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The New England Journal of Medicine Dec 2020Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory...
BACKGROUND
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
METHODS
We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.
RESULTS
We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
CONCLUSIONS
Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Topics: Age of Onset; Aged; Aged, 80 and over; Autoimmune Diseases; Cytokines; Exome; Genetic Diseases, X-Linked; Genotype; Giant Cell Arteritis; Humans; Immunoblotting; Inflammation; Male; Middle Aged; Multiple Myeloma; Mutation, Missense; Myelodysplastic Syndromes; Polyarteritis Nodosa; Polychondritis, Relapsing; Sequence Analysis, DNA; Sweet Syndrome; Syndrome; Ubiquitin-Activating Enzymes
PubMed: 33108101
DOI: 10.1056/NEJMoa2026834 -
Heart (British Cardiac Society) Oct 2021Broadly defined, aortitis refers to inflammation of the aorta and incorporates both infectious and non-infectious aetiologies. As advanced imaging modalities are... (Review)
Review
Broadly defined, aortitis refers to inflammation of the aorta and incorporates both infectious and non-infectious aetiologies. As advanced imaging modalities are increasingly incorporated into clinical practice, the phenotypic spectrum associated with aortitis has widened. The primary large vessel vasculitides, giant cell arteritis and Takayasu arteritis, are the most common causes of non-infectious aortitis. Aortitis without systemic disease or involvement of other vascular territories is classified as clinically isolated aortitis. Periaortitis, where inflammation spreads beyond the aortic wall, is an important disease subset with a distinct group of aetiologies. Infectious aortitis can involve bacterial, viral or fungal pathogens and, while uncommon, can be devastating. Importantly, optimal management strategies and patient outcomes differ between aortitis subgroups highlighting the need for a thorough diagnostic workup. Monitoring disease activity over time is also challenging as normal inflammatory markers do not exclude significant vascular inflammation, particularly after starting treatment. Additional areas of unmet clinical need include clear disease classifications and improved short-term and long-term management strategies. Some of these calls are now being answered, particularly with regard to large vessel vasculitis where our understanding has advanced significantly in recent years. Work extrapolated from temporal artery histology has paved the way for targeted biological agents and, although glucocorticoids remain central to the management of non-infectious aortitis, these may allow reduced glucocorticoid reliance. Future work should seek to clarify disease definitions, improve diagnostic pathways and ultimately allow a more stratified approach to patient management.
Topics: Aorta; Aortitis; Humans; Tomography, X-Ray Computed
PubMed: 33593995
DOI: 10.1136/heartjnl-2020-318085 -
Veterinary Journal (London, England :... 2023Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle,... (Review)
Review
Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle, SRMA is divided into two clinical courses: during the typical acute form, dogs are presented with fever, cervical hyperaesthesia, and reluctance to move. The more protracted form most probably emerges after insufficient immunosuppressive treatment or relapses, with additional neurologic deficits localized in the cervical and thoracolumbar spinal cord or multifocally. The trigger leading to SRMA still remains an unsolved riddle for immunologists and clinical neurologists. In the past, many attempts have been made to clarify the etiology of this disease without success. The purpose of writing this narrative review about SRMA is to summarize new insights on the pathogenesis of SRMA with a focus on immunologic dysregulation. Furthermore, unusual manifestations of the disease, new diagnostic approaches using possible laboratory biomarkers or diagnostic imaging tools, and potential innovative treatment strategies are discussed.
