‘Therapeutic headway’ still lacking for rare VEXAS disease
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VEXAS syndrome is a recently discovered disease that features fever, orchitis, skin nodules and small- or medium-vessel vasculitis, among other symptoms, according to a presenter at the Biologic Therapies Summit.
Peter Grayson, MD, head of the vasculitis translational research program and associate director of the NIAMS Fellowship Program, offered clinicians tips on recognizing this complex, clinically challenging and frequently fatal condition. “We will end by developing a clinical algorithm that will hopefully be helpful to you,” he said.
Because there are so few documented patients with VEXAS syndrome as yet, Grayson framed his discussion by discussing the first case he encountered. In addition to the aforementioned symptoms, the man had been dealing with face swelling, deep vein thrombosis and ear chondritis.
After cycling through a number of ineffective treatments, the patient ultimately arrived at a prednisone dose of 25 mg per day. The patient told Grayson that if he reduced the dose to 20 mg per day or lower, his disease would flare, which it did.
Because Grayson and his group found a medium-vessel vasculitis in this patient’s skin, the working diagnosis was atypical polyarteritis nodosa.
“We struggled for 2 years to get his disease under control,” Grayson said.
The patient experienced skin reactions to anakinra (Kineret, Sobi), bone marrow failure, frequent infections and worsening anemia that required blood transfusions. “There was still no unifying diagnosis,” Grayson said.
The patient later underwent a bone marrow biopsy and received a platelet transfusion as the anemia and cytopenia worsened. He died in 2020 from complications of the disease. “This is one of the cases that stays with you,” Grayson said. “We were not able to make much therapeutic headway.”
In the summer of 2019, a group investigating a similar patient population conducted a genotype-based approach that Grayson said was “agnostic” to clinical phenotype. Results showed impacts in the ubiquitin pathway. Specifically, there was a novel mutation in UVA1 in three men who had a similar constellation of symptoms as Grayson’s initial case patient.
Digging deeper, when they were assessing bone marrow samples for this mutation in UVA1, they found vacuoles. “This was a very unusual finding,” Grayson said.
Grayson said that there are now more than 60 confirmed patients with similar symptomology. He noted that they are all men, with an average age at disease onset of 64 years. He believes because the gene is linked to the X chromosome, women are protected by the second X allele.
In general terms, VEXAS syndrome features inflammatory components and hematologic components. The inflammatory features include fever, skin involvement, chondritis, arthritis, vasculitis, pulmonary infiltrates and eye inflammatory disease. Regarding the hematologic components, macrocytic anemia may be involved, along with thrombocytopenia, bone marrow vacuoles, deep vein thrombosis and monoclonal gammopathy.
In fact, the name “VEXAS” is derived from the presence of vacuoles, E1 ubiquitin-activating enzyme, the fact that it is linked to the X chromosome, is autoinflammatory and is a somatic condition.
Grayson described the chondritis as “subtle,” and “not like cauliflower ear. “Skin manifestations are quite common in the disease,” he said.
Periorbital swelling is also common and a specific feature that may offer an important clue to clinicians with a suspected case. Neutrophilic dermatosis may also be present, while pulmonary involvement can include parenchymal disease or neutrophilic alveolitis.
Unfortunately, no treatment paradigms have emerged. While glucocorticoids have shown efficacy in mitigating the impacts, prolonged, high doses obviously come with consequences.
“The treatment part of the textbook is still being written,” Grayson said.
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Grayson P. How do I recognize and treat the VEXAS syndrome? Presented at: Biologic Therapies Summit IX; May 21-23, 2021 (virtual meeting).
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