A fatal case of VEXAS syndrome with a brief review

Abstract

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described adult-onset autoinflammatory condition characterized by somatic mutations in the X-linked UBA1 gene. UBA1 mutations cause defective protein ubiquitination, driving widespread inflammation and hematologic dysregulation. VEXAS predominantly affects males aged >50 years, with a prevalence of approximately 1 in 4000 in this population.¹ Diagnosis requires strong clinical suspicion and is confirmed via genetic testing. Currently, no standardized treatment exists, and patients often fail conventional immunosuppression. We present a VEXAS case complicated by recurrent thromboinflammatory events and progressive vascular involvement leading to a fatal outcome despite optimal multidisciplinary care. The patient consented to have his case published.

Case report

A 65-year-old man with a complex medical history, including type 2 diabetes mellitus , hyperlipidemia, hypertension, chronic kidney disease, heart failure with preserved ejection fraction, recurrent bilateral proximal and distal lower extremity proximal deep vein thrombosis, macrocytic anemia, asthma, and allergic rhinitis, presented with a 2-year history of feeling unwell with recurrent high-grade fevers (≤103°F), painful skin purpuric rashes, and multiple joints pain and swelling. Pertinent physical examination revealed violaceous discoloration and ulceration of the right second toe and left heel, along with soft tissue swelling and multiple joints and cartilage tenderness (Fig). Laboratory evaluations demonstrated macrocytic anemia with hemoglobin level of 5.2 g/dL and leukopenia with a white blood count of 2.2 thousand/mm³, as well as elevated inflammatory markers (C-reactive protein, 18.3 mg/dL; sedimentation rate, 44 mm/h). Autoimmune workup including C3 and C4 complement levels, antinuclear antibody, antineutrophil cytoplasmic antibodies, cyclic citrullinated peptide antibody, and rheumatoid factor was unremarkable. Skin biopsy of the violaceous left leg skin lesions revealed nonspecific subcutaneous dense collection of neutrophils with concurrent tissue necrosis concerning cutaneous vasculitis. Ankle brachial indices were normal. Computed tomography angiography of the chest, abdomen, and pelvis revealed scattered nonobstructive atherosclerotic disease involving the aorta. Bone marrow biopsy revealed 70% hypercellular marrow with erythroid and granulocytic proliferation but no evidence of malignancy, myeloid neoplasia, or lymphoproliferative disorder. Given his constellation of macrocytic anemia, recurrent fevers, cutaneous lesions, thrombosis, relapsing polychondritis, and systemic inflammation, suspicion for VEXAS syndrome was raised. Genetic testing confirmed somatic mutations in the UBA1 gene (p.Met41Thr), DNMT3A gene (VAF 45%), EZH2 gene (VAF 48%), and TERT gene (VAF 51%), establishing the diagnosis of VEXAS syndrome.

Fig.

Violaceous discoloration and ulceration of the right second toe (A) and left heel (B). The patient consented to the publication of these case details and images.

Besides stabilizing the patient with packed red blood cells transfusion and resuming long-term anticoagulation with low-dose apixaban 2.5 mg twice daily, he was initiated on tocilizumab infusions at a dose of 4 mg/kg administered monthly with significant initial improvement, including reduced fatigue, relief of joint pain, and blood count improvement. A repeat bone marrow biopsy performed following his third tocilizumab injection demonstrated progression to myelodysplastic syndrome (MDS) with trisomy 8 and cytoplasmic vacuoles in both myeloid and erythroid precursors. Considering these results, tocilizumab was changed to azacitidine chemotherapy. He reported a favorable response to chemotherapy, with resolution of inflammatory symptoms and improvement of hemoglobin level and inflammatory markers.

Five months later, he was hospitalized for decompensated heart failure with preserved ejection fraction with progressive fluid overload. Coronary catheterization revealed multivessel nonobstructive coronary artery disease. Despite optimal guideline-directed heart failure therapy, he developed anuric end-stage renal disease that was attributed to inflammatory response and hypoperfusion, requiring permanent dialysis, complicated by uremic encephalopathy.

Over the following 15 months, the patient had multiple hospitalizations for complications, including progressive anemia, respiratory failure owing to interstitial lung disease, decompensated heart failure, recurrent skin infections with sepsis (Fig), and inflammatory flares despite optimal therapy including high-dose steroids with intravenous methylprednisolone, azacitidine infusions, intravenous antibiotics, hemodialysis, and other supportive therapies. Unfortunately, he finally passed away owing to cardiopulmonary arrest after multiorgan failure that was attributed to VEXAS syndrome-related complications.

