A rare case of VEXAS syndrome

Dear Editor, Autoinflammatory disorders have been studied extensively over the past few decades. Unlike autoimmune disorders, which affect adaptive immunity, autoinflammatory disorders involve the innate immune system. A novel autoinflammatory disorder, first described in 2020, is vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome [1]. This monogenic syndrome, involving the UBA1 gene, predominantly affects adult men [2]. It combines clinical features of both rheumatologic and haematologic conditions. Below, we describe the clinical diagnosis and management of a case we encountered in our practice.

A 77-year-old male presented with a month-long history of abrupt-onset symptoms, including transient painful swollen joints, migratory painful subcutaneous nodules and bruises (Supplementary Fig. S1, available at Rheumatology Advances in Practice online), a lace-like rash on the thighs, intermittent shivering and fevers and weight loss. His skin lesions, consistent with panniculitis, healed with residual hyperpigmentation. These fluctuating symptoms, developing without triggers, corresponded with changes in inflammatory markers. Additionally, he experienced swelling of the right ear (sparing the earlobe) and an oral ulcer (Supplementary Fig. S2, available at Rheumatology Advances in Practice online). Relapsing polychondritis was considered as a likely cause for his ear symptoms, while his skin lesions suggested erythema nodosum or sarcoidosis. He later developed bilateral eye redness, diagnosed as anterior uveitis.

Blood tests revealed severe macrocytic anaemia with normal B12 and folate levels, a negative autoimmune screen and elevated beta-2 glycoprotein IgM, IgE, complement C4 and cardiolipin IgM antibodies. His angiotensin-converting enzyme and calcium levels were normal. A CT scan of the neck, chest, abdomen and pelvis with contrast showed mildly enlarged right hilar lymph nodes, a couple of prominent stable left paratracheal lymph nodes and a new 5-mm left lower lung nodule. The lung multidisciplinary team recommended a follow-up CT scan in 3 months. A bone marrow biopsy did not reveal any primary haematological diagnosis. Two skin punch biopsies from his lesions were sampled. The left arm showed mild superficial perivascular lymphocytic infiltrate with some neutrophils and red cell extravasation (Fig. 1A). A small arteriole in the subcutis showed obliterated lumen and infiltration of its muscular wall by neutrophil polymorphs and a crushed small lymphocytic infiltrate was seen in the subcutis (Fig. 1B and C). Appearances supported a small to medium-sized vessel vasculitis. The punch biopsy from the left ear showed very mild superficial perivascular lymphoplasmacytic infiltrate. The cartilage was viable (Fig. 1D).

Figure 1.

Histopathology photomicrographs: (A) haematoxylin and eosin (H&E), 20×, left arm; (B) H&E, 40×, left arm; (C) H&E, 400×, left arm, showing vasculitis in a medium-sized artery; (D) H&E, 20×, left ear

The patient was started on a tapering course of systemic steroids: prednisolone 30 mg once daily (OD) for 7 days, then 20 mg OD for 14 days, 15 mg OD for 14 days, 10 mg OD for 14 days and then decreased to 5 mg for 14 days and stopped. He had shown significant improvement in the symptoms of polychondritis and anaemia while on steroids. As the patient was initially diagnosed to be a case of undifferentiated inflammatory syndrome, he was started on treatment with methotrexate to reduce steroid dependency; he received methotrexate 20 mg weekly with folic acid supplementation. However, his symptoms recurred on stopping the prednisolone, thus he was restarted on a low dose of prednisolone 5 mg OD and methotrexate 25 mg weekly. He was also started on calcium and vitamin D supplementation with alendronic acid.

Considering his clinical presentation, his age and gender, genetic screening for VEXAS syndrome was requested. During a subsequent hospital admission for fever and septic shock, Holter monitoring and transoesophageal echography was performed, which were essentially normal. His clinical presentation was initially thought to be due to an undifferentiated inflammatory disease, but genetic testing for UBA1 later confirmed a VEXAS variant: p.Met41Thr (c.122T>C). Bone marrow transplant was discussed with the haematologists, however, our patient was felt to be an unsuitable candidate due to his age.

He has been maintained on oral prednisolone 5 mg OD and oral methotrexate 25 mg weekly and has been largely stable on it with minimal to no flares. He is followed up in the rheumatology department at 6-month intervals.

VEXAS syndrome is caused by mutations in the X-linked UBA1 gene, which encodes the ubiquitin-activating enzyme E1. These mutations, being somatic, present late in life [3] and are restricted to myeloid and erythroid precursor cells, where vacuoles are commonly observed [4]. The patient’s multisystem disease involving uveitis, polychondritis, cytopenia, polyarthritis, dermatosis, lung nodules and medium vessel vasculitis alongside his positive response to steroids raised the clinical suspicion of VEXAS syndrome. Haematological features included macrocytic anaemia, thrombocytopenia, myeloid dysplasia and bone marrow vacuolization. VEXAS syndrome is associated with considerable morbidity and high mortality [2], with symptoms typically refractory to treatment.

The current goals of treatment focus on managing the symptoms better. High-dose glucocorticoids provide temporary relief, but most patients require additional steroid-sparing agents [5]. Tocilizumab, an IL-6 inhibitor has been considered as the drug of choice for managing many manifestations of VEXAS syndrome due to the elevated serum IL-6 levels noted in these patients. However, it has not shown any efficacy in altering the disease progression [6].

Janus kinase inhibitors, especially ruxolitinib, which work by blocking intracellular signalling pathways activated by cytokine receptors, and hence decreasing immune responses, have shown promise as potential treatment options for VEXAS syndrome [7].

Biologic DMARDs have been shown to bring about improvement in milder skin or rheumatic manifestations of the disease, although they have not been found to be as effective in managing the haematological features in VEXAS syndrome. Azacytidine, a hypomethylating agent, has demonstrated potential in managing VEXAS-related haematological abnormalities [8]. Severe cases of VEXAS syndrome with widespread multisystemic involvement, especially haematological abnormalities, have found relief through bone marrow transplantation—a curative therapeutic option for VEXAS.

Supplementary material

Supplementary material is available at Rheumatology Advances in Practice online.

Data availability

The data underlying this article cannot be shared publicly due to ethical restrictions for ensuring patient confidentiality. The data will be shared upon reasonable request to the corresponding author.

Authors’ contributions

Dr Karishma Gupta-Contributed towards writing the original draft and the review and editing. Also the corresponding and first author. Dr Shawki El-Ghazali-Contributed towards review and editing of the case study and also the co-author. Also helped towards supervision. Dr Faris Kubba-Contributed towards review and editing of the case study and also the co-author.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.