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European Reference Networks (ERNs) are dedicated to rare complex diseases. Systemic autoimmune rheumatic diseases (SARDs) comprise a group of disorders, some of which are rare, complex, and chronic, characterized by relapsing-remitting course and requiring targeted treatments for long periods; SARDs are also associated with various co-morbidities and therefore health-care infrastructures, at the highest level of expertise are required.For the current work, literature on the basic characteristics of a center of excellence dedicated to SARDs, its advantages over the existing health infrastructures in order to improve health and social care, its contribution to the education of health-care workers, and the related research opportunities are presented. In addition, our experience, vision, and initiatives as a new member of the ERNs are reported.A restructure in healthcare policy and resource allocation, based on centers of expertise, is necessary to improve the medical care of patients with SARDs.

Cardiopulmonary Exercise Testing (CPET) is a standardized, non-invasive procedure assessing pulmonary, cardiovascular, hematopoietic, and skeletal muscle functions during a symptom-limited test. Few studies have examined whether CPET is of prognostic value in Systemic Sclerosis (SSc), a disease characterized by highly increased cardiorespiratory morbidity and mortality. To examine the prognostic value of CPET in SSc patients without baseline pulmonary hypertension (PH). Sixty-two consecutive SSc patients underwent CPET, Pulmonary Function Tests (PFTs) and echocardiography at baseline. Four patients with Right Ventricular Systolic Pressure ≥ 40 mmHg, were excluded. Participants repeated PFTs approximately every 3 years. At the end of the follow-up period [median (IQR): 9.79 (2.78) years] patient vital status was recorded. Cox Regression analysis was used to identify predictors of deterioration of PFTs and 10-year survival. Median (IQR) age of 58 patients (90% women) at baseline was 54.0 (15.0) years, whereas 10-year survival was 88%. Baseline respiratory Oxygen uptake (VO2max) predicted PFT deterioration, defined either as a decline in FVC ≥ 10% or a combined decline in FVC 5%-9% plus DLCO ≥ 15%, during follow-up, after correction for age, gender and smoking status (HR: 0.874, 95%CI: 0.779–0.979, p = 0.021). In addition, lower baseline VO2max (HR = 0.861, 95%CI:0.739–1.003, p = 0.054) and DLCO (HR = 0.957, 95%CI: 0.910–1.006 p = 0.088), as well as male gender (HR = 5.68, 95%CI: 1.090–29.610 p = 0.039) and older age (HR = 1.069, 95%CI: 0.990–1.154, p = 0.086) were associated, after adjustment, with an increased risk for death. In the absence of baseline PH, CPET indices may predict pulmonary function deterioration and death in SSc patients during a nearly 10-year follow-up period.

This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades. A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially.

To assess the prevalence of autoantibodies (AAbs) in mechanically ventilated COVID-19 patients and to investigate whether AAbs influence the clinical outcome.Serum samples were drawn within the first 48 hours upon admission to the intensive care unit (ICU) from 217 consecutive patients, from January 1st, 2021, to May 10th, 2021, and investigated for the presence of AAbs using conventional techniques. Serum samples (n=117) of age- and sex-matched healthy individuals collected before COVID-19 pandemic were used as controls.COVID-19 patients in the ICU had more commonly AAbs compared to age- and sex-matched controls (174/217, 80.2% vs. 73/117, 62.4%, p0.001). Patients expressed more frequently ANAs (48.4% vs. 21.4%, p0.001), anti-dsDNA (5.1% vs. 0%, p=0.01), anti-CCP (8.3% vs. 1.7%, p=0.014) and anti-CL IgM AAbs (21.7% vs. 9.4%, p=0.005) than controls, respectively. Simultaneous reactivity against at least three autoantigens, occurred in 144 out of 174 (82.8%) patients. The two groups did not differ in terms of clinicoepidemiologic characteristics or the mortality ratio within the ICU. Patients who died compared to convalescents were older, had higher ferritin, D-dimers levels, APACHE II score, lower oxygen saturation, higher prevalence of comorbidities and cognitive dysfunction. However, AAbs were not found to correlate with the clinical outcome.Patients with severe COVID-19 express AAbs more commonly compared to controls. No correlation was found between AAbs and disease outcome.

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International audience; Immune system provides the mechanisms for attacking foreign invaders, eliminating autologous toxic substances and offering self-tolerance. A reductionist approach of the immune system components and their interactions as provided in this chapter will offer knowledge important to better understand the core mechanisms of autoimmune diseases and design therapies targeting their pathogenic mechanisms. Immunity is divided into (a) innate (or natural), implemented by macrophages, dendritic cells, granulocytes (neutrophils, basophils, and eosinophils), natural killer cells, the complement system, and the acutephase proteins, and (b) adaptive, implemented by B and T cells. Immune cells express sensors on cytoplasmic or endosomal membranes or in the cytoplasm, called “pathogen-associated molecular pattern receptors” (PAMPRs), also called pattern recognition receptors (PRRs), and damage-associated molecular pattern receptors (DAMPRs) to sense foreign invaders or damaged tissues and provide defense against them. Natural immunity cells provide the fjrst line of defense, usually successful in eliminating pathogens, but also they limber up the adaptive immune system to take action in case of any failure of defense. The sensors of B and T cells are their antigen receptors (membrane immunoglobulins and T-cell receptors, respectively) which are dissimilar to each other in terms of specificity; each receptor recognizes very specifically one antigen and especially a few peptide residues on it (epitope). However, by taking as a whole the pool of lymphocytes, their receptors offer a vast array of specificities exceeding 1011 that is more than the genes of the human body. This implies that not particular genes but rather gene fragments are spontaneously rearranged to make an immunoglobulin or a T-cell receptor gene. One such rearrangement for each peptide chain of the receptor is allowed, so the cells will retain their antigenic specificity as long as they live. Immune cells communicate with each other and approach their targets, either by cell-to-cell contact using adhesion molecules or by soluble mediators known as cytokines or chemokines, respectively. Mechanisms like central (taking place in bone marrow and thymus) and peripheral (taking place in the lymph nodes) tolerance ensure that the immune system will not attack self. Braking of tolerance initiates autoimmune reactivity which may be subclinical but, under certain circumstances, may obtain a clinical phenotype.

