In the first reported case of the autoinflammatory VEXAS syndrome in South Africa, J Damelin, J Jacobson, C Bam, L Pillay and J R du Toit highlight the diagnostic importance of recognising sysmptoms in patients with persistent systemic inflammation, characteristic cutaneous or chondral findings, thrombosis and unexplained cytopenias.
They write in the SA Medical Journal:
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an adult-onset autoinflammatory disorder first described in 2020, resulting from somatic mutations in the UBA1 gene on the X chromosome. These impair ubiquitin-activating enzyme function, driving a clonal, myeloid-restricted autoinflammatory state.
Clinically, it’s characterised by recurrent fevers, neutrophilic and vasculitic skin lesions, relapsing polychondritis, pulmonary infiltrates, venous thromboembolism and progressive cytopenias.
A hallmark diagnostic feature is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors. Haematological abnormalities are central to the disease presentation, and myelodysplastic syndromes are common.
It is frequently misdiagnosed as vasculitis, connective tissue disease, infection, or primary haematological pathology, often resulting in years of ineffective immunosuppression and delayed diagnosis. Mortality remains high, with half of all patients dying within five years of diagnosis.
In South Africa, access to advanced molecular diagnostics (including UBA1 sequencing) remains limited, contributing to under-recognition of the condition.
This case is notable in that, to the best of our knowledge, it represents the first reported SA case of VEXAS syndrome with molecular confirmation of a UBA1 mutation.
What and how …
The UBA1 gene encodes the E1 ubiquitin-activating enzyme, which initiates the ubiquitination pathway responsible for tagging proteins for degradation and cellular regulation. Mutations impair this process, leading to abnormal protein accumulation and activation of innate immune pathways that drive systemic inflammation.
These mutations lead to impaired protein homeostasis, clonal expansion of myeloid progenitors and a severe inflammatory phenotype that spans dermatological manifestations, bone marrow dysplasia with cytopenias and systemic inflammation.
The discovery of VEXAS unified several previously unrelated inflammatory and haematological conditions under a single genetic mechanism.
Haematological abnormalities are prominent in VEXAS, with bone marrow examinations frequently demonstrating cytopenias and dysplasia: 50% of patients present with, or later develop, myelodysplastic syndromes (MDS).
MDS itself is a clonal haemopoietic stem cell disorder characterised by ineffective haematopoiesis leading to peripheral cytopenias and dysplasia in ≥1 cell lines.
In VEXAS-associated MDS, disease behaviour is often less aggressive than classic MDS, and may remain stable for prolonged periods despite significant inflammatory activity.
Because VEXAS is newly recognised and has a wide and heterogeneous clinical presentation, clinician awareness remains limited, often resulting in delayed diagnosis. This is clinically significant, as the syndrome carries substantial morbidity and mortality, with up to half of affected patients dying within five years.
Our case highlights the importance of considering VEXAS syndrome in middle-aged male patients with MDS-like features, particularly when preceded by persistent systemic inflammation and dermatological manifestations.
Because access to advanced molecular diagnostics like UBA1 testing remains limited in SA, greater clinician awareness and integration of molecular testing into diagnostic pathways are essential.
As more local cases are identified, emerging data will help to clarify how VEXAS presents across diverse populations and in settings with high infectious and inflammatory burdens.
Case presentation
The patient, a man in his 60s, had a background of ischaemic heart disease with prior coronary artery bypass grafting and coronary stenting. From 2018, he developed recurrent thrombotic events, including multiple deep-vein thromboses, despite therapeutic anticoagulation.
These episodes were frequently accompanied by inflammatory skin changes involving the lower limbs and recurrent episodes of presumed cellulitis. He also experienced recurrent painful swelling and erythema of the external ear, clinically suggestive of auricular chondritis
Over the years, he developed escalating multi-system inflammatory episodes characterised by recurrent fevers, rash, pleuritic symptoms, migratory inflammatory arthralgia, jaw arthritis and recurrent auricular chondritis. Cutaneous examination during inflammatory flares revealed erythematous to violaceous, non-blanching palpable purpuric lesions involving the lower limbs, clinically consistent with cutaneous vasculitis.
A clinical diagnosis of systemicvasculitis with relapsing polychondritis was made, and he was treated with multiple immunosuppressive agents. But he continued having frequent steroid-responsive inflammatory flares.
He also developed progressive multisystem involvement, including recurrent pneumonias, chronic sinus disease requiring surgical drainage, serositis and recurrent episodes of ocular inflammation: the manifestations were characterised by periocular erythema, conjunctival injection and eyelid oedema during inflammatory flares.
He also required repeated hospital admissions for sepsis.
By 2023, he had developed worsening cytopenias. Bone marrow evaluation confirmed MDS with cytoplasmic vacuolation within myeloid and erythroid precursor cells, and he was started on erythropoietin therapy followed by azacitidine.
Given the constellation of systemic inflammation, relapsing polychondritis and newly diagnosed MDS, VEXAS syndrome was suspected.
Genetic testing for UBA1 mutations was performed on peripheral blood, with samples sent to Centogene (Cambridge, MA, USA) for next-generation sequencing.
This identified a pathogenic somatic UBA1 mutation, confirming the diagnosis of VEXAS syndrome.
In 2024, he continued to experience refractory inflammatory activity, recurrent episodes of sepsis and progression of squamous cell carcinoma of the scalp, accompanied by increasing frailty. Although he was evaluated and prepared for allogeneic stem cell transplantation for his MDS, aggressive recurrence of his squamous cell carcinoma ultimately precluded transplantation.
His condition gradually deteriorated, and he was transitioned to palliative care. He died in May 2025.
