VEXAS: where do we stand 2 years later?

Abstract

Purpose of reviewTwo years after the recognition of VEXAS (for Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, we propose an extensive review of the current understanding of VEXAS pathophysiology and therapeutic options.Recent findingsAmong the nearly 150 articles published about VEXAS, some have provided determinant insights into VEXAS pathophysiology and treatment. Clinical data from retrospective series support the JAK inhibitor ruxolitinib as the most efficient strategy to control inflammation, and interesting results were also described with azacytidine. Allogeneic stem cell transplantation remains the only curative option, but should be proposed to carefully selected patients.SummaryAlthough waiting for more robust evidence from prospective clinical trials, therapeutic options emerge from retrospective studies. We propose a set of criteria that should be systematically reported to harmonize the evaluation of therapeutic outcomes. This will allow the collection of high-quality data and facilitate their subsequent meta-analysis with the overall aim of improving the management of VEXAS patients.

VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management

“…Traditional disease-modifying, anti-rheumatic drugs (DMARDs) such as methotrexate, mycophenolate, azathioprine, hydroxychloroquine have not exhibited significant steroid-sparing effect. 15,17,59,60 Drugs such as azathioprine, in particular, should be avoided as it has been associated with therapy related myeloid neoplasms and can propagate clonal transformation. 61 Treatment with targeted biologic therapies has shown variable responses with few studies demonstrating response to tumor necrosis factor alpha inhibitors 17 but the majority not observing long-term sustained benefit.…”

“…To date, approaches to treatment in patients with inflammatory‐dominant features have generally used rheumatologic medications. Traditional disease‐modifying, anti‐rheumatic drugs (DMARDs) such as methotrexate, mycophenolate, azathioprine, hydroxychloroquine have not exhibited significant steroid‐sparing effect 15,17,59,60 . Drugs such as azathioprine, in particular, should be avoided as it has been associated with therapy related myeloid neoplasms and can propagate clonal transformation 61 .…”

Update on autoinflammatory diseases

“…After the publication of this initial report, many others followed describing the various ways in which VEXAS can present, including in patients that had been previously diagnosed with relapsing polychondritis, Sweet syndrome, myelodysplastic syndrome (MDS), multiple myeloma, polyarteritis nodosa (PAN), or giant cell arteritis [41 ▪▪ ,42]. The disease can be lethal; many adults progress to bone marrow failure and hematologic malignancies.…”

“…Multiple treatments have been explored, including glucocorticoids, hypomethylating agents such as azacytidine, calcineurin inhibitors such as cyclosporine, Janus kinase (JAK) inhibitors, and hematopoietic stem cell transplantation (HSCT). However, treatments have been only transiently effective in most cases [41 ▪▪ ,43 ▪ ].…”

Macrocytic anemias

“…VEXAS occurs mainly in men, has an estimated prevalence on the order of 1 in 10 000 [15 ▪▪ ], and is characterized by autoimmune inflammatory disease, macrocytic anemia and hypercellular marrow with vacuolated myeloid and erythroid precursors [16]. Diagnosing VEXAS is important due to other associated hematological disorders including thrombocytopenia, neutropenia, myelodysplasia, thrombosis, multiple myeloma, and hemophagocytic lymphohistiocytosis (HLH) syndrome [17,18]. From the earliest recognized to the most recently identified diseases associated with macrocytic anemia, understanding the mechanisms of macrocytic anemia reviewed here should be informative for clinicians and basic researchers.…”