VEXAS Syndrome in a Patient with Myeloproliferative Neoplasia

Abstract

VEXAS syndrome stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused by a somatic mutation in the UBA1. There is an association between VEXAS and hematological conditions such as myelodysplastic syndrome (MDS), monoclonal gammopathies of uncertain conditions (MGUS), multiple myeloma (MM), and monoclonal B-cell lymphoproliferative conditions. There are not many descriptions of patients having VEXAS in combination with myeloproliferative neoplasm (MPN). With this article, we want to present a case history of a man in his sixties with a JAK2V617F mutated essential thrombocythemia (ET) developing VEXAS syndrome. The inflammatory symptoms occurred three and a half years after the ET diagnosis. He started to experience symptoms of autoinflammation and an overall worsening of his health, and blood work showed high inflammatory markers, leading to repeated hospitalizations. His major complaint was stiffness and pain, and high dosages of prednisolone were necessary to obtain pain relief. He subsequently developed anemia and significantly variable levels of thrombocytes, which previously were at a steady level. To evaluate his ET, we made a bone marrow smear demonstrating vacuolated myeloid and erythroid cells. Having VEXAS syndrome in mind, genetic testing identifying the UBA1 gene mutation was performed, thus confirming our suspicion. The work-up with myeloid panel on his bone marrow identified genetic mutation in the DNMT3 too. After developing VEXAS syndrome, he experienced thromboembolic events with both cerebral infarction and pulmonary embolism. Thromboembolic events are also common in JAK2 mutated patients, but in his case, they presented first after VEXAS had developed. Throughout the course of his condition, several attempts with prednisolone tapering and steroid sparing drugs were tried. He could not get pain relief unless the combination of medications included a relatively high dose of prednisolone. Currently, the patient uses prednisolone, anagrelide, and ruxolitinib, with partial remission and fewer hospitalizations and more stabilized hemoglobin and thrombocytes.

Figure 1

Thrombocyte levels (red line) and C-reactive protein (CRP) (blue line) during the disease course. It also illustrates the uncomplicated levels during the first 40 months, progressing into spiking levels as the clinical course changes and turns more complicated.

Figure 2

Timeline in months showing the most significant events of his disease progress from time of the ET diagnoses until the complicated course of VEXAS syndrome. RBC: red blood cells.

Figure 3

[F¹⁸]FDG-PET-CT showing intense uptake in the central bone marrow.

Figure 4

Picture from bone marrow smear demonstrating vacuolization in erythroid and myeloid cells, next to a normal megakaryocyte.

Figure 5

DNA sequencing report illustrating the mutation in the fifth position. The variant p.Met41Thr exists as the dominant allele.