Presence of coronary aneurysms during Kawasaki Disease (KD) correlates with lower levels of autoantibodies to both full form and spliced variant of immune regulator Del-1.

Kawasaki disease (KD), a rare multisystem inflammatory condition that predominantly affects children under six years of age, is the leading cause of childhood-acquired heart disease in developed countries. The pathogenesis is unknown, but studies support that an infectious stimulus triggers an autoimmune reaction in a genetically susceptible child. Recent studies demonstrated an association with autoantibody response to Del-1 (also known as EDIL3) in children with KD. Del-1 is an extracellular matrix protein that is expressed both in macrophages and vascular endothelium. Del-1 has an anti-inflammatory role by preventing leucocyte migration to inflammatory sites. Del-1 has two expression variants and genetic variants of Del-1 have been associated with the risk of intracranial aneurysms. Due to the physiologic plausibility for a role during KD, we chose to assess if autoantibodies against DEL-1 are seen in a larger cohort of children with KD and to assess if responses correlated to aneurysm formation. Contrary to prior findings, in comparison to febrile controls, autoantibodies were not overall higher in children with KD. Elevation in Post-IVIG samples in comparison to pre-IVIG and convalescent samples supports the commonality of anti-Del-1 antibodies. Autoantibodies were notably lower in children with KD who had coronary Z score elevations in comparison to those who did not.

The mosaic of autoimmunity and autoinflammation and SARS-CoV-2 as an environmental factor

The "Severe Acute Respiratory Syndrome-related Coronavirus type 2” (SARS-CoV-2), the infectious agent responsible for the still ongoing "Coronavirus Disease 2019” (COVID-19) pandemic, represents a major environmental trigger and an important piece of the mosaic of autoimmunity and autoinflammation. Several de novo-onset or flares/relapses of autoimmune/autoinflammatory diseases have been reported associated either directly or indirectly with the viral agent. COVID-19 has represented a unique opportunity for shedding new light and unexpected insights on autoimmune/autoinflammatory diseases. These have, in turn, enabled the discovery of novel aspects of the COVID-19 infection, offering already approved, effective and safe drugs, as options to be repurposed in the fight against the novel coronavirus. However, there is still a dearth of information concerning the long-term impact of the virus on autoimmunity and autoinflammation - the so-called long-COVID or postCOVID, which warrants further investigation. © 2023 Elsevier Inc. All rights reserved.

Immunopharmacology/Musculoskeletal System Pharmacology: Overview

The rapid technological advancement over the past few decades has profoundly influenced the scientific approaches that shape the therapeutic landscape. Undoubtedly, immunopharmacology is an important player in the modern era of transition toward precision medicine that is largely defined by the identification of patient-specific therapies. According to the Immunopharmacology Section - ImmuPhar of the International Union of Basic and Clinical Pharmacology (IUPHAR), immunopharmacology is considered to be the youngest area of pharmacology dealing with the selective modulation, mostly up- or down-regulation, of specific immune responses that are often accomplished by immune cell subsets with specialized functions. Although the recent biotechnological progress has made available new classes of drugs with improved selectivity and/or specificity, agents possessing immunomodulating activities have been used in clinical practice for more than 70years. A pertinent example from the late 1940s is the counteraction of the inflammatory response upon administration of cortisone in patients with rheumatoid arthritis. © 2022 Elsevier Inc. All rights reserved

Leflunomide: Traditional immunosuppressant with concurrent antiviral effects.

Leflunomide is a classic disease-modifying anti-rheumatic drug that is widely used to treat autoimmune diseases. Studies also show its antiviral effects in in vitro and/or in vivo experiments. Considering glucocorticoids, immunosuppressants and newly emerged antibodies commonly used in autoimmune diseases and autoinflammatory disorders bring risk of infection such as viral infection, leflunomide with combination of anti-viral and immunosuppressive features to maintain the balance between infection and anti-inflammation are attractive. Here we summarize the actions and mechanisms of leflunomide in immunoregulatory and antiviral effects.

Potential health risks of mRNA-based vaccine therapy: A hypothesis.

Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.

Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

Bilateral Orbital Inflammation Associated with COVID-19 Infection: A Case Report and Brief Review of the Literature

A 31-year-old woman with no history of systemic autoimmune disease developed bilateral pain, redness, periorbital edema, and proptosis while being hospitalized for mild coronavirus disease 2019 (COVID-19) pneumonia. The onset of ocular symptoms occurred six days after systemic COVID-19 symptoms. Computed tomography examination of the orbit revealed diffuse inflammation involving multiple orbital structures. A complete systemic workup was performed to exclude other systemic inflammatory diseases. She was initially diagnosed with probable orbital cellulitis secondary to sinusitis. However, she did not improve with antibiotic therapy. Empirical administration of systemic corticosteroids led to a dramatic clinical response. The patient has been maintained on a gradual steroid taper without inflammation relapse. This article describes a potential causal association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and orbital inflammation. Ophthalmologists should be aware of this presentation when assessing patients with COVID-19 who present with orbital inflammatory symptoms. © 2022 JHSMR. Hosted by Prince of Songkla University. All rights reserved.

Comprehensive description of adult-onset Still's disease after COVID-19 vaccination.

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management.

Spectrum of Large- and Medium-Vessel Vasculitis in Adults: Neoplastic, Infectious, Drug-Induced, Autoinflammatory, and Primary Immunodeficiency Diseases.

PURPOSE OF REVIEW: To provide a comprehensive review of drugs and neoplastic, infectious, autoinflammatory, and immunodeficiency diseases causing medium- to large-vessel vasculitis in adults with emphasis on information essential for the initial diagnostic process. RECENT FINDINGS: Entities with medium- to large-vessel vasculitis as clinical manifestations have been described recently (e.g., adenosine deaminase-2 deficiency, VEXAS-Syndrome), and vasculitis in established autoinflammatory or immunodeficiency diseases is increasingly being identified. In the diagnostic process of medium- to large-vessel vasculitis in adults, a large variety of rare diseases should be included in the differential diagnosis, especially if diagnosis is made without histologic confirmation and in younger patients. Although these disorders should be considered, they will undoubtedly remain rare in daily practice.

Coronavirus Infection 2019 (COVID-19) and Autoimmunity.

The pandemic of coronavirus disease 2019, etiologically associated with the SARS-CoV-2 virus, has drawn the attention of the medical community to new clinical and fundamental problems in the immunopathology of human diseases. During a detailed analysis of the clinical manifestations and immunopathological disorders in COVID-19, it became apparent that SARS-CoV-2 infection is accompanied by the development of a wide range of extrapulmonary clinical and laboratory disorders, some of which are characteristic of immunoinflammatory rheumatic diseases and other human autoimmune and autoinflammatory diseases. All this taken together served as a theoretical justification for the repositioning of anti-inflammatory drugs in COVID-19, previously specifically designed for the treatment of immunoinflammatory rheumatic diseases. The prospects for studying the autoimmune mechanisms of COVID-19 and the possibility of anti-inflammatory therapy are discussed.

Central nervous system manifestations of monogenic autoinflammatory disorders and the neurotropic features of SARS-CoV-2: Drawing the parallels.

Central nervous system (CNS) involvement in monogenic autoinflammatory disorders (AID) is increasingly recognized and can be life threatening. Therefore, a low threshold to consider CNS disease should be maintained in patients with systemic inflammation. Hyperinflammation is also a key feature of severe acute COVID-19 and post COVID-19 entities such as multisystem inflammatory syndrome in children. Like AID, COVID-19 patients can present with severe CNS involvement. The impact of COVID-19 on AID and CNS involvement in particular is still obscure, nevertheless dreaded. In the current review, we synthesize the spectrum of CNS manifestations in monogenic AID. We explore common pathophysiological and clinical features of AID and COVID-19. Moreover, we assess the impact of immune dysregulation associated with SARS-CoV-2 infections and post COVID-19 hyperinflammation in AID. The striking commonalities found between both disease entities warrant caution in the management of AID patients during the current pandemic.

Clinical impact and disease evolution of SARS-CoV-2 infection in familial Mediterranean fever.

