In late summer of 2019, a 62-year-old Asian male with chronic inactive hepatitis B presented to the hospital for 1–2 weeks of left periorbital pain and swelling. Brain MRI showed findings of left preseptal and orbital cellulitis. He was empirically treated and discharged with intravenous ceftriaxone and vancomycin and symptoms improved.
During that hospital stay, however, additional labs showed positive antinuclear antibody (ANA) with a titer of 1:320 (speckled pattern), erythrocyte sedimentation rate (ESR) of 97 mm/hr (reference range 0–33 mm/hr), C-reactive protein (CRP) of 169 mg/L (reference range < 5 mg/L), and mildly elevated immunoglobulin subclass G4 (IgG4) of 282 mg/dL (reference range 2.4–121.0 mg/dL). Antineutrophil cytoplasmic antibodies (ANCA) were negative and complement C3 and C4 levels were normal. Due to concern for autoimmune etiologies, he was evaluated by our rheumatology consult service and found to have synovitis at the left third proximal interphalangeal (PIP) and right first metacarpophalangeal (MCP) joints. But the patient recovered well and no steroids nor further immunosuppression were recommended at the time. Subsequent outpatient labs were negative for antibodies against double stranded DNA (dsDNA) and Smith.
Two months later however, the patient developed fevers and shortness of breath. He was admitted for hypoxia and computed tomography angiography (CTA) of the chest showed diffuse alveolar infiltrates. He was empirically started on high-dose prednisone, starting dose 60 mg daily, with significant clinical improvement. Although his diagnosis remained unclear, he established care with outpatient rheumatology where his prednisone dose was tapered over the next eight months. Clinically, he continued to feel well. Nevertheless, multiple blood tests during follow-up appointments revealed a persistently elevated serum IgG4 in the 240–270 mg/dL range. ESR and CRP remained at 66 to ≥ 140 mm/hr and 20–90 mg/L, respectively. He was also noted to have persistent macrocytic anemia with mean corpuscular volume (MCV) ranging 102–128 fL (reference range 80–96 fL). Evaluation for vitamin B12 and folate deficiency, alcohol use, and liver disease was negative. Macrocytosis was attributed to his long-term use of tenofovir for hepatitis B.
A few days after the patient tapered prednisone to 7.5 mg daily, his fevers not only returned, but he also developed tender erythema nodosum in his extremities and bilateral periorbital edema. He started azathioprine as a steroid-sparing agent but continued to have a predictable episodic pattern of symptom recurrence whenever prednisone was tapered below 10 mg daily, and brisk improvement after prednisone was increased.
During a particularly severe episode in November 2020, he was admitted and found to have new-onset leukopenia (white blood cells 4,000/µL; reference range 4,400 − 11,000/µL) and thrombocytopenia (platelets 8,100/µL; reference range 150,000-450,000/µL). Hemoglobin was 12.1 g/dL (reference range 14.0-17.5 g/dL) and MCV was 108 fL. He underwent fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan that showed diffuse hypermetabolic uptake in the bone marrow. Bone marrow trephine core biopsy and clot section were performed and showed hypercellularity (approximately 80% cellular) with myeloid predominance and erythroid hypoplasia, increased percentage of plasma cells (approximately 10% cellularity), lymphohistiocytic aggregates, and non-caseating granulomas. Erythroid and myeloid lineages showed no dysplasia. Megakaryocytes showed a range of morphologic findings with occasional hypolobated forms. Bone marrow flow cytometry revealed a minute lambda restricted monotypic plasma cell and a small atypical CD4 dim, T-cell population of unknown etiology. Grocott’s methenamine silver stain (GMS) and acid-fast bacillus (AFB) stains were performed and were negative for fungal or acid-fast organisms.
Although his serum free kappa and lambda light chains were found to be elevated (65 mg/L and 83 mg/L, respectively) and urine protein electrophoresis (UPEP) showed monoclonal lambda, the serum protein electrophoresis (SPEP) showed no monoclonal spike and immunofixation electrophoresis (IFE) was polyclonal, even on repeat measurements over the next few years. Subsequent UPEPs did not reproduce the previously detected monoclonal protein. Over the next year, the patient continued to depend on prednisone doses ≥ 10 mg daily to control breakthrough fevers and erythema nodosum, and associated increases in his already elevated ESR and CRP.
In December 2021, considering his initial manifestations of periorbital/orbital inflammation and elevated baseline serum IgG4, azathioprine was stopped and he was started on rituximab for possible IgG4-related disease. After two infusions of rituximab 1000 mg, symptoms continued to recur. Further rituximab infusions were discontinued.
The patient underwent a second PET scan due to the continued lack of diagnosis and suspicion of malignancy. It again showed diffuse hypermetabolic uptake in the bone marrow, but newly hypermetabolic mediastinal and right hilar lymph nodes. Subsequent bronchoscopy showed multiple white, inflammatory bronchial lesions on an erythematous base, but negative infectious studies on bronchoalveolar washings. Considering the previously detected non-caseating granulomas in his bone marrow and these recent findings, we started infliximab 3 mg/kg for presumed sarcoidosis, two years from initial presentation. The patient however had no clinical improvement after six months and infliximab was discontinued after five doses.
During follow-up appointment in early 2023, the patient continued to report fevers while on prednisone 10 mg daily. He was found to have recurrent erythema nodosum, bilateral periorbital edema, active synovitis at the right third PIP joint, and worsening ESR and CRP.
Given the patient’s treatment failures to azathioprine, rituximab, and infliximab, no evidence of malignancy, and negative infectious workup, the possibility of VEXAS syndrome was considered. He had several compatible features: hypermetabolic bone marrow, macrocytic anemia, inflammatory arthritis, inflammatory lung disease, periorbital edema, erythema nodosum, and symptom relief with steroids. His previous bone marrow biopsy was reexamined and observed to contain myeloid and erythroid precursors with cytoplasmic vacuoles. Megakaryocytes showed occasional monolobated forms with rare eccentrically placed nuclei (Fig. 1). Copper levels and serologies for Coxiella burnetti infection were obtained to rule out alternative etiologies for cytoplasmic vacuoles and previously noted bone marrow granulomas, respectively. A peripheral blood sample was sent to ARUP Laboratories for next-generation sequencing (Myeloid Malignancies Mutation Panel). He was found to have a missense mutation in UBA1 (c.122T > C, pMet41Thr) with a variant allele frequency of 53%. Two other missense mutations DNMT3A (c1979A > G, pTyr660Cys) with variant allele frequency 27.3% and ASXL1 (c.3376C > T, pHis1126Tyr) with variant allele frequency of 46.2% were noted. The DNMT3A is considered a variant of known clinical significance and the ASXL1 mutation is considered a tier 2 mutation (variant of unknown clinical significance). Hence, the diagnosis of VEXAS syndrome was made, about 3.5 years after his disease first presented.