Vexas Syndrome

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a late-onset, treatment-refractory autoinflammatory disorder caused by somatic (acquired) mutations in UBA1 within haematopoietic stem/progenitor cells, producing a combined systemic inflammatory + bone-marrow (haematological) phenotype.

🔑 Key points

• Think VEXAS in an older man with recurrent fevers/inflammation, very high CRP, and macrocytic anaemia (often ± thrombocytopenia/leukopenia), especially if “vasculitis/chondritis/Sweet syndrome” keeps relapsing when steroids are reduced.
• It is genotype-defined (UBA1 mutation). Clinical labels may shift over time (e.g., relapsing polychondritis phenotype → vasculitis phenotype → MDS phenotype).
• Bone marrow often shows cytoplasmic vacuoles in myeloid/erythroid precursors (supportive, not diagnostic on its own).

🧬 Pathophysiology

UBA1 encodes the major E1 ubiquitin-activating enzyme that initiates ubiquitination, a key pathway for protein quality control and immune signalling. Somatic UBA1 mutations create an abnormal myeloid inflammatory clone, driving cytokine-heavy innate immune activation (systemic inflammation) while also impairing haematopoiesis (macrocytosis, cytopenias, MDS-like features). This dual biology explains why patients can look rheumatological and haematological at the same time, and why isolated immunosuppression often struggles to achieve durable control.

👀 Clinical features

🧪 Investigations

• Baseline labs: FBC (look for macrocytosis/cytopenias), film, reticulocytes; CRP/ESR; U&E/LFTs; ferritin; LDH; B12/folate/TSH; haematinics.
• Autoimmune/vasculitis screen (as guided by phenotype): ANA/ENA, complements, ANCA, RF/CCP, cryoglobulins; hepatitis B/C and HIV where relevant.
• Infection exclusion: cultures, viral PCRs, imaging as indicated (VEXAS is often mis-treated as infection).
• Imaging: CT chest/abdomen/pelvis or PET-CT may help map inflammatory foci and exclude malignancy/infection (local protocol-driven).
• Bone marrow: aspirate/trephine if cytopenias/macrocytosis or suspicion of MDS; look for vacuoles in precursors and dysplasia; send cytogenetics/NGS as per haem pathway.
• Definitive test: UBA1 mutation testing on peripheral blood or marrow (liaise with Haematology/Clinical Genetics/local molecular lab route).

✅ Diagnostic approach (practical UK workflow)

1. Recognise the pattern: refractory systemic inflammation + macrocytic anaemia/cytopenias ± chondritis/skin/pulmonary/vasculitic features.
2. Exclude mimics urgently: infection (including endocarditis/TB), malignancy, classic systemic vasculitides, adult-onset Still’s, drug reactions.
3. Engage Rheumatology + Haematology early: this is a cross-specialty disease; avoid prolonged steroid monotherapy.
4. Confirm with genetics: send UBA1 testing; marrow findings support but do not replace genetic confirmation.

🔁 Differentials to actively consider

• Relapsing polychondritis (non-VEXAS)
• ANCA-associated vasculitis / PAN / other systemic vasculitides
• Adult-onset Still’s disease
• Sweet syndrome / neutrophilic dermatoses (secondary causes)
• Myelodysplastic syndrome without systemic autoinflammation
• Occult infection (endocarditis, TB, deep-seated abscess)
• Haematological malignancy with inflammatory paraneoplastic features

💊 Management (principles)

There is no single “one-size-fits-all” regimen. Management balances rapid inflammation control (often steroid-responsive initially) with steroid-sparing therapy and, where appropriate, treatments aimed at the haematopoietic clone. Patients should be managed in a joint Rheumatology–Haematology model, with early consideration of complications (infection, thrombosis, cytopenias, organ involvement).

🩺 Monitoring & follow-up

• Inflammation: symptoms, temperature, CRP/ESR trends (watch for discordance if infection emerges).
• Haematology: serial FBC, MCV, transfusion needs; marrow reassessment if cytopenias evolve.
• Complications: VTE surveillance, infection vigilance, steroid toxicity (bone, metabolic, psychiatric), cardiovascular risk.
• Organ involvement: pulmonary function/imaging, ENT review if airway chondritis suspected, dermatology input for biopsy/phenotyping.

🚨 Red flags needing urgent escalation

• Stridor/voice change or airway symptoms (possible laryngo-tracheal chondritis)
• Rapidly progressive cytopenias or bleeding
• Severe hypoxia / new pulmonary infiltrates (infection vs inflammation)
• Suspected thrombosis (PE/DVT, atypical sites)
• Persistent high fever with immunosuppression (treat as infection until proven otherwise)

📚 References

• Beck DB, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. New England Journal of Medicine (2020). (VEXAS original description).
• NEJM Editorial: VEXAS Syndrome (context and interpretation of discovery).
• Rheumatology review (OUP): recent clinical updates and management considerations.