Diagnostic persistence in geriatric medicine: A case of VEXAS syndrome in an older adult

Abstract

In geriatric medicine, the need to balance thorough diagnostic evaluation with the potential burden of invasive testing is a well-known dilemma. Older adults often present with vague or nonspecific symptoms in the context of multimorbidity, which frequently leads to a pragmatic, symptom-oriented approach rather than an in-depth search for rare underlying conditions. However, a conservative diagnostic approach, although often justified, can delay the recognition of treatable diseases. The combination of diagnostic complexity and the high prevalence of nonspecific inflammatory syndromes increases the risk of missed or delayed diagnoses.

This case highlights the value of diagnostic persistence in such contexts: a 75-year-old man with unexplained systemic inflammation ultimately diagnosed with VEXAS syndrome.

The patient presented to the outpatient geriatric clinic with an 8-month history of unintentional weight loss, fatigue, night sweats and progressive exertional dyspnea. He also experienced diffuse arthralgia without joint inflammation, and intermittent, stabbing pains affecting various parts of the body, which resolved spontaneously within minutes (Fig. 1a). His medical history included type 2 diabetes, atrial fibrillation and a recently treated gastric ulcer.

Physical examination was unremarkable. Blood pressure was 136/86 mmHg, pulse 106 b.p.m. and body mass index 23 (current weight 73 kg). Cardiopulmonary examination revealed an irregular rhythm consistent with atrial fibrillation. No cardiac murmur, endocarditis stigmata, lymphadenopathy, joint swelling or skin abnormalities were observed. Initial laboratory testing revealed an elevated erythrocyte sedimentation rate (122 mm/h), mild macrocytic anemia (hemoglobin 7.7 mmol/L, mean corpuscular volume 102 fL) and hyperferritinemia (439 μg/L). White blood cell and platelet counts were normal. Peripheral blood smear showed atypical lymphocytes and toxic granulation. Electrolytes, C-reactive protein, renal and liver function, lactic dehydrogenase, and vitamin levels were normal. Extensive microbiological testing (including blood cultures, cytomegalovirus/Epstein–Barr virus, hepatitis B/C, HIV, parvovirus B19/toxoplasma/Coxiella burnetii) was negative. Immunological workup showed hypergammaglobulinemia and type III mixed cryoglobulinemia with positive rheumatoid factor, whereas antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative.

A positron emission tomography scan showed diffuse bone marrow activation (Fig. 1b,c) without signs of malignancy, vasculitis or systemic rheumatic disease. Due to persistent symptoms and worsening anemia (hemoglobin 6.4 mmol/L), the patient was referred to hematology. Bone marrow aspiration showed a hypercellular bone marrow with mild hypergranulopoeisis and preserved maturation, initially considered reactive. However, cytogenetic analysis subsequently showed a somatic UBA1 mutation (exon 3, c.122T>C p.(Met41Thr)), confirming the diagnosis of VEXAS (vacuoles, E1 ubiquitin activating enzyme, X-linked, autoinflammatory, somatic) syndrome.

Shortly after diagnosis, the patient developed an erythematous, fine-spotted exanthema on the trunk, axillae, groin and popliteal regions. These skin features are commonly seen in VEXAS.¹ The patient was initially treated with tocilizumab, which led to a clinical response. However, based on current insights and emerging evidence, treatment with azacitidine was initiated.²

VEXAS syndrome is a recently described autoinflammatory disorder caused by somatic mutations in the UBA1 gene on the X chromosome.³

Predominantly affecting older men, VEXAS remains underrecognized. The precise prevalence is currently unknown. A genome-first study found VEXAS to be more prevalent than previous estimates.⁴ Clinical features include fever, fatigue, progressive cytopenias, skin lesions and thromboembolic events all attributed to the inflammation that arises in VEXAS syndrome. Bone marrow typically shows cytoplasmic vacuolization in myeloid and erythroid precursors.⁵

Diagnosing VEXAS can be particularly challenging in older adults, who often present with nonspecific symptoms and elevated inflammatory markers, features that overlap with more common rheumatologic, infectious or hematologic disorders.^5-7 Currently, no diagnostic criteria or guidelines exist for UBA1 testing. A pragmatic approach to hyperinflammation is common in geriatric care, especially when a definitive diagnosis proves elusive.

Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment, although it is rarely feasible in older adults due to age and comorbidities. Treatment is typically focused on inflammation control, with corticosteroids often used as first-line therapy. Steroid-sparing agents, such as anakinra and tocilizumab, have shown promise. In patients with co-existing marrow dysplasia, azacitidine, commonly used in myelodysplastic syndromes, might offer additional benefit, and was therefore initiated in the present patient.^{2, 8, 9}

This case shows the need to remain vigilant for rare autoinflammatory syndromes. VEXAS should be considered in all older patients presenting with unexplained inflammatory symptoms and cytopenias, irrespective of age. This is particularly relevant for individuals, such as this patient, who have manageable comorbidities and a good quality of life before the onset of debilitating symptoms.

A systematic and persistent diagnostic approach, including the thoughtful use of invasive diagnostic procedures, can lead to actionable diagnoses and improved patient outcomes. Although the present patient was evaluated in an academic setting, diagnostic tools, such as bone marrow aspiration and FDG PET-CT, are widely available and can be applied in various clinical settings. A conservative diagnostic approach, although often appropriate, should not preclude adequate care, particularly when effective treatment options are available.

The authors declare no conflict of interest.

Written consent was obtained from the patient for publication.

None.

This article was written with the assistance of ChatGPT's translation tool. The figure was created using BioRender.