VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases

Abstract

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described pathological entity. It is an acquired monogenic autoinflammatory disease caused by somatic mutations of the UBA1 gene in blood cells precursors; the gene encodes one of the two E1 enzyme isoforms that initiates ubiquitylation in cell’s cytoplasm. VEXAS syndrome leads to systemic inflammation, with all organs and tissues potentially involved. The clinical picture may be extremely heterogenous, mimicking different other systemic rheumatologic entities coexisting with haematological disorders, especially myelodysplastic syndrome. This new disease represents a very intriguing clinical condition in several respects: it accounts for the paradigm of adult-onset monogenic autoinflammatory diseases determined by a genetic mosaicism resulting in the development of a challenging multiorgan inflammatory condition. Moreover, VEXAS syndrome is perhaps not an exceptionally rare condition and represents an example of a systemic genetic autoinflammatory disease drawing its origin in bone marrow disorders. VEXAS syndrome should be strongly considered in each adult patient with an unexplained systemic inflammatory condition, especially when recurrent fevers, neutrophilic dermatosis, relapsing polychondritis, ocular inflammation and other systemic inflammatory symptoms accompanying myelodysplastic syndrome or other haematological disorders. The syndrome deserves a multidisciplinary approach to reach the diagnosis and ensure the best management of a potentially very challenging condition. To quickly describe the clinical course, long-term outcomes, and the optimal management of this new syndrome it is essential to join forces internationally. To this end, the international AutoInflammatory Disease Alliance (AIDA) registry dedicated to VEXAS syndrome has been developed and is already active.

Case report: Schnitzler-like syndrome without monoclonal gammopathy

“…However, a genetic analysis failed to establish an association of Schnitzler`s syndrome with germline or somatic mutations in the NLRP3 gene locus except in rare individual cases ( 15 , 18 , 25 – 28 ). Nevertheless, it is probable that Schnitzler’s syndrome is caused by an acquired mutation, like in VEXAS syndrome ( 29 , 30 ), or in acquired Familial Mediterranean Fever ( 31 ) and acquired NLRC4-associated CAPS ( 32 ). Interestingly, a somatic NLRP3 mutation (NLRP3: c.1709A>G (p.Tyr570Cys)) identical to that reported in a Neonatal Onset Multisystem Inflammatory Disease (NOMID, or Chronic Infantile Neurological, Cutaneous and Articular Syndrome, CINCA) case was also found in a patient with a clinical picture closely resembling Schnitzler’s syndrome, and without gammopathy and without bone pain like in our patient ( 22 ).…”

VEXAS syndrome: a new discovered systemic rheumatic disorder

“…The autoantibodies are detectable in only a very few patients. The initial stage lasts various durations and subsequently other manifestations become detectable [ 2 ]. The most common clinical manifestations of the syndrome are summarized in Table I .…”

“…Further insight and investigations of other cohorts led to the discovery of a larger group of patients with clinical symptoms like those of the original three patients, and the syndrome was established as a new clinical entity [ 2 ]. Since its discovery more than 165 papers addressing the VEXAS syndrome have appeared in print, and several new cases have been reported.…”

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort

“…8,9 As a result, collaboration among different specialties is of paramount importance to promptly identify and correctly diagnose patients, usually men in their sixth and seventh decade of life. 10 In a study exploring the prevalence of UBA1 variants in the general population, exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative were queried. 11 Disease-causing UBA1 variants were found in 1 in $4000 men over 50 years, and in about 1 in 14 000 individuals, a prevalence similar to that of MDS.…”

“…Besides MDS, macrocytic anemia (regardless of an overt MDS diagnosis), plasma cell dyscrasia, and recurrent thrombosis are among the most frequent hematological features, whereas inflammatory manifestations encompass skin (chiefly, Sweet syndrome or Sweet syndrome‐like lesions), joints, lung, gastrointestinal, ocular and kidney involvement as well as noninfectious fever, nose, and ear chondritis 8,9 . As a result, collaboration among different specialties is of paramount importance to promptly identify and correctly diagnose patients, usually men in their sixth and seventh decade of life 10 …”