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Background: In ∼50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Ca v 1.2) and inhibiting the related current (I CaL )., Objectives: The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults., Methods: Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on I CaL and Ca v 1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated., Results: Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited I CaL and chronically down-regulated Ca v 1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Ca v 1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without., Conclusions: Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation., Competing Interests: Funding Support and Author Disclosures This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN), and Bando 2017, protocollo 2017XZMBYX (to Dr Lazzerini and Dr Capecchi); a Merit Review grant I01 BX002137 from Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development (to Dr Boutjdir); National Heart, Lung, and Blood Institute grant 1R01HL164415-01 (to Dr Boutjdir); and U.S. Department of Defense award number W81XWH-21-1-0424 (to Dr Boutjdir). Dr Lazzerini has received a grant from Roche Italia S.p.A. outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Anti-cytosolic 5'-nucleotidase 1A (anti-cN1A) antibodies were proposed as a biomarker for the diagnosis of inclusion body myositis (IBM), but conflicting specificity and sensitivity evidence limits its use. Our study aimed to assess the diagnostic accuracy of anti-cN1A in a cohort of patients who underwent a myositis line immunoassay for suspected idiopathic inflammatory myopathies (IIM). We also assessed the agreement between two testing procedures: line immunoassay (LIA) and enzyme-linked immunoassay (ELISA)., Materials and Methods: We collected retrospective clinical and serological data for 340 patients who underwent a myositis antibody assay using LIA (EUROLINE Autoimmune Inflammatory Myopathies 16 Ag et cN-1A (IgG) line immunoassay) and verification with an anti-cN1A antibody assay using ELISA (IgG) (Euroimmun Lubeck, Germany)., Results: The serum samples of 20 (5.88%) patients (15 females, 5 males, mean age 58.76 ± 18.31) tested positive for anti-cN1A using LIA, but only two out of twenty were diagnosed with IBM. Seventeen out of twenty tested positive for anti-cN1A using ELISA (median IQR, 2.9 (1.9-4.18))., Conclusions: Our study suggests excellent concordance between LIA and ELISA for detecting anti-cN1A antibodies. LIA may be a rapid and useful adjunct, and it could even replace ELISA for cN1A assay. However, the high prevalence of diseases other than IBM in our cohort of anti-cN1A-positive patients did not allow us to consider anti-cN1A antibodies as a specific biomarker for IBM.

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., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie.)

Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms., Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro ., Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (I Kr )., Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies., Competing Interests: PL received a grant from Roche Italia S.p.A. outside the submitted work in 2018. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lazzerini, Accioli, Acampa, Zhang, Verrengia, Cartocci, Bacarelli, Xin, Salvini, Chen, Salvadori, D’errico, Bisogno, Cevenini, Marzotti, Capecchi, Laghi-Pasini, Chen, Capecchi and Boutjdir.)

Objectives: Adipokines play an important role in the pathophysiology of rheumatoid arthritis (RA), provide a link between the disease and overweight, contributing to explain the enhanced cardiovascular (CV) risk and influence the response to disease-modifying anti-rheumatic drugs. The aim of this study was to determine the possible effects of intravenous (IV) tocilizumab (TCZ), an interleukin-6 receptor antagonist, on serum levels of leptin, adiponectin, resistin, visfatin, and chemerin., Methods: Forty-four RA patients with active disease (DAS28-ESR ≥3.2) were treated with IV TCZ (8 mg/kg) once every 4 weeks for six months: 20 patients received TCZ as monotherapy and 24 in association with methotrexate (MTX). At baseline and monthly, before each infusion, body mass index, DAS28-ESR and Health Assessment Questionnaire (HAQ) were recorded. The laboratory parameters, including the adipokines serum levels were collected at baseline and after six months., Results: At the end of the follow-up, ESR, CRP, DAS28-ESR and HAQ resulted significantly improved in patients received TCZ as monotherapy or combined with MTX. Lipid profile showed only a significant increase of total cholesterol. A significant reduction of chemerin and an increase of adiponectin were observed in the whole population and in the subgroups of the patients analysed (TCZ mono or combined therapy) without any significant correlations with clinical and biochemical parameters. No changes in the leptin and resistin levels were detected., Conclusions: TCZ is able to regulate serum levels of chemerin and adiponectin in RA patients, independently of the disease treatment response, which contributes to explain the CV safety of TCZ.

Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other "classical" risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required.

Background: In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP., Methods and Results: Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region., Conclusions: Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk., (© 2016 American Heart Association, Inc.)