Investigations
• Full blood count: macrocytic anaemia, lymphopenia and mild thrombocytopenia on all consecutive blood counts from 2022 to 2025
• Erythrocyte sedimentation rate and C-reactive protein: always mildly elevated from 2022 to 2025
• Bone marrow biopsy: bone marrow aspirate demonstrated prominent cytoplasmic vacuoles in myeloid and erythroid precursors
• Molecular analysis: molecular analysis of the UBA1 gene confirmed the pathogenic variant c.122T>C p.(Met41Thr), (NM_003334.3:c.122T>C), first reported by Beck et al. This substitution results in a methionine-to-threonine substitution at codon 41 within exon 3 (of 26). This substitution is one of the canonical Met41 variants described in VEXAS syndrome, known to impair ubiquitin-activating enzyme function and drive myeloid-restricted autoinflammation.
Discussion
VEXAS syndrome typically affects men of >50 owing to its X-linked association with somatic UBA1 mutations.
Our patient’s presentation illustrates the characteristic overlap between haematological, dermatological and rheumatological features, and the delay in diagnosis frequently described in international cohorts.
The UBA1 p.Met41Thr (c.122T>C) variant identified in this case is a canonical mutation often associated with typical manifestations that include cytopenias, MDS overlap, cutaneous inflammation and thromboembolic disease. The diagnostic hallmark remains cytoplasmic vacuoles in myeloid and erythroid precursors, originally reported in all patients in the first case series, although the underlying mechanism is still not fully understood.
Macrocytic anaemia and progressive cytopenias are common and often parallel, worsening systemic inflammation.
Mutations affecting the methionine-41 (Met41) residue of the UBA1 gene represent the most frequently reported pathogenic variants associated with VEXAS syndrome. Variants including p.Met41Thr, p.Met41Val and p.Met41Leu occur within a recognised mutational hotspot and have been described in multiple international cohorts since the initial description of the syndrome.
These variants impair cytoplasmic translation of the ubiquitin-activating enzyme E1, resulting in defective ubiquitination and activation of innate immune pathways that drive the systemic inflammatory phenotype characteristic of VEXAS syndrome.
The p.Met41Thr variant identified in our patient is one of these canonical mutations and has been reported in association with cytopenias and systemic inflammation, and in frequent overlap with MDS.
Cutaneous involvement is one of the earliest and most frequent manifestations, reported in >80% of patients.[5] Presentations include neutrophilic dermatoses, leukocytoclastic vasculitis, urticaria-like lesions and relapsing polychondritis. Genotype-phenotype correlations have been noted: p.Met41Leu variants are more often associated with neutrophilic dermatoses, while p.Met41Val variants more frequently show vasculitic patterns.
Given the high prevalence and early presentation of skin disease clinicians should maintain a high index of suspicion for VEXAS in older male patients with neutrophilic dermatoses or vasculitic lesions, particularly when accompanied by cytopenias or systemic inflammation. Early UBA1 genetic testing is crucial, as the identified variant may aid in prognostication and therapeutic decision-making.
Because VEXAS is multisystemic, the clinical spectrum is broad and frequently misdiagnosed. Constitutional symptoms, pulmonary infiltrates, arthralgia, recurrent fevers and venous thromboembolism are common, as demonstrated in the large cohort.
Steroids provide rapid symptom control in most patients, but relapse and toxicity are frequent, emphasising the need for steroid-sparing therapies.
Evidence to guide treatment remains limited. In the largest retrospective cohort to date, JAK inhibitors and IL-6 blockade showed the highest response rates, whereas IL-1 and TNF-α inhibitors demonstrated minimal benefit. None of these agents significantly reduced UBA1 clonal burden, highlighting the role of disease-modifying strategies in patients with MDS overlap.
Azacitidine is emerging as an important therapeutic option in VEXAS with associated MDS. Data from the French VEXAS registry and a subsequent phase II study showed clinical or haematological responses in ~70%-78% of patients, including improved cytopenias, reduced inflammation and steroid-sparing effects.
This informed the decision to initiate azacitidine in our patient, aiming to control systemic inflammation and stabilise marrow function.
Allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy.
Recent European Bone Marrow Transplant data in 19 patients with VEXAS demonstrated encouraging molecular responses and sustained disease control, although treatment-related morbidity remained significant.
Given the constraints of the SA setting, early multidisciplinary evaluation and referral to transplant centres, locally or internationally, should be considered for appropriate candidates.
Conclusion
This molecularly confirmed SA case illustrates the diagnostic importance of recognising VEXAS syndrome in patients with persistent systemic inflammation, characteristic cutaneous or chondral findings, thrombosis and unexplained cytopenias.
Bone marrow vacuolation should prompt consideration of UBA1 testing, particularly when conventional immunosuppressive treatment has failed. Earlier diagnosis may allow timely multidisciplinary assessment and consideration of disease-modifying treatment, including transplantation in suitable patients.
Improving access to molecular testing and documenting local cases will help define the burden and clinical spectrum of VEXAS in SA.
- In August last year, the American College of Rheumatology issued the world’s first Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel, and published in Arthritis & Rheumatology.
J Damelin,¹ MB BCh, Dip HIV Man (SA); J Jacobson,¹ MB BCh, Dip HIV Man (SA); C Bam,² MB ChB, Dip HIV Man (SA); L Pillay,³ MB ChB, FC Derm (SA); J R du Toit,¹ MB ChB, Cert Clin Haematol (SA) Phys
1 Wits Donald Gordon Cellular and Immunotherapy Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand;
2 Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town;
3 Department of Dermatology, Helen Joseph Hospital and School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand.
SA Medical Journal article – First case of VEXAS syndrome in South Africa (Creative Commons Licence)
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