ObjectiveTo describe data on the safety and efficacy of molnupiravir (MP) and nirmatrelvir/ritonavir (NM/R) in patients with systemic autoimmune rheumatic diseases (SARDs).MethodsAmong patients with SARD being followed in 2 tertiary outpatient rheumatology clinics, we retrospectively identified those infected with SARS-CoV-2 between February and August 2022 who received MP or NM/R. Patients' medical files were reviewed for demographics and disease-related characteristics, as well as coronavirus disease (COVID-19) characteristics, including vaccination status, antiviral treatment, side effects, and COVID-19 outcomes.ResultsSeventy-four patients with SARD (52 females) were identified who had been infected with SARS-CoV-2 and received MP (n = 26, 35.1%) or NM/R (n = 48, 64.9%). Most patients were vaccinated against SARS-CoV-2 (n = 62, 83.8%). Among frequently used regimens were glucocorticoids (n = 43, 58.1%), mycophenolate mofetil (n = 26, 35.1%), tumor necrosis factor inhibitors (n = 14, 18.9%), methotrexate (n = 13, 17.6%), and rituximab (n = 12, 16.2%). Common adverse events were reported only by 4 patients receiving NM/R (metallic taste, gastrointestinal upset, hypertension), not leading to drug discontinuation. During follow-up, all but 2 patients (n = 72, 97.3%) recovered at home without COVID-19–related complications. Nonetheless, we describe 2 presumptive cases of COVID-19 rebound who progressed to severe COVID-19.ConclusionThese data show a favorable outcome and acceptable safety profile of the 2 oral antiviral therapies MP and NM/R among a high-risk SARD population. However, cases of COVID-19 rebound are being increasingly identified. These findings call for continuous surveillance to capture the real-world efficacy and safety profiles in our subpopulations of interest.

Objectives To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. Methods A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. Results Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. Conclusions In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

Perinuclear anti-neutrophilic cytoplasmic antibodies (P-ANCA) recognize heterogeneous antigens, including myeloperoxidase (MPO), lactoferrin, elastase, cathepsin-G and bactericidal/permeability-increasing protein. Although P-ANCA have diagnostic utility in vasculitides, they may also be found in patients with various other systemic autoimmune rheumatic diseases (SARDs). Nevertheless, the clinical significance and the targets recognized by P-ANCA in such patients remain unclear. For this purpose, herein we investigated the occurrence of ANCA-related antigenic specificities in 82 P-ANCA-positive sera by multiplex ELISA, as well as their association with other autoantibodies. The P-ANCA-positive sera corresponded to patients with vasculitides (n = 24), systemic lupus erythematosus (n = 28), antiphospholipid syndrome (n = 5), Sjögren’s syndrome (n = 7), rheumatoid arthritis (n = 3), systemic scleroderma (n = 1), sarcoidosis (n = 1) and Hashimoto′s thyroiditis (n = 13). In most P-ANCA-positive patients studied (51/82, 62.3%), these autoantibodies occurred in high titers (&gt, 1:160). The analysis of P-ANCA-positive sera revealed reactivity to MPO in only 50% of patients with vasculitides, whereas it was infrequent in the other disease groups studied. Reactivity to other P-ANCA-related autoantigens was also rarely detected. Our findings support that high P-ANCA titers occur in SARD. The P-ANCA-positive staining pattern is associated with MPO specificity in vasculitides, while in other autoimmune diseases, it mostly involves unknown autoantigens.

Objective Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominantly inherited autoinflammatory disease caused by mutations of the TNFRSF1A gene. To address the association between TNFRSF1A mutations and clinical phenotype, we analyzed four pedigrees of TRAPS patients. Methods Four Greek patients with TRAPS-like clinical features were screened for TNFRSF1A mutations by sequencing exons 2, 3 and 4. Following positive testing, twenty-two members of their families were also genetically and clinically screened. Results Twenty-six members of four unrelated Greek families were investigated. The C73Y (c.305G>A) mutation of the TNFRSF1A gene was identified in five patients, with two of the five carrying a concomitant R92Q variation. We also identified seven C73W (c.306C>G), two T50M (c.236C>T) and seven R92Q (c.362G>A) carriers. Symptoms varied and the C73Y, C73W and T50M mutations were associated with the most severe clinical manifestations. The R92Q phenotype ranged from asymptomatic to mild disease. Molecular modelling linked pathogenicity with aberrant TNFRSF1A disulphide bond formation. Conclusion In this first pedigree analysis of TRAPS in Greece, we identified the rare C73Y TNFRSF1A mutation. A wide clinical spectrum was observed with the C73Y, C73W and T50M mutations that affect TNFRSF1A disulphide bonds and are associated with worse symptoms.

