Faculty Bibliography

OBJECTIVES/OBJECTIVE:, is an autoinflammatory disease. METHODS:mutations on protein function and immune signalling. RESULTS:T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. CONCLUSION/CONCLUSIONS:and some features of disease are amenable to immunomodulatory therapy.

Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly described disease due to somatic mutations in UBA1, encoding ubiquitin-activating enzyme 1. Patients with VEXAS syndrome have hematologic features, such as macrocytic anemia and myelodysplastic syndrome, and systemic inflammation, including cutaneous involvement. Our aim was to characterize the spectrum of skin manifestations in a large cohort of patients with VEXAS. 87 males and 1 female with genetically confirmed VEXAS syndrome were included in this retrospective study. Mean age at disease onset was 64 years (range 39-78). Most patients (n=71, 81%) had skin involvement. Initial disease presentation was confined to skin in 16 patients (18.2%) or to skin with systemic features in 19 (21%) patients. Skin lesions were painful/tender (n=15, 21.1%) or pruritic (n=13, 18.3%), characterized by erythema (n=20, 28.2%) or nodules (n=17, 23.9%), and occurred most frequently in an acral distribution (n=25, 35.2%). 110 skin biopsies were performed in 45 patients. Skin biopsies were interpreted as small or medium vessel vasculitis (n=29, 26.4%), Sweet syndrome (n=24, 21.8%), connective tissue disease (n=9, 8.2%), or erythema nodosum (n=7, 6.4%). Histologic review of 11 cases identified a neutrophilic predominance (n=6, 54.5%) in the epidermis (n=2, 18.2%), papillary dermis (n=6, 54.5%) and reticular dermis (n=5, 45.5%). Skin lesions improved with glucocorticoids in 85.5% of patients (n=47/55), but relapse after tapering was common (60%, n=33/55). Severe injection site reactions to anakinra were frequent (64.3%, n=9/14). Skin lesions are a common, early feature of VEXAS syndrome and share similarities in clinical and histologic presentation with other inflammatory skin disease. Appreciation of the spectrum of skin findings in VEXAS will facilitate early diagnosis.
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Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome was recently identified by genotype-driven approach. This syndrome is characterised by the presence of somatic mutations affecting methionine-41 (p.Met41) in UBA1 gene. All the identified patients were adult males who had recurrent fevers, cytopenias, dysplastic bone marrow with vacuoles in myeloid and erythroid precursors, neutrophilic skin and lung tissue inflammation and often had treatment refractory and fatal disease course. The various phenotypes reported with VEXAS syndrome include relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, Sweet's syndrome, myelodysplastic syndrome and multiple myeloma.

BACKGROUND:A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. OBJECTIVE:This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. METHODS:A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. RESULTS:A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. CONCLUSION/CONCLUSIONS:VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.

The objective of this study is to describe the clinical features and outcomes of patients with the newly defined vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nine men with somatic mutations in the UBA1 gene were identified; the most frequent variant was p.Met41Thr (7 of 9, 78%). The median age at VEXAS diagnosis was 74 (67, 76.5) years, and patients had a median duration of symptoms for 4 years before diagnosis. Refractory constitutional symptoms (88%), ear and nose chondritis (55%), and inflammatory arthritis (55%) were common clinical features. Vasculitis was noted in 44%. All patients had significantly elevated inflammatory markers and macrocytic anemia. Thrombocytopenia was present in 66% at diagnosis of VEXAS. Eight patients had bone marrow biopsies performed. All bone marrows were hypercellular, and there was vacuolization of the erythroid (100%) or myeloid precursors (75%). Glucocorticoids attenuated symptoms at prednisone doses ≥20 mg per day, but no other immunosuppressive agent showed consistent long-term control of disease. One patient with coexisting plasma-cell myeloma received plasma-cell-directed therapy with improvement of the inflammatory response, which is a novel finding. In conclusion, VEXAS syndrome is a clinically heterogeneous, treatment-refractory inflammatory condition caused by somatic mutation of the UBA1 gene. Patients often present with overlapping rheumatologic manifestations and persistent hematologic abnormalities. As such, internists and subspecialists, including pathologists, should be aware of this condition to avert diagnostic delay, now that the etiology of this syndrome is known.

OBJECTIVE:Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. METHODS:Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. RESULTS:/μl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity. CONCLUSION/CONCLUSIONS:Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.