The innate immune system is critically involved in the pathogenesis of familial Mediterranean fever (FMF), characterized by dysregulated inflammasome activity and recurrent inflammatory attacks: this is the most common among monogenic autoinflammatory diseases, which shares some biochemical pathways with the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. In this short review we explore the overlap in the pathophysiology of FMF and SARS-CoV-2 infection, discussing how to understand better the interaction between the two diseases and optimize management. A poorer outcome of SARS-CoV-2 infection seems not to be present in infected FMF patients in terms of hospitalization time, need for oxygen support, need for intensive care, rate of complications and exitus. Long-term surveillance will confirm the relatively low risk of a worse prognosis observed so far in SARS-CoV-2-infected people with FMF. In these patients COVID-19 vaccines are recommended and their safety profile is expected to be similar to the general population.

Implications of SARS-CoV-2 Infection in Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is a serious multifactorial autoinflammatory disease with a significant mortality rate due to macrophage activation syndrome (MAS). Recent research has deepened the knowledge about the pathophysiological mechanisms of sJIA-MAS, facilitating new targeted treatments, and biological disease-modifying antirheumatic drugs (bDMARDs), which significantly changed the course of the disease and prognosis. This review highlights that children are less likely to suffer severe COVID-19 infection, but at approximately 2-4 weeks, some cases of multisystem inflammatory syndrome in children (MIS-C) have been reported, with a fulminant course. Previous established treatments for cytokine storm syndrome (CSS) have guided COVID-19 therapeutics. sJIA-MAS is different from severe cases of COVID-19, a unique immune process in which a huge release of cytokines will especially flood the lungs. In this context, MIS-C should be reinterpreted as a special MAS, and long-term protection against SARS-CoV-2 infection can only be provided by the vaccine, but we do not yet have sufficient data. COVID-19 does not appear to have a substantial impact on rheumatic and musculoskeletal diseases (RMDs) activity in children treated with bDMARDs, but the clinical features, severity and outcome in these patients under various drugs are not yet easy to predict. Multicenter randomized controlled trials are still needed to determine when and by what means immunoregulatory products should be administered to patients with sJIA-MAS with a negative corticosteroid response or contraindications, to optimize their health and safety in the COVID era.

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation.

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.

[Colchicine: old medication with new benefits : Use in rheumatology and beyond]. / Colchicin: altes Medikament mit neuem Nutzen : Einsatz in der Rheumatologie und darüber hinaus.

Colchicine, the toxin of the autumn crocus, has various anti-inflammatory effects. For this reason, it is being used for the treatment of several autoinflammatory diseases, such as gout or familial Mediterranean fever (FMF). In addition, some interesting studies have been published which suggest the benefits of colchicine in cardiovascular diseases. Furthermore, various anti-inflammatory therapeutic approaches are currently being tested in clinical trials for the treatment of COVID-19. First publications suggest a potential benefit of colchicine in certain disease phases of the virus infection. This article provides an overview of the mechanisms of action, benefits and side effects as well as the various possible uses of colchicine in rheumatology. Furthermore, a brief preview of potential new areas for use of the drug, which are also of interest to rheumatologists, are presented.

The Influence of Immune Immaturity on Outcome After Virus Infections.

Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.

Inflammasomes and Childhood Autoimmune Diseases: A Review of Current Knowledge.

Inflammasomes are multiprotein complexes capable of sensing pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and cellular perturbations. Upon stimulation, the inflammasomes activate the production of the pro-inflammatory cytokines IL-1ß and IL-18 and induce gasdermin D-mediated pyroptosis. Dysregulated inflammasome signaling could lead to hyperinflammation in response to environmental triggers, thus contributing to the pathogenesis of childhood autoimmune/autoinflammatory diseases. In this review, we group childhood rheumatic diseases into the autoinflammation to autoimmunity spectrum and discuss about the involvement of inflammasomes in disease mechanisms. Genetic mutations in inflammasome components cause monogenic autoinflammatory diseases, while inflammasome-related genetic variants have been implicated in polygenic childhood rheumatic diseases. We highlight the reported associations of inflammasome signaling-related genetic polymorphisms/protein levels with pediatric autoimmune disease susceptibility and disease course. Furthermore, we discuss about the use of IL-1 receptor antagonist as an adjunctive therapy in several childhood autoimmune diseases, including macrophage activation syndrome (MAS) and multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. A comprehensive multi-cohort comparison on inflammasome gene expression profile in different pediatric rheumatic diseases is needed to identify patient subsets that might benefit from the adjunctive therapy of IL-1ß inhibitors.