Clinical data on vaccinated patients with coronavirus disease 2019 (COVID-19) who have systemic autoimmune and autoinflammatory rheumatic diseases (SAARD) are limited. This observational study aimed to report the clinical features and outcomes of COVID-19 among cases with SAARD that were unvaccinated or were 2- and 3-dose vaccinated against SARS-CoV-2 and were consecutively recorded by the treating physician. Unvaccinated and 2- and 3-dose vaccinated patients were compared in terms of COVID-19 symptomatology, hospitalizations, oxygen supplementation requirements, and death rates. From the beginning of the pandemic to February 15, 2022, 134 vaccine-naïve COVID-19 cases were recorded among our study cohort. From March 1, 2021 to February 15, 2022, 89 2-dose vaccinated and 105 3-dose vaccinated patients who were infected with SARS-CoV-2 ≥14 days after the second dose were included. The hospitalization rate was higher in the unvaccinated (n = 36, 26.9%) than in the 2-dose (n = 13, 14.6%, p = 0.03) or 3-dose (n = 5, 4.8%, p 0.001) vaccinated patients. Severe/critical COVID-19 cases requiring oxygen supplementation were the least among 3-dose vaccinated (n = 4, 3.8%) compared to both 2-dose vaccinated (n = 12, 13.5%, p = 0.018) and unvaccinated (n = 25, 18.7%, p 0.001) patients. ICU admission and death rates were similar among unvaccinated (n = 5, 3.7% and n = 3, 2.2%, respectively) and 2-dose vaccinated patients (n = 4, 4.5%; and n = 2, 2.2%, respectively), while no 3-dose vaccinated patients died or required ICU admission. Logistic regression analysis revealed a significant inverse association between 3-dose vaccination and severe/critical COVID-19 (OR = 0.078, 95% CI: 0.022-0.273, p 0.001). In conclusion, these findings argue in favor of booster vaccination against SARS-CoV-2 in patients with SAARD.

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4, however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.

Introduction: Sjogren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed.Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.

Bronchocentric granulomatosis (BcG) is characterized by granulomatous destruction of bronchial or bronchiolar walls and adjacent parenchyma, with debris and exudates filling the airway lumen. Approximately 50% of total cases have been associated with asthma and allergic bronchopulmonary aspergillosis, while it has been rarely reported in the context of rheumatoid arthritis (RA). We describe the case of a 69-year-old female RA patient with BcG presenting as a solitary cavitary pulmonary mass. In addition, we conducted a literature review about the clinical and imaging features of BcG in RA patients. A chronically immunosuppressed 69-year-old female patient with a 16-year history of RA presented with constitutional symptoms (low-grade fever, excessive sweating and malaise) and a sizeable cavitary lung lesion. Open lung biopsy was performed and histopathological findings were consistent with the diagnosis of BcG. Other seven cases of BcG have been previously reported in the context of RA, with clinical and laboratory characteristics described in five of them. Overall, pulmonary nodules or masses were the most frequent imaging finding of BcG, while no clear relationship with disease activity or previous treatment modalities could be established. Surgical resection followed by administration of oral steroids was effective for achieving complete remission of symptoms and radiological stability in most cases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, which has affected more than 6 million people worldwide causing more than 400 000 deaths. The disease affects predominantly the upper and lower respiratory tracts causing severe pulmonary disease which often evolves to a multiorgan systemic disease.1 This is evidenced by thromboembolic lesions of the heart and lungs, pulmonary haemorrhage, muscle weakness, hyperbilirubinaemia and lymphopenia suggesting that COVID-19 affects epithelial barriers, endothelial cells, coagulation, fibrinolysis and the immune system.2 In patients who are severely ill, innate immune hyperactivity causes a cytokine storm which disturbs microcirculation resulting in shock and acute respiratory distress syndrome.3 Systemic disease perpetuation may be due to the virus itself, infecting cells via ACE2 receptor or, following the cytokine storm, due to autoinflammatory and/or autoimmune mechanisms.4 Earlier studies reported that certain autoantibodies such as anti-cardiolipin (a-CL), anti-β2GPI and lupus anticoagulant might associate with the thromboembolic complications occurring …

