VEXAS syndrome is a monogenic disease that is mostly seen in men and is caused by somatic mutations in UBA1 in hematopoietic progenitor cells. Patients are seen to develop inflammatory and hematologic symptoms in this condition. This article explains the epidemiology, serology and treatment of this new entity.

What is VEXAS syndrome?

VEXAS is an acronym that stands for Vacuoles E1 ubiquitin-activating enzyme X linked Autoinflammatory Somatic. It is a novel adult-onset monogenic autoinflammatory disorder published recently in the New England Journal of Medicine by Beck et.al in October 2020 in the middle of the COVID era. It is caused by somatic mutation in the UBA1 gene at amino acid position 41 (Methionine). This enzyme is responsible for the activation of ubiquitin-proteasome pathways vital for various cellular functions like protein degradation, membrane trafficking, autophagy etc. There are three variants demonstrated to date i.e p.Met41Thr, p.Met41Val and p.Met41Leu.

These mutations are lineage-restricted and are seen in cells of myeloid lineage i.e neutrophils and monocytes in peripheral blood. In bone marrow aspirate, this mutation is seen in various haematopoietic progenitor cells. It is not seen in mature lymphocytes and fibroblasts.

Somatic mutations are postzygotic acquired mutations that are not hereditary in contrast to germline mutations. Somatic mutations are well demonstrated as the cause of various solid and haematological malignancies but are now evident as a cause of autoinflammatory disease. Hence opens a newer scope for research.

Epidemiology

Being an X- linked disease, it is mainly seen in males. A female with VEXAS has not been reported to date. It is seen more commonly in an elderly population of or above the fifth decade. It is a rare entity; prevalence in the general population is not known. About 8% of patients with initially diagnosed relapsing polychondritis have an underlying UBA1 gene mutation.

Clinically, it presents as an overlapping feature of systemic autoinflammatory and haematological manifestation. This entity usually goes undiagnosed for a long time as undifferentiated fever or undifferentiated autoinflammatory syndrome. The clinical spectrum ranges from recurrent refractory fever, arthritis, chondritis involving ear and nose, sterile pulmonary neutrophilic infiltrate, systemic vasculitis (antibody negative), cutaneous vasculitis, neutrophilic dermatoses like sweet syndrome, eye involvement as uveitis, scleritis, or urogenital manifestations like epididymitis or orchitis.

Haematological manifestation ranges from macrocytic anaemia not related to vitamin deficiencies, cytopenia, bone marrow have evidence of dysplastic cells, monoclonal gammopathy, multiple myeloma. In peripheral blood smear and bone marrow aspirate - vacuoles are present in myeloid lineage cells and hematopoietic progenitor cells.

Serology

All the patients have very high acute phase reactants and high inflammatory cytokines like IL 6, IL 1, TNF a, IFN gamma etc. It is a clinical entity that can fulfil classification criteria of various conditions like:

1. Relapsing polychondritis (RP)
2. Sweet syndrome
3. Polyarteritis nodosa
4. Antibody negative systemic vasculitis
5. Myelodysplastic syndrome (MDS)
6. Multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS)

VEXAS RP is a subgroup of relapsing chondritis patients having UBA1 gene mutation. Patients of VEXAS RP are male elderly gentleman have a worse prognosis compared to isolated RP.

Treatment

These patients are highly treatment-refractory, life-threatening conditions requiring a higher dosage of corticosteroids. It doesn't respond to conventional synthetic DMARDs. Colchicine also has not shown a good response. Biological agents like IL1 receptor antagonist i.e Anakinra and IL 6 receptor antagonist Tocilizumab have been tried with varying responses. An allogeneic transplant can be a therapeutic option in future but require further exploration.

Prognosis and mortality

VEXAS is a treatment-refractory disease that might progress to certain haematological malignant conditions like MDS or multiple myeloma or MGUS or it can be fatal. It has a mortality rate of 40 to 50% published in the case of series to date.

VEXAS syndrome is a relatively new entity discovered in late 2020. It is due to somatic mutation in the UBA1 gene. It is seen more commonly in males and the elderly population. Prevalence in the general population is unknown. It has an overlapping clinical manifestation of varying specialities. It fulfils clinical classification criteria of various other diseases and should be carefully sought. Hence, for various reasons a rheumatologist, dermatologist, geriatric physician, internist, otorhinolaryngologist, hemato-oncologist should be aware of this refractory and life-threatening condition which has a mortality of 40 to 50%.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.