A new guidance document from the ACR provides physicians with key expertise for the diagnosis and management of the rare condition VEXAS (vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome), a multisystem disorder with important rheumatologic impacts.1
VEXAS Background
Scientists first described VEXAS in late 2020.2 Affected individuals acquire pathogenic somatic mutations in the UBA1 gene, which makes the major E1 enzyme responsible for ubiquitylation, an important post-translational modification of peptides. The adult-onset condition is often refractory to treatment and sometimes fatal, occurring with a variety of hematologic and inflammatory features.
David B. Beck, MD, PhD, an assistant professor of medicine and head of the Inflammatory Disease Genetics Clinic at New York University Grossman School of Medicine, New York City, is one of the co-last authors of the recent guidance statement. “We don’t yet have clear studies that have defined the best ways to identify and treat patients,” he says, “but we wanted to set the groundwork for the studies that will come next.”
Dr. Matthew Koster
One of the guidance statement’s co-first authors is Matthew J. Koster, MD, a rheumatologist and associate professor of medicine at the Mayo Clinic, Rochester, Minn. He points out that not all patients have access to centers with VEXAS expertise, at least not for all their care. “It’s important for people providing local assistance in managing these patients to have guidance from experts who have seen it more frequently.”
A multidisciplinary and international panel of experts in VEXAS contributed to the project, including rheumatologists, hematologists, dermatologists, immunologists, infectious disease specialists and others. Relying on a literature review and expert opinion, they created the conditionally recommended guidance statements across four different areas: 1) clinical and laboratory features, 2) mutation screening methods, 3) diagnosis of myelodysplastic syndromes (MDS; present in one-third to one-half of VEXAS patients), and 4) prognosis and management.
Clinical & Laboratory Features
From an epidemiological perspective, clinicians should be most suspicious of VEXAS in men over the age of 50. (The very strong predominance in men is thought to be due to the UBA1 gene’s location on the X chromosome). The condition is genetic, but not thought to be heritable, as it derives from an acquired and not an inherited mutation. A clonal group of cells with mutations in UBA1 come to populate cells with a myeloid lineage, leading to disease symptoms.
VEXAS has a heterogenous presentation and many potential hematologic and inflammatory aspects, including persistent elevation of inflammatory lab markers. Among the most common disease features outlined in the guidance document are dermatologic symptoms, such as neutrophilic dermatosis (Sweet syndrome), auricular or nasal chondritis, ocular involvement witsh periorbital swelling, groundglass or nodular pulmonary infiltrates, leukocytoclastic vasculitis, thromboembolic disease and fever of unknown origin.
However, patients may also have less common inflammatory-type symptoms, with involvement of the peripheral nervous system, heart, kidneys and/or other types of skin manifestations.
“It’s really about understanding some of the particular features of the disease,” says Dr. Koster. “Not all patients are going to have auricular or nasal chondritis, for example, but if you have an older man with auricular or nasal chondritis, you need to have VEXAS in the differential.”
Macrocytic anemia is very commonly, but not universally, present, especially in the earliest stages of the progressive disease. Dr. Koster also highlights the possibility of monocytopenia, an unusual finding in the setting of many other rheumatologic diseases, which often display a reactive monocytosis instead. Thrombocytopenia and lymphopenia can also occur, as can vacuoles in early erythroid or myeloid precursor cells on bone marrow aspirate.
Some of these patients have previously received a rheumatic diagnosis, such as anti-neutrophil cytoplasmic antibody (ANCA) vasculitis or relapsing polychondritis. However, these patients usually have very atypical presentations, and they are often glucocorticoid-dependent and poorly responsive to standard treatments.
Management of VEXAS
A key thrust of the guidance document is the need for collaboration in both diagnosing and managing such patients. “It’s really a team-based approach, with rheumatologists and hematologists as two of the most important coordinators,” says Dr. Koster. “It’s critical to have both perspectives because rheumatologists are not as comfortable with cytopenias, and hematologists are not as comfortable with managing and monitoring inflammatory states.”
Click to enlarge.
Disease activity in VEXAS can be defined by inflammation or worsening bone marrow failure. Treatment (see Figure 1) must encompass controlling inflammation, treating bone marrow failure and addressing any secondary complications from treatment (e.g., glucocorticoid toxicities).