Standard echocardiography is important for pulmonary arterial hypertension (PAH) screening in patients with connective tissue disease (CTD), but PAH diagnosis and monitoring require cardiac catheterization. Herein, using cardiac catheterization as reference, we tested the hypothesis that follow-up echocardiography is adequate for clinical decision-making in these patients. We prospectively studied 69 consecutive patients with CTD-associated PAH. Invasive baseline pulmonary artery systolic pressure (PASP) was 60.19 &plusmn, 16.33 mmHg (mean &plusmn, SD) and pulmonary vascular resistance (PVR) was 6.44 &plusmn, 2.95WU. All patients underwent hemodynamic and echocardiographic follow-up after 9.47 &plusmn, 7.29 months, 27 patients had a third follow-up after 17.2 &plusmn, 7.4 months from baseline. We examined whether clinically meaningful hemodynamic deterioration of follow-up catheterization-derived PASP (i.e., &gt, 10% increase) could be predicted by simultaneous echocardiography. Echocardiography predicted hemodynamic PASP deterioration with 59% sensitivity, 85% specificity, and 63/83% positive/negative predictive value, respectively. In multivariate analysis, successful echocardiographic prediction correlated only with higher PVR in previous catheterization (p = 0.05, OR = 1.235). Notably, in patients having baseline PVR &gt, 5.45 WU, echocardiography had both sensitivity and positive predictive values of 73%, and both specificity and negative predictive value of 91% for detecting hemodynamic PASP deterioration. In selected patients with CTD-PAH echocardiography can predict PASP deterioration with high specificity and negative predictive value. Additional prospective studies are needed to confirm that better patient selection can increase the ability of standard echocardiography to replace repeat catheterization.

Objectives This study aimed to investigate whether positive serum autoantibodies (AAbs) have any impact on survival and time evolution of radiological findings and pulmonary function indices in patients with interstitial lung disease (ILD). Patients and methods Ninety four patients with regular clinical, functional and high resolution computed tomography (HRCT) imaging follow-up for at least 12 consecutive months and complete testing for a panel of AAbs most commonly associated with ILD were enrolled in this retrospective two-center study. Eligible patients were divided into two groups based on the presence [ILD/AAb(+)] (n = 69) or absence [ILD/AAb(−)] (n = 25) of positive serum AAbs. All-cause mortality and longitudinal indicators of ILD progression such as a sustained decrease from baseline in absolute measurements of forced vital capacity (FVC) of ≥10% or single-breath diffusion capacity (DLCOSB) of ≥15% were the primary study endpoints. DLCOSB Results ILD/AAb(+) patients were predominantly female (71% vs 32%), were significantly younger (54.8 ± 14.6 vs 66.8 ± 10.1 years), and had longer duration of follow-up (78.1 ± 53.1 vs 41.6 ± 26.7 months), compared with ILD/AAb(−) patients (p Conclusions AAb(+) patients with ILD seem to have a more favorable prognosis regarding all-cause mortality, long-term deterioration in lung function parameters and progression of HRCT findings than their AAb (−) counterparts.

Non-Infectious Primary systemic vasculitides (NIPSV) encompass a subset of autoimmune diseases, characterized mainly by intramural inflammation of the vascular wall. The increased mortality that some exhibit is partially attributed to vascular complications involving both micro- and macro- circulation. Beyond the disease specific pathways of vascular damage, emerging evidence suggest that the classical pathways of arterial damage, namely, atheromatosis, inappropriate arterial remodeling and arteriosclerosis are accelerated in several NIPSV; thus participating in the development of vascular complications in NIPSV patients. The aim of the current research protocol is to optimize the understanding of vascular pathology in NIPSV and to identify useful, easy to measure, non-invasive vascular tools for the diagnosis and follow-up of NIPSV patients. Moreover, the study aims to generate hypothesis regarding the molecular basis of the association of inflammation with classical vascular pathology.

Myositis-specific (MSAs) or-associated autoantibodies (MAAs) have been linked to particular clinical phenotypes of idiopathic inflammatory myopathies (IIM) and appear to aid diagnosis. The objective of this study was to analyze the prevalence of MSAs and MAAs and their possible clinical associations in Greek IIM patients. This study comprised 95 IIM patients classified based on the 2017 EULAR/ACR classification criteria. All patients had MSAs and MAAs measured in their sera by line immunoblot assay. Dermatomyositis was the most prevalent IIM clinical subtype. MSAs were found in 44% of the patients, whereas MAAs in 23%. The most frequently detected MSA was anti-Jo-1 (22%), while the most frequently detected MAA was anti-Ro-52 (30%). The distributions of MSAs/MAAs did not differ between the five IIM subgroups, except for anti-Mi-2 which was only detected in dermatomyositis patients. Patients with at least one MSA and/or MAA positivity showed more frequently IIM characteristic skin rashes, while those presenting solely MAA positivity had more often puffy hands and Raynaud's phenomenon. Anti-Jo1-positive patients presented more frequently lung disease, while anti-Ro52 positivity related to mechanic's hands. Anti-Ro-52 and anti-Jo-1 strongly associated with one another. Prevalence of IIM subtypes and of MSAs/MAAs in our patients is in line with published reports in populations of similar geographic distribution. While MSA and/or MAA positivity did associate with particular clinical manifestations, it did not predict in our cohort specific IIM subgroup as defined by the latest EULAR/ACR classification criteria. Future studies are warranted to conclusively decide if these autoantibodies, measured with a standardized method, should or not be incorporated in every day clinical practice to aid IIM diagnosis.

