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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 -
Yonsei Medical Journal Jan 2023Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises group of small vessel vasculitides, including granulomatosis with polyangiitis (GPA),... (Review)
Review
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises group of small vessel vasculitides, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In 2022, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) jointly proposed new classification criteria for AAV (the 2022 ACR/EULAR criteria). In this review, we briefly summarize the 2022 ACR/EULAR criteria for GPA, MPA, and EGPA, and introduce our clinical experience with applying them to patients who were previously diagnosed with AAV based on three criteria: firstly, the classification criteria for GPA and EGPA proposed by the ACR in 1990; secondly, the algorithm for the classification of AAV and polyarteritis nodosa proposed by the European Medicines Agency algorithm in 2007 (the 2007 EMA algorithm); and thirdly, the revised International Chapel Hill Consensus Conference nomenclature of vasculitides in 2012 (the 2012 CHCC definitions). We found that concordance rate was highest in patients with MPA (96.6%), followed by those with EGPA (86.3%) and GPA (73.8%). In addition, compared to previous criteria, we noted several issues of the undervalued or overvalued items in the 2022 ACR/EULAR criteria for classifying AAV and provided several suggestions. To increase the diagnostic accuracy and reduce the discordance rate among the new and previous criteria for AAV, we suggest that the previous criteria should be considered together with the 2022 ACR/EULAR criteria when applying the classification criteria for AAV to patients suspected of AAV.
Topics: Humans; United States; Granulomatosis with Polyangiitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Rheumatology; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis
PubMed: 36579374
DOI: 10.3349/ymj.2022.0435 -
Frontiers in Medicine 2022Vasculitis is an inflammatory disorder of the blood vessels that causes damage to a wide variety of organs through tissue ischemia. Vasculitis is classified according to... (Review)
Review
Vasculitis is an inflammatory disorder of the blood vessels that causes damage to a wide variety of organs through tissue ischemia. Vasculitis is classified according to the size (large, medium, or small) of the blood vessels. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a novel autoinflammatory syndrome, was described. Somatic mutations in methionine-41 of UBA1, the major E1 enzyme that initiates ubiquitylation, are attributed to this disorder. This new disease entity connects seemingly unrelated conditions: inflammatory syndromes (relapsing chondritis, Sweet's syndrome, or neutrophilic dermatosis) and hematologic disorders (myelodysplastic syndrome or multiple myeloma). Notably, such patients sometimes develop vasculitis, such as giant cell arteritis and polyarteritis nodosa, and fulfill the corresponding classification criteria for vasculitis. Thus, vasculitis can be an initial manifestation of VEXAS syndrome. In this research topic exploring the link between autoinflammatory diseases and vasculitis, we first provide an overview of the disease mechanisms and clinical phenotypes of VEXAS syndrome. Then, a literature review using the PubMed database was performed to delineate the clinical characteristics of vasculitis associated with VEXAS syndrome. Finally, the therapeutic options and unmet needs of VEXAS syndrome are discussed.
PubMed: 36045928
DOI: 10.3389/fmed.2022.983939 -
Respiratory Medicine Dec 2018The hallmark of vasculitis is autoimmune inflammation of blood vessels and surrounding tissues, resulting in an array of constitutional symptoms and organ damage. The... (Review)
Review
The hallmark of vasculitis is autoimmune inflammation of blood vessels and surrounding tissues, resulting in an array of constitutional symptoms and organ damage. The lung is commonly targeted in the more familiar ANCA-associated small vessel vasculitidies, but large and medium vessel vasculitides, including Takayasu arteritis, giant cell arteritis, polyarteritis nodosa, Behcet's disease, and necrotizing sarcoid granulomatosis, may also feature prominent pulmonary involvement. Pulmonary manifestations of these conditions include pulmonary arterial aneurysms, pulmonary hypertension, diffuse alveolar hemorrhage, pulmonary nodules, and parenchymal infiltrates. An understanding of the diverse manifestations of vasculitis and a high index of clinical suspicion are essential to avoid delays in disease recognition that may result in permanent or life threatening morbidity. In this review, we outline the general clinical manifestations, pulmonary manifestations, diagnostic workup, imaging findings, and treatment of medium, large, and variable vessel vasculitides.
Topics: Aneurysm; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Behcet Syndrome; Giant Cell Arteritis; Hemorrhage; Humans; Hypertension, Pulmonary; Lung Diseases; Polyarteritis Nodosa; Pulmonary Alveoli; Pulmonary Artery; Takayasu Arteritis
PubMed: 30509707
DOI: 10.1016/j.rmed.2018.11.003 -
Therapeutic Advances in Gastroenterology 2022Patients with inflammatory bowel disease (IBD) often have other immune-mediated inflammatory diseases (IMIDs), and the prevalence of any IMID is higher in IBD patients... (Review)
Review
Patients with inflammatory bowel disease (IBD) often have other immune-mediated inflammatory diseases (IMIDs), and the prevalence of any IMID is higher in IBD patients than in the general population. IBD and other IMIDs involve alterations in innate and adaptive immune responses. Their co-occurrence depends on shared immune and inflammatory processes, pathogenic mechanisms, and genetic and environmental risk factors, including drugs, especially tumor necrosis factor inhibitors. The more common IMIDs associated with IBD have been widely described, so this review focuses on the less frequent associations. The IMIDs discussed here are skin disorders (psoriasis, atopic dermatitis, vitiligo, epidermolysis bullosa acquisita, cutaneous polyarteritis nodosa, and hidradenitis suppurativa), hepato-pancreatic diseases (autoimmune hepatitis, granulomatous hepatitis, and autoimmune pancreatitis), endocrine diseases (autoimmune thyroid diseases, and type 1 diabetes mellitus), multiple sclerosis, and respiratory diseases (asthma, bronchiectasis, and interstitial pneumonia). The early detection of IMIDs in IBD patients is important to prevent their deleterious clinical course and limit their psychological impact. Care for IBD patients with IMIDs should be multispecialist, with a single therapeutic strategy instead of treating each disease separately.
