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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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is a heterogeneous disease with a complex and yet not fully understood pathophysiology, where numerous different cell-types contribute to a destructive process of the joints. This complexity results into a considerable interpatient variability in clinical course and severity, which may additionally involve genetics and/or environmental factors. After three decades of focused efforts scientists have now achieved to apply in clinical practice, for patients with RA, the "treat to target" approach with initiation of aggressive therapy soon after diagnosis and escalation of the therapy in pursuit of clinical remission. In addition to the conventional synthetic disease modifying anti-rheumatic drugs, biologics have greatly improved the management of RA, demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion, and preventing loss of function. Nonetheless, despite the plethora of therapeutic options and their combinations, unmet therapeutic needs in RA remain, as current therapies sometimes fail or produce only partial responses and/or develop unwanted side-effects. Unfortunately the mechanisms of 'nonresponse' remain unknown and most probable lie in the unrevealed heterogeneity of the RA pathophysiology. In this review, through the effort of unraveling the complex pathophysiological pathways, we will depict drugs used throughout the years for the treatment of RA, the current and future biological therapies and their molecular or cellular targets and finally will suggest therapeutic algorithms for RA management. With multiple biologic options, there is still a need for strong predictive biomarkers to determine which drug is most likely to be effective, safe, and durable in a given individual. The fact that available biologics are not effective in all patients attests to the heterogeneity of RA, yet over the long term, as research and treatment become more aggressive, efficacy, toxicity, and costs must be balanced within the therapeutic equation to enhance the quality of life in patients with RA., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Platelet factor 4 tetramers (CXCL4 chemokine) form complexes with β2glycoprotein I (β2GPI), recognized by anti-β2GPI antibodies leading to platelet activation in antiphospholipid syndrome (APS), either primary (PAPS) or secondary (SAPS). Increased plasma levels of CXCL4 may favor this process; therefore we measured plasma levels of CXCL4, a CXCL4 variant (CXCL4L1) and as controls, platelet-derived chemokines CXCL7 (NAP-2) and CCL5 (RANTES), in APS, and disease controls such as patients with systemic lupus erythematosus (SLE) coronary artery disease (CAD) and healthy donors (HDs)., Methods: Plasma samples and platelets were isolated from patients with APS (n = 87), SLE (n = 29), CAD (n = 14) and 54 HDs. Plasma levels of CXCL4, CXCL4L1, CXCL7 and CCL5 as well as intracellular platelet CXCL4 and CXCL4L1 were measured using ELISA. Platelet CXCL4 and CXCL4L1 RNA levels were determined by RT-PCR., Results: CXCL4, CXCL7 (NAP-2) and CCL5 (RANTES) plasma levels were significantly higher in patients with APS compared to both control groups (SLE, CAD) and HDs. CXCL4L1 plasma levels were also significantly higher in APS than in SLE and HDs, but lower from that of CAD patients. Statistically significant concordance was detected between CXCL4 and CXCL7 (p < 0.0001) or CCL5 (p < 0.0001) plasma levels in patients with APS, either PAPS or SAPS. CXCL4L1 plasma levels were inversely correlated with CXCL4 (P = 0.0027), CXCL7 (p = 0.012) and CCL5 (p = 0.023) in PAPS and positively with CXCL4 (p = 0.0191), CCL5 (p < 0.0001) and CXCL7 (P < 0.0001), in SAPS. Levels of CXCL4, CXCL4L1, CXCL7 and CCL5 were divided in "high" (exceeding a level defined as the mean of HDs and 3 SD) and "low" (below this level); The "CXCL4L1 high" group was characterized by increased IgG aCL, (p = 0.0215), double antibody positivity (either aCL or anti-β2GPI plus LA), (p = 0.0277), triple antibody positivity (aCL plus anti-β2GPI plus LA), (p = 0.0073) and thrombocytopenia (p = 0.0061), as well as with at least 1 thrombotic event or the last 5 years (p = 0.0001), or more than 3 thrombotic events ever (p = 0.0151)., Conclusions: Chemokines associated with platelet activation and immune cell chemotaxis were found to be elevated in APS patients' plasma and may contribute to the pathogenesis of the syndrome. High CXCL4L1 plasma levels are associated with the clinical expression of APS and should be prospectively evaluated as a biomarker., (Copyright © 2015. Published by Elsevier Ltd.)

Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Antiphospholipid antibody syndrome (APS) is an autoimmune thrombophilia mediated by autoantibodies directed against phospholipid-binding plasma proteins, mainly β2 Glycoprotein I (β2GPI)-a plasma apolipoprotein and prothrombin (PT). A subgroup of these antibodies termed "Lupus Anticoagulant" (LA) elongate in vitro the clotting times, this elongation not corrected by adding normal plasma in the detection system. The exact mechanism by which these autoantibodies induce thrombosis is not well understood. Resistance to natural anticoagulants such as protein C, impaired fibrinolysis, activation of endothelial cells to a pro-coagulant phenotype and activation of platelets, are among the mechanisms partially supported by experimental evidence. Artificially dimerized β2GPI binds tightly to platelet membrane activating them. We search for mechanisms of natural dimerization of β2GPI by proteins of the platelet membranes and found that platelet factor 4 (PF4) assembled in homotetramers binds two molecules of β2GPI and this complex is recognized by anti-β2GPI antibodies, the whole complexes being thrombogenic in terms of activating platelets as confirmed by p38MAP kinase phosphorylation and thromboxane B2 production. Of note PF4/heparin complexes are also immunogenic triggering the production of anti-PF4/heparin antibodies which activate also platelets (the so-called "heparin-induced thrombocytopenia and thrombosis syndrome", HITT). The anti-β2GPI antibodies activate platelets by their F(ab)2, while the anti-PF4/heparin by their Fc fragments. Thus PF4 is a common denominator in the pathogenesis of APS and HITT which share also clinical characteristics such as thrombocytopenia and thrombosis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The heterogeneity of autoantibody specificities occurring in sera from patients with systemic sclerosis (SSc) raised the necessity of developing various methodologies for their detection. A cohort of 150 SSc patients were selected and tested by Indirect Immunofluorescence (IIF), Counterimmunoelectrophoresis (CIE), Immunoblot (IB) using various extracts as antigenic source and RNA precipitation. By preparing a nuclear (IB-nuclear) and a metaphase chromosomal-enriched extract (IB-MC-pellet) from HeLa cells as well as a nucleolar (IB-nucleolar) and a histone (IB-histone) extract from rat liver nuclei, we assessed their sensitivity and specificity for anti-Topo I, anti-U3RNP, anti-H1, anti-snRNPs antibodies and ACA. IB-nuclear revealed the highest frequency of anti-Topo I antibodies, while CIE, IB-nucleolar and IB-MC-pellet, when compared to IB-nuclear showed a sensitivity of 89%, 87% and 95%, respectively. IB-MC-pellet was unique for ACA recognition, while IB-nucleolar and IB-MC-pellet showed excellent sensitivity for anti-U3RNP and anti-H1 antibody detection. We conclude that IB-nuclear is a highly sensitive system for anti-Topo I antibodies determination, but CIE reveals a good sensitivity to be used as a first screening test. IB-nucleolar or IB-MC-pellet are important techniques to detect the variety of antibodies to nucleolus and chromatin-related constituents. A novel specificity against a 28kD nucleolar protein, non-associated with RNAs is also presented.