The impact of SARS-CoV-2 infection in patients with autoimmune/auto-inflammatory rheumatic diseases (AARD) under immunomodulatory treatment has been a focus of interest during the COVID-19 pandemic. In this observational study, demographic data, disease related features and comorbidities, COVID-19 manifestations and outcome as well as antibody responses to SARS-CoV-2 were recorded among 77 consecutive patients with underlying AARD infected by SARS-CoV-2. Analysis of data was performed using univariate and multivariate models. Most patients (68.8%) had a mild COVID-19 course. The predominant clinical manifestations were fatigue (58.4%), low grade fever (45.4%) and upper respiratory tract symptoms (68.8%). About a quarter of patients required hospitalization (23.3%) and the mortality rate was 1.3%. Regarding COVID-19 severity, prior treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in patients who developed a more serious disease course (60.0 vs 29.9%, p = 0.003, 40.0 vs 7.5%, p = 0.003, 10.0 vs 0.0%, p = 0.009, respectively). When disease related features and comorbidities were considered in multivariate models, older age and lung disease in the context of the AARD were found to be independent predictive factors for hospitalization (OR [95%]: 1.09 [1.03-1.15] and 6.43 [1.11-37.19]). Among COVID-19 related features, patients with shortness of breath and high-grade fever were more likely to get hospitalized (OR [95%]: 7.06 [1.36-36.57], 12.04 [2.96-48.86]), while anosmia was independently associated with lower hospitalization risk (OR [95%]: 0.09 [0.01-0.99]). Though the majority of AARD patients displayed a mild COVID-19 course, certain underlying disease features and COVID-19 related manifestations should prompt alertness for the physician to identify patients with AARD at high risk for severe COVID-19 and need for hospitalization.

In the context of the current COVID-19 pandemic, traditional, complex and lengthy methods of vaccine development and production would not have been able to ensure proper management of this global public health crisis. Hence, a number of technologies have been developed for obtaining a vaccine quickly and ensuring a large scale production, such as mRNA-based vaccine platforms. The use of mRNA is not a new concept in vaccine development but has leveraged on previous knowledge and technology. The great number of human resources and capital investements for mRNA vaccine development, along with the experience gained from previous studies on infectious diseases, allowed COVID-19 mRNA vaccines to be developed, conditionally approved and commercialy available in less than one year, thanks to decades of basic research. This review critically presents and discusses the COVID-19 mRNA vaccine-induced immunity, and it summarizes the most common anaphylactic and autoimmune adverse effects that have been identified until now after massive vaccination campaigns.

Β2-Glycoprotein I (β2GPI) is an important anti-thrombotic protein and is the major auto-antigen in the antiphospholipid syndrome (APS). The clinical relevance of nitrosative stress in post translational modification of β2GPI was examined.The effects of nitrated (n)β2GPI on its anti-thrombotic properties and its plasma levels in primary and secondary APS were determined with appropriate clinical control groups. β2-glycoprotein I was nitrated at tyrosines 218, 275 and 309. β2-glycoprotein I binds to lipid peroxidation modified products through Domains IV and V. Nitrated β2GPI loses this binding (p

The aims of this study were to estimate the frequency of central nervous system (CNS) involvement in Greek patients with granulomatosis with polyangiitis (GPA) and describe the related clinical characteristics and long-term outcomes of these patients. Medical charts of all ANCA-associated vasculitis patients were retrospectively reviewed, and GPA patients with CNS involvement were identified. Demographics, serological, and clinical features throughout the disease course were recorded. Comparisons of disease characteristics and long-term outcomes were performed between GPA patients with and without CNS involvement. Seventy-seven GPA patients were studied. Of these, 9 (11.7%) developed CNS manifestations. At the time of CNS involvement, all patients had increased acute phase reactants, and all but one had vasculitic manifestations in multiple systems and increased ANCA titers. CNS manifestations included the following: sensor/sensorimotor symptomatology (33.3%), severe headache and hearing loss (33.3%), delirium/seizures (22.2%), diplopia (11.1%), and cerebellar symptoms (11.1%). At initial GPA diagnosis, patients with CNS involvement, compared to those without, had ENT involvement more frequently (77.8 versus 25.4%, p = 0.004) along with a lower disease activity (BVAS) while during the overall disease course, they experienced lung vasculitis less frequently (44.4 vs. 79.4%, p = 0.02). Comparisons between the two groups did not reveal any differences regarding the long-term outcomes, including relapse rate, treatment-related adverse events, and patient survival. CNS involvement was recorded in 11.7% of our GPA patients. At disease onset, ENT involvement and lower BVAS scores were more common in GPA patients with CNS manifestations. Based on our results, CNS involvement did not affect the long-term outcomes of GPA patients.

Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) stems from autosomal dominantly inherited mutations in the TNFRSF1A (accession number: NM_001065) gene, encoding for the receptor of tumor necrosis factor α (TNFR1). Objectives: The aim of the study was to report a novel TNFRSF1A mutation and to describe the clinical phenotypes in families carrying different TNFRSF1A mutations. Methods: Four Greek patients with TRAPS-like clinical features were evaluated for TNFRSF1A gene mutations. Direct sequencing of exons 2, 3 and 4 of the gene was performed. Following positive testing of the index cases, samples from other family members were collected and screened. Results: A total of eighteen members deriving from four unrelated Greek families were investigated. In the first family, a novel (heterozygous) mutation in cysteine residue in exon 3 of the TNFRSF1A gene C73Y (c.305G>A) was identified in three members. Interestingly, in the same family a patient carrying the low penetrance TNFRSF1A R92Q mutation, as well as a patient with concomitant R92Q and C73Y mutations were identified. In the second family, the TNFRSF1A C73W (c.306C>G) heterozygous mutation was identified in seven members. In the third family, the TNFRSF1A T50M mutation was detected in two members while in the fourth family six members carried the TNFRSF1A R92Q mutation in heterozygous state. Clinical manifestations amongst members of the affected families were diverse with the most serious being present in patients carrying the TNFRSF1A C73Y, C73W and T50M mutations. Cardinal features included disease onset in childhood (66.7% for C73Y, 85.7% for C73W and 100% for T50M), arthritis (67% for C73Y, 100% for C73W and 100% for T50M), persistent pyrexia (67% for C73Y, 100% for C73W and 100% for T50M), abdominal pain (66.7% for C73Y, 100% for C73W and 100% for T50M), recurrent adhesive ileus (33.3% for C73Y, 14.3% for C73W and 100% for T50M) anterior uveitis (33.3% for C73Y), and diffuse maculopapular rash (14.3% for C73W and 50% for T50M). The clinical presentation was more severe in the patient with concomitant R92Q and C73Y, suggesting an additive effect. On the contrary, (as expected) the disease spectrum associated with R92Q mutation found in six members encompassed a mild phenotype, extending from asymptomatic state (four members) to adult-onset disease associated with intermittent low-grade fever, arthritis and elevated inflammation markers (two members). Conclusion: This was the first pedigree analysis of TRAPS in Greece, depicting four families with unique mutations, along with analysis of the clinical manifestation. The site of mutation might explain the diversity of clinical phenotypes in TRAPS patients that extends from mild to severe disease. In our patients, it appeared that mutations in the cysteine residues as well as in T50M were associated with more severe clinical manifestations. Among these was a novel mutation described for the first time in the literature. Disclosure of Interests: Adrianos Nezos: None declared, Ourania Argyropoulou: None declared, Eleni Klinaki: None declared, Nikolaos Marketos: None declared, KARAGIANNI PANAGIOTA: None declared, Despoina Maritsi: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared, Athanasios Tzioufas Grant/research support from: ABBVIE, PFIZER, AMGEN, NOVARTIS, GSK

Background The role of Nailfold Video Capillaroscopy (NVC) in the identification of patients with Raynaud phenomenon (RP) at risk to develop systemic sclerosis (SSc) is well established. However, it is not clear if certain capillaroscopic indices perform better than others at predicting SSc development and which NVC parameters have a prognostic value in established SSc. Objectives To comparatively assess the performance of different NVC parameters in predicting development of SSc, very early diagnosis of SSc (VEDOSS), or mixed connective tissue disease (MCTD) in patients with RP. Also, to longitudinally examine the consistency of clinical correlations of NVC parameters in SSc patients at two different time points and evaluate the prognostic capacity of NVC in SSc. Methods Consecutive RP patients referred to our department for NVC (138 with SSc, 12 with VEDOSS, 6 with MCTD, 36 with primary RP, and 50 with non-SSc secondary RP) were evaluated at baseline, both clinically and capillaroscopically; 175 were reevaluated after a mean±SD of 3.34±1.48 years. Sixty-two healthy volunteers served as controls. Qualitative assessment of NVC images permitted categorization of patients to a normal, early, active or late capillaroscopic pattern. Capillary loss, dilated, giant or ramified capillaries and micro-hemorrhages were evaluated by a semi-quantitative score (0-3), derived as the mean of three 1mm fields in each of the 2nd, 3rd, 4th and 5th finger of both hands. FVC and DLCO were recorded, if performed within 6 months of NVC. FVC and DLCO deterioration were considered clinically significant if >10% and >15%, respectively. Skin thickening was measured using the modified Rodnan Skin Score (mRSS). MRSS deterioration was considered clinically significant if >3.5. First occurrence of digital ulcers in patients with no prior such history and vital status were also recorded at follow-up. Results Capillary loss score had the highest diagnostic accuracy at discriminating patients with an SSc-spectrum disorder from patients with RP of different etiology and from controls, as defined by ROC curve analysis [AUC (95% CI)=0.925 (0.893-0.956)], followed by dilatation score [AUC (95% CI)=0.904 (0.807- 0.938)] and giant score [AUC (95% CI)=0.856 (0.810-0.902)]. By contrast, micro-hemorrhages [AUC (95% CI)=0.727 (0.669-0.786)] and ramification scores [AUC (95% CI)=0.588 (0.521-0.654)] did not perform equally well. Notably, clinical correlations of capillaroscopic parameters in SSc were found not to be consistent over time, when longitudinally assessed at two different time points by univariate and multivariate analysis. Binary logistic regression analysis indicated that baseline capillaroscopic pattern could predict occurrence of a combined adverse disease outcome (FVC deterioration>10% and/or DLCO deterioration>15% and/or mRSS deterioration>3.5 and/or first occurrence of digital ulcers and/or death), after a mean±SD follow up of 3.28±1.45 years in 94 SSc patients with available follow-up data (OR=3.43, p=0.031 for active versus early pattern, OR=8.778, p=0.007 for late versus early pattern). Conclusion Dilatation score performs best of all semi-quantitative NVC parameters in diagnosing SSc and although clinical correlations of capillaroscopic findings change over time, an active or late capillaroscopy pattern at baseline is associated with an adverse prognosis. Disclosure of Interests Vasiliki-Kalliopi Bournia: None declared, Konstantinos Kottas: None declared, Stylianos Panopoulos: None declared, George Konstantonis: None declared, Alexios Iliopoulos: None declared, Athanasios Tzioufas Grant/research support from: ABBVIE, PFIZER, AMGEN, NOVARTIS, GSK, Petros Sfikakis: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared

