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.

Keywords: Diagnosis; Genetics; Haematology; Monogenic autoinflammatory diseases; Ocular inflammation; Treatment.

Fig. 1

The cartoon describes the main clinical and laboratory hematological manifestations in VEXAS patients. Frequencies are driven from literature, especially Georgin-Lavialle et al. [5], who described the widest number of VEXAS patients so far, Obiorah et al. [10], who described the haematological involvement in 16 patients with VEXAS syndrome, and Groarke et al. [29], who deeply described thromboembolism in VEXAS syndrome

Fig. 2

Erythematous plaques in the right lower limb in a patient with VEXAS syndrome

Fig. 3

Orbital inflammation associated to conjunctival chemosis and eyelid oedema are observed in the left eye from a VEXAS patient

Fig. 4

Bone aspirate smear showing vacuoles in erythroid precursors (signed with “*”) and in a myeloid precursor (signed with “**”)

Fig. 5

Bone aspirate smear from a VEXAS patient. Vacuoles are observed in plasma cells (signed with “*”)

Fig. 6

Multifocal lung inflammation in a patient with VEXAS syndrome. Peribronchial inflammation and multifocal ground glass (marked with arrows) in a patient with lung involvement is observed. The patient carries the p.Met41Val mutation on UBA1 gene. Clinical picture is compatible with the cluster 2 according with Georgine-Lavialle et al. [5]