Clinicians should start glucocorticoids for all patients with confirmed VEXAS and inflammatory manifestations. Glucocorticoid-sparing agents can be added as well, with some small studies and experience at expert centers showing potential benefits for anti-interleukin (IL) 6 or anti-IL-1 therapies, or Janus kinase (JAK) inhibitors. These agents, targeting inflammatory pathways, appear to be more effective than conventional disease-modifying anti-rheumatic drugs or B cell-directed therapies. Although many centers are using anti-IL-6 agents as the first-line therapy, not enough evidence exists to establish that definitively.
Dr. David Beck
“When you start a second medication, taper the steroids slowly and cautiously, because patients can have acute inflammatory episodes from rapid tapers,” says Dr. Beck. Patients are rarely able to get off steroids completely, at least with current treatments from the rheumatology armamentarium; some patients cannot decrease their steroid dose at all, although steroid-sparing medications may improve quality of life.
Rheumatologists should coordinate with hematology for management of such issues as cytopenias and MDS. Allogeneic hematopoietic stem cell transplantation can provide a potential curative option for select patients.
Azacitidine, a hypomethylating agent often used in certain blood cancers and in MDS, is another management option for hematologic manifestations, as it can reduce numbers of the abnormal clonal cells. A recent retrospective study found that azacitidine helped reduce the frequency of clones with the UBA1 mutation, improving not only hematologic responses but also inflammatory findings.3
“I think that a lot of future work will go into understanding when and how we should use azacitidine more broadly in VEXAS,” says Dr. Beck. “VEXAS has more hematologic involvement than a classic rheumatic condition, but also more opportunity for treatment using medications outside of those already used in rheumatology.”
VEXAS patients are at increased risks for both infections—from the disease itself and from immunosuppressive treatments—as well as thromboembolic disease. Thus, the guidance document also highlights the need for considering prophylaxis for both (e.g., viral prophylaxis or prophylaxis for such organisms as pneumocystis or mycobacteria).
The guidance document also highlights another key management concern: both infection and thromboembolic disease can mimic disease flares. Dr. Koster adds that sequential treatments can sometimes help establish the true cause, if unclear. “First, initiate treatment for what you most suspect, then assess,” he says. “If you use antimicrobials and prednisone simultaneously, it’s very hard to know which one led to the benefit.”
For more information about other aspects of the diagnosis and management of VEXAS, including detailed recommendations on screening for UBA1 mutations and diagnosis of MDS in patients with VEXAS, see the full guidance document (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.43287).
Moving Forward
Although the disease is rare, rheumatologists may encounter more of these patients in the future. “We think the vast majority of patients aren’t diagnosed now,” says Dr. Beck, “but UBA1 is going to be added to more next-generation sequencing panels for anemia or cytopenias, and many patients will be diagnosed through this kind of broad testing.”
Like all ACR guidance documents, this initial VEXAS guidance will evolve as new information becomes available. For example, a study of the JAK inhibitor pacritinib in patients with VEXAS is now open—the first randomized, double-blind, placebo-controlled trial for the disease.4
“In less than five years we’ve gone from an initial index cohort to rapid escalation of knowledge, with national databases and an international, multispecialty consensus document,” says Dr. Koster. “That’s phenomenal. We’re going into a hyper-accelerated timeframe of identifying diseases, collaborating internationally and moving toward dedicated clinical trials.”
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
References
- Mekinian AM, Georgin-Lavaille S, Ferrada MA, et al. American College of Rheumatology guidance statement for diagnosis and management of VEXAS developed by the international VEXAS working group expert panel. Arthritis Rheumatol. 2025 Aug 11. Online ahead of print.
- Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020 Dec 31;383(27):2628–2638.
- Jachiet V, Kosmider O, Beydon M, et al. Efficacy and safety of azacitidine for VEXAS syndrome: A large-scale retrospective study from FRENVEX. Blood. 2025 Sep 18;146(12):1450–1461.
- Beck DB, Heiblig M, Savic S, et al. POS0379 PAXIS: A randomized, double-blind, placebo-controlled dose finding phase 2 study (part 1) followed by an open-label period (part 2) to assess the efficacy and safety of pacritinib in patients with VEXAS syndrome [abstract]. Ann Rheum Dis. June 2025;84(S1):623–624.