Background Identification of the risk factors for the development of serious infections in patients with rheumatoid arthritis (RA) is critical for designing preventive measures and early treatment. Objectives To identify risk factors for serious infections and to validate the RABBIT risk score in RA patients in daily clinical practice. Methods Multicenter, prospective study of RA patients in Greece. Demographics, disease characteristics, treatments and co-morbidities were prospectively collected via a web-based platform at baseline and one year later. The observed incidence of serious infections was compared to the one estimated by the RABBIT score. Results 1.549 RA patients were included (women: 78%, mean age: 63 years, mean disease duration: 10.4 years, RF and/or anti-CCP positive: 54%, mean DAS28: 3.4, mean HAQ: 0.5, bDMARD use: 46%, corticosteroid use: 36%). During follow-up, 38 serious infections were recorded (incidence: 2.3/100 patient-years). Patients who developed a serious infection had longer disease duration (14.2 vs. 10.3 years, p=0.02), higher HAQ at baseline (0.85 vs. 0.5, p=0.006), a history of previous serious infection (26% vs. 10%, p=0.002) and were more likely to have chronic lung disease (23% vs. 9%, p=0.008) or cardiovascular disease (23% vs. 11%, p=0.04). Disease duration (OR: 1.04, CI: 1.01-1.08, p=0.025), history of previous infection (OR: 3.3, CI: 1.3-8.1, p=0.01) and chronic lung disease (OR: 3.03, CI: 1.17-7.85, p=0.023) remained statistical significant in multivariate logistic regression analysis. bDMARD use was not associated with increased risk in uni-or multi-variate analysis. Data for RABBIT score calculation were available in 1.349 patients. Estimated incidence per 100 patient-years was divided in Q1-Q4 quartiles (25-50-75th percentiles: 0.94-1.35-2.15). Estimated and observed incidence rates were in Q1: 0.8 and 0.54, Q2: 1.14 and 0.79, Q3: 1.76 and 1.84 and Q4: 3.7 and 5.6, respectively (Hosmer Lemeshaw test, p=0.9). Conclusion In this large, real life, prospective study of RA patients, the incidence of serious infections was 2.3/100 patient-years. Longer disease duration, history of previous serious infections and chronic lung disease were independently associated with the development of serious infections. RABBIT score predicted rather accurately the risk for serious infections in our cohort. References [1] Zink et al, Ann Rheum Dis. 2014 Sep; 73(9): 1673–1676. Acknowledgement Supported by grants from the Greek Rheumatology Society and Professional Association of Rheumatologists. Disclosure of Interests Konstantinos Thomas: None declared, Argyro Lazarini: None declared, Evripidis Kaltsonoudis: None declared, Alexandros Drosos: None declared, Ioannis Papalopoulos: None declared, Prodromos Sidiropoulos: None declared, Panagiota Tsatsani: None declared, Sousana Gazi: None declared, Lina Pantazi: None declared, Kyriaki Boki: None declared, Pelagia Katsimbri: None declared, Dimitrios Boumpas: None declared, Kalliopi Fragkiadaki: None declared, Maria Tektonidou: None declared, Petros Sfikakis: None declared, Konstantina Karagianni: None declared, Lazaros Sakkas: None declared, Gerasimos Evangelatos: None declared, Alexios Iliopoulos: None declared, Eleftheria Grika: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared, Theodoros Dimitroulas: None declared, Alexandros Garyfallos: None declared, Konstantinos Melissaropoulos: None declared, Panagiotis Georgiou: None declared, Maria Areti: None declared, Constantinos Georganas: None declared, Periklis Vounotrypidis: None declared, Georgios Georgiopoulos: None declared, George D Kitas Speakers bureau: GDK has received honoraria for lectures, participation in advisory boards and/or hospitality by Roche, Abbvie, Pfizer, Novartis, UCB, BMS, GSK and received grant support from Lilly., Dimitrios Vassilopoulos: None declared

The contribution of nailfold video capillaroscopy (NVC) in identifying patients with Raynaud's phenomenon (RP) at risk for systemic sclerosis (SSc) is well established. Herein we comparatively assess the performance of different capillaroscopic parameters in diagnosing SSc among patients with RP and evaluate the prognostic capacity of NVC in SSc.At baseline we clinically and capillaroscopically evaluated 242 consecutive patients referred to our department for NVC (138 with SSc); 175 were reevaluated after 3.38±1.47 years. Sixty-two healthy volunteers served as controls. Capillaroscopy pattern (normal/early/active/late) was qualitatively defined. Capillary loss, dilated, giant or ramified capillaries and micro-haemorrhages were scored semi-quantitatively.Capillary loss score had the highest diagnostic accuracy at discriminating patients with an SSc-spectrum disorder from patients with RP of different etiology and controls, as defined by ROC curve analysis [AUC (95% CI)=0.905 (0.869-0.942)], followed by dilatation score [0.863 (0.818-0.907)] and giant score [0.835 (0.787-0.884)]. By contrast, micro-haemorrhages [0.720 (0.662-0.779)] and ramifications scores [0.604 (0.539-0.670)] performed worse. Multivariate analysis in 94 SSc patients indicated that active (OR=3.305, p=0.043) and late (OR=6.900, p=0.023) baseline capillaroscopy pattern predicted occurrence of a combined adverse disease outcome [forced vital capacity (FVC) deterioration10% and/or DLCO deterioration15% and/or mRSS deterioration3.5 and/or first occurrence of digital ulcers and/or death)] at 3 year follow-up.Dilatation score performs best of all semi-quantitative NVC parameters in diagnosing SSc. In addition, our study confirms earlier reports that worse capillaroscopy pattern at baseline correlates with higher likelihood for adverse prognosis.

