Novel genetic mutation in myositis-variant of VEXAS syndrome

Rheumatology key message.

• Myositis can be a prominent presenting symptom of VEXAS and may therefore drive treatment decisions.

Dear Editor, Herein we describe a novel phenotype of the recently described vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome [1]. A 57-year-old male with previously documented mild leukopenia (2.1–2.8 K/μl) and neutropenia (0.8–1.3 cells/μl) in 2018 had been otherwise healthy. In January 2021, he presented with a week of self-resolving laryngitis and horizontal diplopia with decreased ductions of the right eye. MRI imaging of his ocular orbits revealed increased T2 signal enhancement of his right medial rectus, consistent with orbital myositis (Fig. 1). In April 2021, diplopia recurred with decreased ductions of the left eye, and stiffness of his left wrist and third proximal interphalangeal joint, which self-resolved after a few days. In July 2021, he developed right ear chondritis and ankle stiffness, which resolved following a methylprednisolone dose-pack. As part of an evaluation for noted leucopenia, a bone marrow biopsy revealed hypercellularity without increased number of blasts or vacuoles. Laboratory data showed elevated erythrocyte sedimentation rate 125 mm/h (normal <20.0 mm/h) and C-reactive protein 24.8 mg/l (normal <5.0 mg/l). Anti-nuclear antibodies were positive at 1:320 titre in speckled pattern, while anti-Ro, anti-La, anti-Jo-1, anti-ds-DNA antibodies and ANCA were negative.

Fig. 1.

Fasciitis, myositis and genotype of case

(A) Diffuse anasarca of right forearm. (B) MRI T2 imaging showing enhancement of right medial rectus, indicative of orbital myositis. (C) Extensive intramuscular and fascial oedoema, extensive fasciitis of bilateral thighs. (D) CD68 staining showing epimysial facia inflammation and small foci of myophagocytosis. (E) Haematoxylin and eosin staining showing vacuoles alongside muscle atrophy (arrows). (F) Sanger sequencing of the patient’s whole blood and single cell genotypes from subcloning demonstrating both novel mutations (c.119G>C; p. Gly40Ala, c.121 A>T; p. Met41Leu) are in cis. (G) Immunoblotting of 293T cells transfected with UBA1 HA constructs in which the p. Met41Leu c.121 A>T causes expression of the UBA1c isoform similar to known VEXAS syndrome mutation p. Met41Val c.121 A>G. The p. Gly40Ala c.119G>C variant does not alter expression of UBA1a or UBA1b, either on its own or in the context of UBA1 c.121 A>T; p. Met41Leu.

In August 2021, he experienced 3 weeks of progressive swelling and stiffness in his four extremities (legs>arms), and worsening dyspnoea that prompted hospital admission (Fig. 1A). On examination, he was hypoxic (75% SpO₂), had diffuse anasarca, decreased bibasilar lung sounds, 4+/5 strength of his deltoids, biceps and triceps, and 4−/5 hip flexor strength. Laboratory examination revealed a macrocytic anaemia (haemoglobin 9.4 g/dl; mean corpuscular volume 106 fl), an elevated alanine aminotransferase (51 IU/l), and persistently elevated inflammatory markers. Aldolase was markedly elevated (41.4 U/dl), though his creatine kinase (172 U/l) and myositis antibody panel were normal. A CT scan of his chest showed bilateral pleural effusions without parenchymal infiltrate or other abnormalities, and a transthoracic echo showed an ejection fraction of 65% with otherwise normal heart dynamics. Subsequent thigh muscle MRI demonstrated extensive intramuscular and fascial oedema of the bilateral flexor and extensor compartments greatest at the distal vastus lateralis and medialis with extensive fasciitis especially of the posterior compartment (Fig. 1C). EMG revealed mild irritable myopathy, and a biopsy showed striking perimysial, epimysial and fascial macrophagic CD68 positive inflammation with moderate necrotizing myopathy (Fig. 1D, E). Prominent intramuscular non-red-rimmed vacuoles were noted. Thoracentesis, diuresis and high dose steroids (initially 1.0 mg/kg/day) improved his anasarca and hypoxia. Following discharge, VEXAS was confirmed by two previously undescribed mutations at c.119 G > C; p. Gly40Ala and c.121 A > T; p. Met41Leu in the UBA1 gene occurring in cis, within the same cell (Fig. 1F) [2]. These mutations led to loss of UBA1b expression and emergence of UBA1c, similar to previously reported pathogenic variants (Fig. 1G). He subsequently began sarilumab 200 mg subcutaneously every 2 weeks. Specifically for his myositis and fasciitis, he was most recently initiated on mycophenolate mofetil 1500 mg twice daily and intravenous immunoglobulin 2 g/kg monthly with improvement in his muscle strength.

Since its first description in December 2020, various phenotypes including myelodysplasia, relapsing polychondritis, haemophagocytic lymphohystiocytosis and systemic lupus erythematosus have been described [3]. Recently, a case report noted myofasciitis as a manifestation of VEXAS, though the myositis was late in its presentation, 10 years after the initial diagnosis of neutrophilic dermatosis [4]. While our case demonstrated typical VEXAS features of macrocytic anaemia, relapsing polychondritis and synovitis, it is the second documented case of orbital myositis involvement and the first report of necrotizing myositis with significant fasciitis as a presenting symptom in the setting of novel mutations involving the same UBA1 gene [5]. Clearly, our case demonstrates that myositis can be a prominent presenting feature of this newly described syndrome, and most likely occurs because of ongoing systemic inflammation attributable to the disrupted function of cytoplasmic UBA1b. To our knowledge, it is yet unclear whether the two novel mutations detailed above directly relate to this prominent muscle involvement, though this association warrants further study. The expanse of possible VEXAS presentations continues, highlighting the importance of maintaining a genotype-centred approach as we continue to combine apparently disparate conditions into a cohesive disease set.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research. All data relevant to the study are included in the article.