Topics: Animals; Dogs; Meningitis; Arteritis; Biomarkers; Steroids; Dog Diseases
PubMed: 37704169
DOI: 10.1016/j.tvjl.2023.106030 -
Annals of Laboratory Medicine Jul 2019The platelet-to-lymphocyte ratio (PLR) has emerged as an informative marker revealing shifts in platelet and lymphocyte counts due to acute inflammatory and... (Review)
Review
The platelet-to-lymphocyte ratio (PLR) has emerged as an informative marker revealing shifts in platelet and lymphocyte counts due to acute inflammatory and prothrombotic states. PLR has been extensively examined in neoplastic diseases accompanied by immune suppression and thrombosis, which can be predicted by combined blood cell counts and their ratios. Several large observational studies have demonstrated the value of shifts in PLR in evaluating the severity of systemic inflammation and predicting infections and other comorbidities, in inflammatory rheumatic diseases. The value of PLR as an inflammatory marker increases when its fluctuations are interpreted along with other complementary hematologic indices, particularly the neutrophil-to-lymphocyte ratio (NLR), which provides additional information about the disease activity, presence of neutrophilic inflammation, infectious complications, and severe organ damage in systemic lupus erythematosus. PLR and NLR have high predictive value in rheumatic diseases with predominantly neutrophilic inflammation (e.g., Behçet disease and familial Mediterranean fever). High PLR, along with elevated platelet count, is potentially useful in diagnosing some systemic vasculitides, particularly giant-cell arteritis. A few longitudinal studies on rheumatic diseases have demonstrated a decrease in PLR in response to anti-inflammatory therapies. The main limitations of PLR studies are preanalytical faults, inadequate standardization of laboratory measurements, and inappropriate subject selection. Nonetheless, accumulating evidence suggests that PLR can provide valuable information to clinicians who encounter multisystem manifestations of rheumatic diseases, which are reflected in shifts in platelet, lymphocyte, neutrophil, or monocyte counts. Interpretation of PLR combined with complementary hematologic indices is advisable to more accurately diagnose inflammatory rheumatic diseases and predict related comorbidities.
Topics: Anti-Inflammatory Agents; Biomarkers; Blood Platelets; Giant Cell Arteritis; Humans; Lymphocytes; Neoplasms; Rheumatic Diseases
PubMed: 30809980
DOI: 10.3343/alm.2019.39.4.345 -
Best Practice & Research. Clinical... Mar 2023The recent publication of the American College of Rheumatology (ACR)-European Alliance of Associations for Rheumatology (EULAR) classification criteria for large vessel... (Review)
Review
The recent publication of the American College of Rheumatology (ACR)-European Alliance of Associations for Rheumatology (EULAR) classification criteria for large vessel vasculitis and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) has provided modern criteria for the classification of these conditions, which incorporate contemporary methods of investigation and diagnosis. Further validation is required in independent cohorts, especially from populations that were not well represented in the development cohort. Studies of the occurrence of large vessel vasculitis report that Takayasu arteritis is a rare disease in most populations, and giant cell arteritis is the most common vasculitis in older populations. The incidence of AAV appears to have plateaued, but the prevalence is increasing as a result of lower mortality. The new classification criteria may affect the reported incidence and prevalence, and studies will be needed to confirm this. The impact of COVID-19 on the occurrence of the vasculitides is not completely known, but there is evidence of reduced occurrence of Kawasaki disease and IgA-associated vasculitis following lockdowns with reduced transmission of possible trigger infectious agents.
Topics: Humans; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Giant Cell Arteritis; Takayasu Arteritis; Rheumatology
PubMed: 37468418
DOI: 10.1016/j.berh.2023.101845 -
Autophagy Dec 2020The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is the most recent example of an emergent coronavirus that poses a significant threat to human health. Virus-host... (Review)
Review
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is the most recent example of an emergent coronavirus that poses a significant threat to human health. Virus-host interactions play a major role in the viral life cycle and disease pathogenesis, and cellular pathways such as macroautophagy/autophagy prove to be either detrimental or beneficial to viral replication and maturation. Here, we describe the literature over the past twenty years describing autophagy-coronavirus interactions. There is evidence that many coronaviruses induce autophagy, although some of these viruses halt the progression of the pathway prior to autophagic degradation. In contrast, other coronaviruses usurp components of the autophagy pathway in a non-canonical fashion. Cataloging these virus-host interactions is crucial for understanding disease pathogenesis, especially with the global challenge of SARS-CoV-2 and COVID-19. With the recognition of autophagy inhibitors, including