Looking beyond VEXAS: Coexistence of undifferentiated systemic autoinflammatory disease and myelodysplastic syndrome

Oganesyan, Artem; Hakobyan, Yervand; Terrier, B.; Georgin‐Lavialle, Sophie; Mékinian, A.

doi:10.1053/j.seminhematol.2021.10.003

Cited by 11 publications

(9 citation statements)

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“…We additionally report that 5 of the 7 patients diagnosed with myeloid malignancies in the retrospective cohort carrying somatic UBA1 non-M41 variants (A478S, E597, S621C, P749L, P1014L) showed immunodysregulatory symptoms (Table 1 ), although a clinical rheumatologic diagnosis was recorded in only one variant (P1014L). Undifferentiated inflammatory symptoms are frequently observed in patients harboring UBA1 M41 mutations [ 6 , 28 , 45 , 46 ], and our records on patients carrying UBA1 non-M41 variants would contribute to the shaping of VEXAS Syndrome as a spectrum of inflammatory manifestations.…”

Section: Discussionmentioning

confidence: 85%

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

et al. 2023

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UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1non-M41) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.

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Section: Discussionmentioning

confidence: 85%

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

et al. 2023

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“… 128 Allogenic hemopoetic stem cell transplantation is more likely to offer a curative treatment, recently a case series of six patients who received a transplant were described. 129 At the time of publication five of the six patients were in complete remission, one unfortunately died post-transplant. 129 The lack of effective safe treatments requires further evaluation.…”

Section: Vexasmentioning

confidence: 99%

“… 129 At the time of publication five of the six patients were in complete remission, one unfortunately died post-transplant. 129 The lack of effective safe treatments requires further evaluation.…”

Section: Vexasmentioning

confidence: 99%

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Improving Diagnosis and Clinical Management of Acquired Systemic Autoinflammatory Diseases

Al‐Hakim¹,

Mistry²,

Savic³

2022

JIR

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Systemic autoinflammatory diseases (SAID) are conditions caused by dysregulation or disturbance of the innate immune system, with neutrophils and macrophages the main effector cells. Although there are now more than 40 distinct, genetically defined SAIDs, the genetic/molecular diagnosis remains unknown for a significant proportion of patients with the disease onset in adulthood. This review focuses on new developments related to acquired/late onset SAID, including phenocopies of monogenic disorders, Schnitzler’s syndrome, Adult onset Still’s disease, VEXAS syndrome, and autoinflammatory complications associated with myelodysplastic syndrome.

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“…К ним можно отнести болезнь Стилла взрослых (БСВ) (пример комплекс ного САВЗ) [297], палиндромный ревматизм [298][299][300], «полимилгический» вариант РА у пожилых людей [301][302][303]. Описаны «перекресты» БСВ с анкилозирующим спондилоартритом и псоратическим артритом [304], семейной средиземноморской лихорадкой [305,306]; ассоциация БСВ c другими ИВЗ, включая болезнь Крона [307][308][309], саркоидоз [310,311], синдром VEXAS (vacuoles, E1 enzyme, X-linked, autoinfl ammatory, somatic) [312][313][314], синдром Шницлера [315,316], нейтрофильный уртикарный дерматоз [317,318], а также неклассифицируемого САВЗ, миелодиспластического синдрома и синдрома VEXAS [319]. У пациентов с серонегативным РА в полости сустава могут выявляться кристаллы мочевой кислоты, которые, активируя NLRP3-инфламмасому, индуци руют синтез ИЛ-1β [320].…”

Section: таблица 3 системные аутовоспалительные заболевания: общая ха...unclassified

The role of interleukin 1 in the development of human diseases: focus on Anakinra (IL-1 receptor antagonist)

Насонов

Samsonov

2022

Naučno-praktičeskaâ revmatologiâ

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According to modern concepts, human immune-mediated inflammatory diseases (IMIDs), depending on the prevailing mechanisms of immunopathogenesis, are divided into two main categories – autoimmune and autoinflammatory.At the same time, both autoimmune and autoinflammatory mechanisms are involved in the pathogenesis of most IMIDs, the complex interaction of which is reflected in the polymorphism of clinical manifestations, course variants, outcomes, and therapy efficacy. It is assumed that hyperproduction of cytokines of the interleukin (IL) 1 family, which is one of the key regulators of innate immunity, determines the “crossover” between the mechanisms of autoinflammation and autoimmunity in IMIDs. Anakinra is currently used in clinical practice to suppress the pathological effects of IL-1. An analysis of the results of the clinical use of Anakinra indicates that treatment with this drug should be considered as a promising direction in the pharmacotherapy of systemic autoinflammatory diseases (SAIDs) and critical conditions in children and adults associated with the development of hyperinflammation. The main directions of the Anakinra clinical research program are presented, including: determining the place of the drug in the implementation of the "Treat to Target" strategy and personalization of therapy, primarily in patients with “resistant” (difficult-to-treat) subtype of rheumatoid arthritis and comorbid pathology, as well as with severe forms of microcrystalline arthritis; the possibility of using Anakinra to improve the early diagnosis of SAIDs in children and adults; creation of the Russian register of patients with SAIDs, who are potentially indicated for treatment with Anakinra.

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Looking beyond VEXAS: Coexistence of undifferentiated systemic autoinflammatory disease and myelodysplastic syndrome

Cited by 11 publications

References 100 publications

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

Improving Diagnosis and Clinical Management of Acquired Systemic Autoinflammatory Diseases

The role of interleukin 1 in the development of human diseases: focus on Anakinra (IL-1 receptor antagonist)

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