A 61-year-old man with a 2-year history of relapsing rheumatoid arthritis (RA), treated with abatacept, presented with dyspnea on effort and right pleuritic chest pain, progressively deteriorating during the past 2 months. On admission the patient had diminished breath sounds, decreased vocal fremitus, and increased …

One of the very first publications showing promising results from the blockade of interleukin-6 signalling by the use of tocilizumab in patients with severe COVID-19 was that of Ramiro et al in July 2020, during the first wave of the pandemic.1 However, the results from further studies and randomised controlled trials regarding this issue hitherto remain inconclusive.2–7 To further support the work done by Ramiro et al (as well as those of other researchers), we would like to report the successful use of a single dose of intravenous 8 mg/kg tocilizumab in our department as a compassionate treatment in three consecutive patients during the second wave of the pandemic. These patients exhibited a rapid (within 24–72 hours) respiratory deterioration, despite already receiving the maximum indicated treatment. The administration of tocilizumab halted the further deterioration of these patients and prevented them from being intubated. Patient 1, a middle-aged overweight man with medical history of arterial hypertension, presented to the emergency room (ER) on day 8 after initiation of COVID-19 symptoms, due to dyspnoea. He was tachypneic (respiratory ratio (RR)=25 breaths/min), while receiving 3 L/min of oxygen via a nasal cannula (arterial oxygen partial pressure (pO2)/fraction of inspired oxygen (FiO2)=216.6 mm Hg). His laboratory tests showed increased C reactive protein (CRP) …

ObjectiveTo investigate the pathophysiologic mechanism of encephalopathy and prolonged comatose or stuporous state in severally ill patients with coronavirus disease 2019 (COVID-19).MethodsEight COVID-19 patients with signs of encephalopathy were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the serum and CSF using a Food and Drug Administration-approved and independently validated ELISA. Blood-brain barrier (BBB) integrity and immunoglobulin G (IgG) intrathecal synthesis were further tested using albumin and IgG indices. The CSF was also tested for autoimmune encephalitis antibodies and 14-3-3, a marker of ongoing neurodegeneration.ResultsAll patients had anti–SARS-CoV-2 antibodies in their CSF, and 4 of 8 patients had high titers, comparable to high serum values. One patient had anti–SARS-CoV-2 IgG intrathecal synthesis, and 3 others had disruption of the blood-brain barrier. The CSF in 4 patients was positive for 14-3-3-protein suggesting ongoing neurodegeneration. In all patients, the CSF was negative for autoimmune encephalitis antibodies and SARS-CoV-2 by PCR. None of the patients, apart from persistent encephalopathic signs, had any focal neurologic signs or history or specific neurologic disease.ConclusionsHigh-titer anti-SARS-CoV-2 antibodies were detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or BBB disruption. A disrupted BBB may facilitate the entry of cytokines and inflammatory mediators into the CNS enhancing neuroinflammation and neurodegeneration. The observations highlight the need for prospective CSF studies to determine the pathogenic role of anti–SARS-CoV-2 antibodies and identify early therapeutic interventions.

This chapter presents essential knowledge on systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and mixed connective tissue disease (MCTD). These diseases share common features in the sense that they are systemic, can be overlapping, and present with nondestructive arthritis.

Therapy of systemic autoimmune rheumatic diseases can still be a challenge for clinicians despite enormous progress made in the last decades on the understanding of the pathophysiological mechanisms involved in these diseases. The use of biologic targeted therapies as an adjunct to disease-modifying antirheumatic drugs (DMARDs) for the treatment of autoimmune rheumatic diseases has completely changed standard of care and is still expanding.

Autoimmune diseases present with a wide range of symptoms able to affect nearly all body organs. Differential diagnosis of these symptoms can be difficult, as a particular presenting symptom may be encountered in distinct autoimmune diseases, and at the same time many non-rheumatic diseases may share similar clinical manifestations. In the large overlapping field of infections and rheumatology, many autoimmune diseases may present as fever of unknown origin, and on the other hand, many different infectious agents cause signs and symptoms mimicking a systemic autoimmune disease. Clinical manifestations affecting the skin and its annexes, oral cavity, joints, and periarticular structures but also major organs such as the heart and vascular system, lung, liver, spleen, and gastrointestinal tract can be initial symptoms of a systemic autoimmune disease. The good knowledge of underlying pathogenetic mechanisms of particular clinical manifestations, the thorough physical examination, and the accurate use and interpretation of laboratory, serological, and imaging findings are necessary skills in overcoming the challenging differential diagnosis.