the controversial drug chloroquine, as possible treatments for COVID-19, understanding how autophagy affects the virus will be critical going forward. : 3-MA: 3-methyladenine (autophagy inhibitor); AKT/protein kinase B: AKT serine/threonine kinase; ATG: autophagy related; ATPase: adenosine triphosphatase; BMM: bone marrow macrophage; CGAS: cyclic GMP-AMP synthase; CHO: Chinese hamster ovary/cell line; CoV: coronaviruses; COVID-19: Coronavirus disease 2019; DMV: double-membrane vesicle; EAV: equine arteritis virus; EDEM1: ER degradation enhancing alpha-mannosidase like protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; GFP: green fluorescent protein; HCoV: human coronavirus; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IBV: infectious bronchitis virus; IFN: interferon; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCoV: mouse coronavirus; MERS-CoV: Middle East respiratory syndrome coronavirus; MHV: mouse hepatitis virus; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2 (autophagy receptor that directs cargo to phagophores); nsp: non-structural protein; OS9: OS9 endoplasmic reticulum lectin; PEDV: porcine epidemic diarrhea virus; PtdIns3K: class III phosphatidylinositol 3-kinase; PLP: papain-like protease; pMEF: primary mouse embryonic fibroblasts; SARS-CoV: severe acute respiratory syndrome coronavirus; SKP2: S-phase kinase associated protein 2; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; ULK1: unc-51 like autophagy activating kinase 1; Vps: vacuolar protein sorting.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; CHO Cells; COVID-19; Coronavirus; Coronavirus Infections; Cricetinae; Cricetulus; Humans; Mice; Pandemics; SARS-CoV-2; Signal Transduction
PubMed: 32964796
DOI: 10.1080/15548627.2020.1817280 -
Cardiovascular Diagnosis and Therapy Apr 2018Aortitis is aortic inflammation, which can be due to inflammatory or infectious diseases. Left undiagnosed, aortitis can lead to aneurysm formation and rupture, in... (Review)
Review
Aortitis is aortic inflammation, which can be due to inflammatory or infectious diseases. Left undiagnosed, aortitis can lead to aneurysm formation and rupture, in addition to ischemic compromise of major organs. Infectious aortic diseases include mycotic aneurysm and graft infection; the most common inflammatory diseases are Takayasu's and giant cell arteritis. We review the epidemiology, etiology, presentation and diagnosis, and treatment of these entities.
PubMed: 29850419
DOI: 10.21037/cdt.2017.09.03 -
Annals of the Rheumatic Diseases Jun 2023Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be...
BACKGROUND
Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.
METHODS
A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.
RESULTS
The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.
CONCLUSIONS
The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.
Topics: Adult; Humans; Arthritis, Rheumatoid; COVID-19; Interleukin-6; Receptors, Interleukin-6; Still's Disease, Adult-Onset; Inflammation
PubMed: 35953263
DOI: 10.1136/ard-2022-222784 -
Pediatric Nephrology (Berlin, Germany) Sep 2010Medium-size-artery vasculitides do occur in childhood and manifest, in the main, as polyarteritis nodosa (PAN), cutaneous PAN and Kawasaki disease. Of these, PAN is the... (Review)
Review
Medium-size-artery vasculitides do occur in childhood and manifest, in the main, as polyarteritis nodosa (PAN), cutaneous PAN and Kawasaki disease. Of these, PAN is the most serious, with high morbidity and not inconsequential mortality rates. New classification criteria for PAN have been validated that will have value in epidemiological studies and clinical trials. Renal involvement is common and recent therapeutic advances may result in improved treatment options. Cutaneous PAN is a milder disease characterised by periodic exacerbations and often associated with streptococcal infection. There is controversy as to whether this is a separate entity or part of the systemic PAN spectrum. Kawasaki disease is an acute self-limiting systemic vasculitis, the second commonest vasculitis in childhood and the commonest cause of childhood-acquired heart disease. Renal manifestations occur and include tubulointerstitial nephritis and renal failure. An infectious trigger and a genetic predisposition seem likely. Intravenous immunoglobulin (IV-Ig) and aspirin are effective therapeutically, but in resistant cases, either steroid or infliximab have a role. Greater understanding of the pathogenetic mechanisms involved in these three types of vasculitis and better long-term follow-up data will lead to improved therapy and prediction of prognosis.
Topics: Child; Child, Preschool; Disease Progression; Female; Heart Diseases; Humans; Kidney Diseases; Male; Mucocutaneous Lymph Node Syndrome; Polyarteritis Nodosa; Treatment Outcome
PubMed: 19946711
DOI: 10.1007/s00467-009-1336-1 -
Reumatismo Mar 2018Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant... (Review)
Review
Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.
Topics: Adaptive Immunity; Aged; B-Lymphocytes; Biomarkers; Cell Differentiation; Evidence-Based Medicine; Giant Cell Arteritis; Humans; Immunity, Innate; Polymyalgia Rheumatica; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 29589398
DOI: 10.4081/reumatismo.2018.1048