first to evaluate adipokine levels in RA patients (including a small population with RA-ILD) after six months of baricitinib treatment with a novel multiplex method. RESULTS:The modulatory effects of baricitinib on lipid mediators were associated with clinical and functional improvement, demonstrated by the significant increase in DLco and KCO percentages after six months of treatment. Baricitinib decreased the systemic inflammation by lowering expression of IL-6 and CRP and reducing ESR and serum concentrations of adiponectin. A significant reduction of KL-6 levels in RA-ILD patients after six months of baricitinib therapy reflects the stability of interstitial lung involvement in these patients. CONCLUSION:Baricitinib was demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement.

Background: Exosomes generated great resonance in the last few years due to their important roles in different biological pathways and diseases, including systemic sclerosis (SSc) (1). They are lipid-like nanovesicles containing biomarkers, such as proteins, lipids, macromolecules and nucleic acids, including microRNA (miRNA) (2). Exosomes are implicated in intercellular communication by fusing and releasing their cargo into the target cells (3). Objectives: In the present study, we evaluated the potential of exosomes deriving from plasma of SSc patients or generating from cultured SSc fibroblasts to drive the fibrotic signaling in the disease. Methods: Exosomes were isolated from plasma of n=10 SSc patients and from n=10 control subjects. Exosomes were also purified from cell culture supernatants of SSc fibroblasts and of control fibroblasts. Exosome size and concentration were assessed by Nanosight Particle Tracking Analysis (NTA) and by transmission electron microscopy (TEM). The content of anti-fibrotic (let-7a, 146a, 200a, 223a) and pro-fibrotic (150, 155) miRNAs was assessed in all the plasma-derived and cell culture-derived exosome populations by semiquantitative real time PCR. Finally, isolated exosomes were used to stimulate control dermal fibroblasts in culture. Gene expressions (COL1A1, ACTA2 and TAGLN) were assessed by quantitative real time PCR (qRT-PCR) and protein levels (type-I-collagen, α-SMA and SM22) by immunofluorescence (IF). Results: Exosomes isolated from SSc plasma samples showed higher concentration (3.3x10 10 ±1.1x10 10 particles/mL) compared to those isolated from control plasma ones (1.5x10 10 ±0.4x10 10 particles/mL) (p<0.01). The exosome size did not differ between SSc and control plasma samples and ranged from 50nm to 150nm. Similar results were obtained with exosomes generated from fibroblast cultures: the concentration was higher in SSc fibroblasts (1.1x10 10 ±0.2x10 10 particles/mL) than in control ones (0.4x10 10 ±0.1x10 10 particles/mL) (p<0.05) with no significant differences in size distribution. The content of all anti-fibrotic (let-7a, 146a, 200a, 223a) miRNAs was decreased in exosomes coming from both SSc plasma samples and from SSc fibroblasts with respect to control plasma samples (p<0.05) and to control fibroblasts (p<0.05). On the contrary, the pro-fibrotic (150, 155) miRNAs were significantly upregulated in exosomes deriving from SSc plasma samples and from SSc fibroblasts, with respect to control plasma samples (p<0.05) and to control fibroblasts (p<0.05). Finally, only exosomes coming from SSc plasma samples or SSc fibroblast cultures were able to induce pro-fibrotic gene (COL1A1, ACTA2 and TAGLN) and protein (type-I-collagen, α-SMA and SM22) expression in control fibroblasts. No pro-fibrotic induction was seen in presence of exosomes isolated from control plasma samples or control fibroblast cultures. Conclusion: This study demonstrates that plasma from SSc patients contains higher concentration of exosomes compared to plasma from control subjects and SSc-derived exosomes contain specific pro-fibrotic miRNA signatures that can induce myofibroblast differentiation in vitro . These results suggest that exosomes could be fibrotic drivers towards non-affected areas in vivo , and they might represent novel targets for precision medicine treatments in SSc. References: [1]Zhu T, Wang Y, Jin H, Li L. The role of exosome in autoimmune connective tissue disease. Ann Med. 2019 Mar;51(2):101-108. [2]Wermuth PJ, Piera-Velazquez S, Rosenbloom J, et al. Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol. 2018 Jul;14(7):421-432. [3]Colletti M, Galardi A, De Santis M, et al. Exosomes in Systemic Sclerosis: Messengers Between Immune, Vascular and Fibrotic Components? Int J Mol Sci. 2019 Sep 4;20(18). pii: E4337. Disclosure of Interests: Claudio Corallo: None declared, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha, Stefano Soldano: None declared, Enrico Selvi: None declared, Francesca Bellisai: None declared, Nicola Giordano: None declared

Background Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap‐junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine‐mediated changes in connexin expression. Methods and Results Fifty‐four patients with different inflammatory diseases and elevated C‐reactive protein were prospectively enrolled, and electrocardiographic P‐wave dispersion indices, cytokine levels (interleukin‐6, tumor necrosis factor‐α, interleukin‐1, interleukin‐10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C‐reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin‐6 on connexin expression were studied in HL‐1 mouse atrial myocytes. In patients with active inflammatory diseases, P‐wave dispersion indices were increased but rapidly decreased within days when C‐reactive protein normalizes and interleukin‐6 levels decline. In inflammatory disease patients, both P‐wave dispersion indices and interleukin‐6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin‐6 significantly reduced connexin expression in HL‐1 cells. Conclusions Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin‐6 elevation, rapidly induces atrial electrical remodeling by down‐regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.