Objectives: Idiopathic recurrent acute pericarditis (IRAP) represents the most troublesome complication of acute pericarditis and is an autoimmune process. White adipose tissue produces more than 50 adipokines that participate in inflammation and autoimmunity. This study investigated whether serum leptin, resistin, visfatin and adiponectin are increased in IRAP versus healthy controls and if their levels correlate with parameters of disease activity., Methods: Serum leptin, resistin, visfatin and adiponectin levels were assayed by enzyme-linked immunosorbent assay in 14 IRAP patients during recurrences (group 1), in 23 IRAP patients during symptom-free intervals (group 2) and in 18 healthy controls (group 3). Assessment parameters included demographic characteristics of patients and controls, clinical characteristics of patients and markers of inflammation. Comparisons between groups as well as reciprocal comparisons were evaluated., Results: Group 1 showed serum leptin (p<0.008), visfatin (p<0.002), and adiponectin (p<0.04) significantly higher than group 2 and control group, whereas resistin serum levels did not significantly differ (p=0.69). Among IRAP patients, serum leptin significantly correlated with serum amyloid A (SAA) levels (rs=0.43, r2= 0.27, p<0.02). Other than this correlation, none of the considered adipokines significantly correlated with the other considered variables in univariate analysis., Conclusions: Leptin, adiponectin and visfatin are increased in IRAP patients versus healthy controls. Our data suggest that these adipokines might be involved in IRAP pathogenesis and that a possible increased cardiovascular risk in these patients, through an early onset atherosclerosis, should be kept in mind. SAA might be a link between IRAP and increased cardiovascular diseases.

Objectives: The aims of our study were to evaluate serum leptin, resistin, visfatin and adiponectin levels in patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS), in comparison to healthy controls, and to correlate their levels to parameters of disease activity and/or severity., Methods: Serum leptin, resistin, visfatin and adiponectin levels were obtained from 14 TRAPS patients carrying mutations involving cysteine residues, from 16 TRAPS patients carrying other mutations, and from 16 healthy controls. Demographic, clinical and laboratory parameters, including amyloidosis were entered for each patient. Comparisons between groups as well as reciprocal comparisons have been evaluated., Results: Serum leptin, resistin, visfatin and adiponectin did not significantly differ among the 3 groups. Patients carrying cysteine residues mutations showed lower visfatin serum levels than patients carrying other mutations (p<0.02). Serum leptin significantly correlated with the number of attacks/year (multiple R=0.32, multiple adjusted R2= 0.19, p <0.03). Serum adiponectin levels significantly correlated with the presence of amyloidosis (multiple R=0.79, multiple adjusted R2=0.57, p<0.03). Adiponectin values were a significant predictor for amyloidosis (AUC 0.75, 95 CI: 0.56-0.94, p<0.03), with a predicting cut-off value set at 23.16 pg/ml, the predictive positive value was 53.8%. Visfatin serum levels resulted respectively related to leptin (rs=0.42, r2=0.18, p<0.02) and to resistin (rs=0.57, r2=0.32, p<0.01) serum levels; whilst leptin and resistin serum levels did not reciprocally correlate., Conclusions: Although a prospective design study and larger cohort are mandatory, adipokines serum levels and their correlations with parameters of disease activity and/or severity seem to show a baseline pattern in TRAPS patients.

Objectives: Vaspin and omentin are two recently discovered adipokines that have been involved in chronic inflammatory processes. The aims of our study were to evaluate their serum levels in patients affected by juvenile idiopathic arthritis (JIA), in comparison to healthy controls, and to correlate circulating levels to parameters of disease activity., Methods: Serum levels of omentin and vaspin were assayed by enzyme-linked immunosorbent assay in 40 patients with JIA classified according to the ILAR criteria and 26 healthy controls., Results: Serum omentin levels were significantly higher in JIA patients versus healthy controls (p<0.0001) whereas serum vaspin levels did not significantly differ between the two groups. JIA children with active joints showed higher omentin serum levels than JIA children without active joints (p<0.001) and omentin serum levels significantly correlated with the presence of active joints (p<0.0001). Omentin serum levels were also significantly related with the number of active joints (p<0.002). Vaspin serum level did not show statistical significant differences between JIA children with active joints and those with no active joints. There was no correlation between plasma vaspin levels and the presence of active joints, or the number of active joints, Conclusions: Our study is the first report on the new adipokines vaspin and omentin in patients with JIA, and it shows that omentin is significantly higher in JIA patients in comparison with healthy controls. In addition, we also report that omentin plasma levels are significantly correlated with the presence and the number of active joints.