PubMed: 35924080
DOI: 10.1177/17562848221115312 -
Clinical and Experimental Rheumatology 2018Polyarteritis nodosa (PAN) is a rare form of primary systemic vasculitis with heterogeneous presentations, treatments and disease course. Historical approaches to... (Review)
Review
Polyarteritis nodosa (PAN) is a rare form of primary systemic vasculitis with heterogeneous presentations, treatments and disease course. Historical approaches to classification and diagnostic terminology are reviewed. Since differentiation of PAN from microscopic polyangiitis (MPA) and other ANCA vasculitides by the Chapel Hill conference statements, and with hepatitis associated PAN defined as a secondary vasculitis, the phenotyping and subclassification of PAN has received little attention. Monogenic disorders similar to PAN have been described (familial Mediterranean fever, Adenosine Deaminase-2 deficiency), and cutaneous PAN and single organ vasculitis, discussed. The overlapping phenotypes between PAN and other primary vasculitic syndromes and subphenotypes within PAN are explored. This work will underpin development of newer treatment regimens and future genetic and related aetiologic studies.
Topics: Disease Progression; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Phenotype; Polyarteritis Nodosa; Research
PubMed: 29465365
DOI: No ID Found -
Reumatologia Clinica Jan 2024VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene... (Review)
Review
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.
Topics: Adult; Humans; Myelodysplastic Syndromes; Glucocorticoids; Immunosuppressive Agents; Mutation; Skin Diseases, Genetic
PubMed: 38160120
DOI: 10.1016/j.reumae.2023.12.004 -
Journal of Clinical Immunology Jul 2018Deficiency of ADA2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by biallelic hypomorphic mutations in the ADA2 gene that... (Review)
Review
Deficiency of ADA2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by biallelic hypomorphic mutations in the ADA2 gene that encodes the adenosine deaminase 2 (ADA2) protein. Over 60 disease-associated mutations have been identified in all domains of ADA2 affecting the catalytic activity, protein dimerization, and secretion. Vasculopathy ranging from livedo reticularis to polyarteritis nodosa (PAN) and life-threatening ischemic and/or hemorrhagic stroke dominate the clinical features of DADA2. Vasculitis and inflammation can affect many organs, explaining the intestinal, hepatological, and renal manifestations. DADA2 should be primarily considered in patients with early-onset fevers, rashes, and strokes even in the absence of positive family history. Hematological manifestations include most commonly hypogammaglobulinemia, although pure red cell aplasia (PRCA), immune thrombocytopenia, and neutropenia have been increasingly reported. Thus, DADA2 may unify a variety of syndromes previously not thought to be related. The first-line treatment consists of TNF-inhibitors and is effective in controlling inflammation and in preserving vascular integrity. Hematopoietic stem cell transplantation (HSCT) has been successful in a group of patients presenting with hematological manifestations. ADA2 is highly expressed in myeloid cells and plays a role in the differentiation of macrophages; however, its function is still largely undetermined. Deficiency of ADA2 has been linked to an imbalance in differentiation of monocytes towards proinflammatory M1 macrophages. Future research on the function of ADA2 and on the pathophysiology of DADA2 will improve our understanding of the condition and promote early diagnosis and targeted treatment.
Topics: Adenosine Deaminase; Animals; Combined Modality Therapy; Disease Management; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Intercellular Signaling Peptides and Proteins; Mutation; Phenotype; Quantitative Trait Loci; Treatment Outcome; Vasculitis
PubMed: 29951947
DOI: 10.1007/s10875-018-0525-8 -
Biomedicines May 2021The term coronary "artery vasculitis" is used for a diverse group of diseases with a wide spectrum of manifestations and severity. Clinical manifestations may include... (Review)
Review
The term coronary "artery vasculitis" is used for a diverse group of diseases with a wide spectrum of manifestations and severity. Clinical manifestations may include pericarditis or myocarditis due to involvement of the coronary microvasculature, stenosis, aneurysm, or spontaneous dissection of large coronaries, or vascular thrombosis. As compared to common atherosclerosis, patients with coronary artery vasculitis are younger and often have a more rapid disease progression. Several clinical entities have been associated with coronary artery vasculitis, including Kawasaki's disease, Takayasu's arteritis, polyarteritis nodosa, ANCA-associated vasculitis, giant-cell arteritis, and more recently a Kawasaki-like syndrome associated with SARS-COV-2 infection. This review will provide a short description of these conditions, their diagnosis and therapy for use by the practicing cardiologist.
PubMed: 34072772
DOI: 10.3390/biomedicines9060622