VEXAS syndrome causing fever of unknown origin

Clinical record

A 69‐year‐old man had three hospital admissions from April to July 2021 with persistent fever of unknown origin. The onset was within one week of robotic radical prostatectomy for localised prostate adenocarcinoma. Associated features included diaphoresis, pruritis, anorexia with 15kg of weight loss, sinus tachycardia, an urticarial rash over the torso and limbs, and chondritis of the left ear. The past medical history included hypertension, dyslipidaemia, gastro‐oesophageal reflux disease, asthma and multiple superficial venous thromboses.

Laboratory evaluation was notable for progressive pancytopenia with transient neutropenia and macrocytic anaemia, requiring blood transfusion. The C‐reactive protein concentration was persistently elevated (>200mg/L; reference interval [RI], <8mg/L) and the erythrocyte sedimentation rate was raised (78mm; RI, 1–15mm).

Lower limb duplex venous ultrasound detected a left femoral deep vein thrombus, and computed tomography (CT) pulmonary angiography showed multiple right‐sided pulmonary emboli. Subsequent CT imaging of the chest revealed bilateral upper lobe ground‐glass opacities and perihilar bronchial wall thickening that resolved on follow‐up studies. There was diffusely increased bone marrow uptake on positron emission tomography (PET) scan (Box 1).

A skin biopsy was performed and histology was consistent with acute febrile neutrophilic dermatosis (Sweet syndrome). The results of a bone marrow biopsy were in keeping with a reactive process, and no comment was made about the presence or absence of vacuoles. Chromosomal analysis was normal. After extensive investigation, a diagnosis of VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome was confirmed by genetic sequence analysis of a peripheral blood sample when a Met41Thr somatic variant was detected in the UBA1 (ubiquitin‐like modifier activating enzyme 1) gene.

Management initially included several courses of broad‐spectrum antimicrobials without clinical response, and anticoagulation was initiated for venous thromboembolism. Following the diagnosis of VEXAS syndrome, prednisolone 30mg (0.5mg/kg) daily was commenced, with a dramatic improvement in symptoms and the resolution of fever and tachycardia within 48 hours. After 5weeks of treatment, the C‐reactive protein concentration had normalised. A slow steroid wean was commenced and treatment with the Janus kinase inhibitor tofacitinib was planned.

Discussion

VEXAS syndrome is an acquired monogenic disorder with haematological and rheumatological features that was first described in October 2020.1 It is an adult‐onset myeloid‐driven autoinflammatory condition caused by a somatic mutation in the UBA1 gene on the X chromosome of haematopoietic progenitor cells. The novel genotype‐driven approach to its discovery has linked several discrete conditions together into a heterogenous disease entity. Since the 2020 publication,1 there have been several case reports and case series of VEXAS syndrome internationally, demonstrating a broad clinical phenotype.2 All cases have occurred in men, except for one occurrence in a woman with monosomy X.3 The median age of onset is about 65years, but can range from the fifth to the ninth decade of life.1,4 Clinical features include inflammation of multiple organ systems (skin, lungs, cartilage, blood vessels) and haematological abnormalities (cytopaenias, thromboembolic disease) which may have been previously diagnosed as an alternative condition (Box 2).1,2,3 Glucocorticoids are currently the mainstay of initial treatment but are only temporising.2,4 There has been a poor response to traditional disease‐modifying antirheumatic drugs and research is ongoing into other steroid‐sparing therapies, including biological agents.4 Allogenic stem cell transplant may be a curative treatment option.5

To our best knowledge, this is the first published case report of postoperative onset VEXAS syndrome in Australia, although the timing may be coincidental. The phenotype in this case is a relapsing febrile illness with raised inflammatory markers, widespread neutrophilic dermatosis, fluctuating cytopaenias, recurrent thromboembolism, chondritis and a marked steroid response. It corresponds well with the original disease description, with all of these features being present in one or more of the 25 initial cases identified.1 There was a significant delay to diagnosis on this occasion, which was likely in part due to poor recognition given its recent discovery. The rapid reporting of a number of cases in the 12 months since VEXAS syndrome was first described suggests that its prevalence may be underappreciated.2,4 Increasing awareness of VEXAS syndrome among clinicians is likely to lead to increased rates of new and retrospective diagnosis, which will drive research into expanding treatment options.

Box 1 – Positron emission tomography scan showing diffuse bone marrow uptake (maximum standardised uptake value, 6.6 in L2 vertebral body)

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