Objective: Recent evidence suggests that anti-Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti-Ro/SSA-positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10-60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti-Ro/SSA-associated QTc prolongation in adult patients with CTD is related to antibody level and specificity., Methods: Forty-nine adult patients with CTD underwent a resting 12-lead electrocardiogram recording to measure QTc interval, and a venous withdrawal to determine anti-Ro/SSA antibody level and specificity (anti-Ro/SSA 52 kd and anti-Ro/SSA 60 kd) by immunoenzymatic methods and Western blotting., Results: In our population, a direct correlation was demonstrated between anti-Ro/SSA 52-kd level and QTc duration (r = 0.38, P = 0.007), patients with a prolonged QTc had higher levels of anti-Ro/SSA 52 kd with respect to those with a normal QTc (P = 0.003), and patients with a moderate to high level (≥50 units/ml) of anti-Ro/SSA 52 kd showed a longer QTc interval (P = 0.008) and a higher QTc prolongation prevalence (P = 0.008) than those with a low positive/negative level (<50 units/ml). On the contrary, no association was found between QTc and anti-Ro/SSA 60-kd level., Conclusion: In anti-Ro/SSA-positive adult patients with CTD, the occurrence of QTc prolongation seems strictly dependent on the anti-Ro/SSA 52-kd level. This finding, possibly explaining the different QTc prolongation prevalence reported, strengthens the hypothesis that an extremely specific autoimmune cross-reaction is responsible for the anti-Ro/SSA-dependent interference on ventricular repolarization., (Copyright © 2011 by the American College of Rheumatology.)

OBJECTIVE: To test the prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic sclerosis (SSc) and to verify a possible association of ANCA with normotensive renal involvement in SSc. PATIENTS AND METHODS: 51 patients affected by SSc, 35 with diffuse scleroderma (dSSc) and 16 with limited scleroderma (lSSc), were tested for ANCA by indirect immunofluorescence (IIF) on human ethanol and formalin-acetone-fixed granulocytes (before and after DNase treatment), by conventional enzyme linked immuno-sorbent assay (ELISA) and by capture-ELISA. RESULTS: Six out of 51 selected SSc patients had ANCA by IIF (11.7%) and five presented a perinuclear/nuclear atypical ANCA pattern. In all cases we only found anti-proteinase3 (aPR3) antibodies. All ANCA positive patients had diffuse form of SSc (17.1%), all were anti-Scl70 positive (aScl70), five patients had proteinuria, three had microscopic haematuria. All ANCA positive patients were normotensive with normal renin plasma levels, the mean erythrocyte sedimentation rate (ESR) was higher in this group compared to the other SSc patients. CONCLUSIONS: Our study shows that aPR3 is not rare in dSSc. According to the clinical and serological findings and to the recent literature, we can hypothesise that when ANCA are found in SSc, an overlapping of scleroderma with systemic necrotizing vasculitis should be suspected.

Objective: To compare the performance characteristics of various tests commonly used to detect anti-SSA/Ro autoantibodies in the sera of patients affected by connective tissue diseases (CTD)., Methods: Indirect immunofluorescence (IIF) with HEp-2000 as substrate (ImmunoConcepts, USA), Ouchterlony's double immunodiffusion (ID) (home made), commercial Varelisa ReCombi anti-Ro kit (Pharmacia & Upjohn, Germany), research kits (60 kDa and 52 kDa) with human recombinant antigens (Pharmacia & Upjohn, Germany) and a commercial western blot (WB) kit (MarDx, USA) were evaluated in our study. Sixty-four sera from patients affected by CTD were tested: 15 had primary Sjögren's syndrome (SS), 34 only had sicca syndrome, and 15 had systemic lupus erythematosus (SLE). Thirty sera from healthy subjects were selected as controls., Results: 54 sera were positive by at least one method. The specificity of all tests was good. The prevalence of anti-SSA antibodies on 54 positive sera was 76% (ID), 89% (IIF), 89% (Varelisa), 89% (ELISA Ro-60 kDa), 67% (ELISA Ro-52 kDa) and 85% (WB). Some differences were found between WB and ELISA in the detection of anti-60 kDa SSA and anti-52 kDa SSA; in 3 SS sera only anti-52 kDa protein was found by WB., Conclusion: Our data confirm that, although IIF HEp 2000 (Immuno Concepts) and Varelisa anti-Ro (Pharmacia & Upjohn) both performed well, a combination of 2 or more methods must still be recommended for anti-SSA antibody detection.