Discussion

A recently discovered adult-onset autoinflammatory illness known as VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is characterized by somatic mutations in the UBA1 gene on the X chromosome. This gene encodes the E1 ubiquitin-activating enzyme, which is critical to the ubiquitin-proteasome system and is required for cellular homeostasis and protein degradation. This process is impeded by UBA1 mutations, which cause the accumulation of faulty proteins, systemic inflammation, and hematological abnormalities.² Vasculitis, thrombosis, and MDS are among the clinical indications of VEXAS syndrome, which mostly affects elderly men. Although there is a male predominance owing to the X-linked nature of the disease, females may also manifest VEXAS syndrome when a somatic UBA1 mutation coexists with X monosomy.³ Diagnosis of VEXAS syndrome is based on the history, clinical presentation, and a combination of laboratory evaluation of pathogenic bone marrow or peripheral cytology. The confirmation of diagnosis usually requires genetic testing for UBA1 mutation.^2,4 It is often misdiagnosed or associated with other inflammatory or hematological disorders such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or MDS, which may delay accurate diagnosis and appropriate management.²

Our patient had a typical presentation with a long history of constitutional symptoms, recurrent venous thromboembolism, vasculitis, cellulitis, relapsing polychondritis, inflammatory polyarthritis, and cardiovascular and pulmonary manifestations. This constellation of findings is consistent with the typical vascular phenotype described in VEXAS syndrome, in which recurrent venous thrombosis and cutaneous vasculitis are defining features.^2,4 The close alignment of his presentation with this characteristic thromboinflammatory pattern strengthened clinical suspicion for VEXAS, which was ultimately confirmed based on the genetic testing. The vascular involvement and systematic inflammatory nature of VEXAS make early recognition by vascular surgeons very important, because they may be the first providers to evaluate patients with this emerging disease with multiple vascular manifestations. Because of its diagnostic complexity and multisystem manifestations, we recommend a multidisciplinary approach, including vascular medicine, hematology, and rheumatology specialists.

The management of VEXAS syndrome is very challenging given the heterogeneous presentation and absence of evidence-based and standardized strategies. Corticosteroids may be used during the acute presentation with constitutional symptoms, vasculitis, or musculoskeletal symptoms.⁵ Unfortunately, conventional steroid-sparing agents such as methotrexate and azathioprine provide only transient benefit.⁶

The use of newer biologic therapies has become increasingly common.⁷ Tocilizumab, an interleukin(IL)-6 blocker, was found to reduce inflammation but rarely improves cytopenia, whereas other IL-6 blockers, such as siltuximab and sarilumab, have only limited data.^5,8 Therefore, IL-6 blockers may provide symptomatic relief but do not adequately control decrease progression.⁵

Janus kinase (JAK) inhibitors, including ruxolitinib and baricitinib, may better achieve sustained disease control, improve arthritis, vasculitis, and cutaneous symptoms when compared with IL-6 blockers.^5,8,9 Momelotinib (a JAK inhibitor) showed added promise relative to other agents by improving both inflammation and anemia.¹⁰ Last, hypomethylating agents can be considered in patients with concurrent MDS, but may only offer short-lived partial hematological responses.^5,11

Allogeneic hematopoietic stem cell transplantation remains the only curative treatment option and can induce both hematological and inflammatory disease remission. However, it carries a high morbidity and mortality, which limit its consideration to few patient populations.^5,10,12

Treatment requires balancing rapid inflammatory control with strategies targeting the hematological clone. Although corticosteroids are considered a reasonable initial step to control inflammation, IL-6 inhibitors, JAK inhibitors, or hypomethylating agents, with hematopoietic stem cell transplantation may provide high-risk curative potential.

Our patient had a short-lived initial response to corticosteroids and tocilizumab, then was transitioned to azacitidine in addition to frequent transfusions to address the MDS. JAK inhibitors were avoided owing to his significant comorbidities. Hematopoietic stem cell transplantation was not pursued given his poor overall functional status, ongoing infections, and the high procedural risk with his complex medical conditions.

Conclusions

This case underscores the diagnostic and management challenges of VEXAS syndrome, particularly when complicated by MDS and other systemic issues. Even with available therapies, long-term outcomes remain poor, with reported mortality ranging from 20% to 50%.¹³ We recommend considering VEXAS among the differential diagnoses in patients presenting with the following constellation of constitutional symptoms: thrombosis, inflammation, and pulmonary and cardiovascular pathologies. We recommend confirming the diagnosis by obtaining UBA1 genetic testing.

While awaiting more research to standardize diagnostic criteria and management strategies, we recommend multidisciplinary collaboration between rheumatology, hematology, infectious disease, nephrology, and vascular medicine physicians to offer an appropriate management plan.

Funding

None.

Disclosures

None.