The Vexing VEXAS Syndrome

Just over one year ago, a multidisciplinary team of clinicians and scientists at the National Institutes of Health (NIH) discovered a new, adult-onset syndrome that links seemingly disparate hematologic and autoimmune symptoms. The first description of the disorder, called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, was published in The New England Journal of Medicine (NEJM) in December 2020.¹

The path to the discovery began with David Beck, MD, PhD, a clinical geneticist at the NIH’s National Human Genome Research Institute. Dr. Beck decided to look for gene mutations within the ubiquitin pathway, a set of enzymes that add a small regulatory protein called ubiquitin to other proteins to mark that protein for one of several fundamental tasks in the cell, including protein degradation, shuttling to a different part of the cell, and folding or altering ubiquitin’s interactions with other proteins. This led to the identification of the first three patients with a genetic variant in the UBA1 gene.

“After David identified the common variant, we went and looked at the charts of these patients to see if they had symptoms in common,” said Peter Grayson, MD, chief of the Vasculitis Translational Research Program at the National Institute of Arth­r­itis and Musculoskeletal and Skin Diseases, a rheumatologist and lead author of the publication. “The patients turned out to all be older men who had very difficult-to-treat inflammation plus bone marrow failure.”

To identify novel disorders, researchers typically begin with a group of patients who have similar symptoms. But Dr. Beck took a phenotypically agnostic approach. After the initial finding, the NIH group, including Dr. Grayson, identified another 22 patients.

For a long time, there has been a documented clinical association between bone marrow disorders, such as myelodysplastic syndromes, and systemic autoimmune inflammatory features.

“VEXAS syndrome has been hiding out among that group of patients in plain sight,” Dr. Grayson said. “These patients are cared for by a lot of dif­fer­ent doctors, including hematologists, dermatologists, and rheumatologists, but there was never a good biological ex­­plan­ation for all of their symptoms.”

He reflected further, noting, “These patients would see a hematologist who might say, ‘Your primary problem is inflammation.’ Then they would see their rheumatologist who would say, ‘I can’t get your inflammation under control because I think the primary problem is in your bone marrow.”

VEXAS syndrome connects hematology and rheumatology, providing an explanation for the constellation of treatment-refractory symptoms in these patients. During late adulthood, patients develop symptoms in multiple organs, including fevers; cytopenias; neutrophilic, cutaneous, and pulmonary inflammation; chondritis and vasculitis; vacuoles in myeloid and erythroid precursor cells; and dysplastic bone marrow.

ASH Clinical News spoke with Dr. Grayson and other clinicians studying VEXAS syndrome who are involved in compiling databases of these patients and disseminating information about the novel disorder to the medical community.

The Genetics of VEXAS Syndrome

The UBA1 (ubiquitin like modifier activating enzyme 1) gene encodes for the major E1 enzyme that initiates ubiquitylation – that is, the process of attaching a small protein called ubiquitin to another targeted protein that has fundamental functions in all cells of the body. Ubiquitylation is a post-translational modification that allows cells and tissues to reversibly regulate important processes. Dysregulation of the process can lead to a wide range of developmental disorders, cancer, and neurodegeneration.

Patients with VEXAS syndrome acquire one of several somatic inactivating mutations in UBA1 in their hematopoietic and myeloid progenitor cells in the bone marrow in adulthood. The disorder is X-lined, as the UBA1 gene is located on the X chromosome. Thus, the vast majority of patients with VEXAS syndrome are men. Only a handful of cases have been identified in women, all of whom have monosomy of the X chromosome. In the initial NEJM publication describing VEXAS syndrome, authors reported that none of the family members of the 25 patients were affected or harbored a UBA1 gene mutation.

Several somatic mutations in UBA1 that result in VEXAS syndrome have now been identified,^2,3 and others will likely follow as additional patients are recognized. There are other patients with the hematologic and inflammatory clinical features that overlap with those of VEXAS syndrome but who do not harbor a mutation in UBA1.

“For these additional patients, we need to investigate whether there are additional mutations in ubiquitylation pathways or related pathways that can also lead to this specific syndrome or a related one,” said Louis Terriou, MD, an immunologist at the Lille University Hospital and Lille Inflammation Research International Center in France, who cares for patients with the syndrome.

For Srinivas Tantravahi, MBBS, a hematologist/oncologist at the University of Utah who specializes in myeloid neoplasms and bone marrow failure disorders, a major question is: What clonal, survival advantage might a UBA1 mutation confer on the mutated hematopoietic progenitor cells?

Increased Awareness = Increased Diagnoses

In the initial NEJM publication describing VEXAS syndrome, the 25 patients had mutant myeloid cells (neutrophils and monocytes) but wild-type lymphocytes (T and B cells) in their peripheral blood. Hematopoietic stem cells and multipotent progenitors in the bone marrow were mutated, but the mutations were absent from mature lymphocytes. Median age of symptom onset was 64 years.

The group of 25 male patients had numerous findings that exemplify the disorder. Most of the patients had recurrent fevers, hematopoietic dyspoiesis, and bone marrow vacuolization restricted to myeloid and erythroid precursor cells. Specifically, 22 patients had skin involvement, 18 had pulmonary infiltrates, 16 had ear and nose chondritis, 11 had venous thromboembolism, and 24 had macrocytic anemia. Eighteen of the patients tested had bone marrow vacuoles. Additionally, 15 patients had relapsing polychondritis, eight had acute febrile neutrophilic dermatosis (Sweet Syndrome), six had myelodysplastic syndromes, and five had multiple myeloma.

A transcriptome analysis revealed that the patients had activation of multiple innate immune pathways and, consistently, patients had elevated levels of serum cytokines.

Among the 25 patients, 40% (n=10) died from ­disease-related causes – respiratory failure or progressive anemia or complications related to treatment.

“The prognosis is poor, mainly because most of the patients are steroid refractory and have high morbidity,” Dr. Terriou said.

Dr. Grayson has since gone back to sequence the UBA1 gene among the NIH’s cohort of patients with relapsing polychondritis and identified seven out of 92 patients with the mutation – all older men who also have hematologic manifestations.⁴ The publication lays out a clinical algorithm of how to spot a patient who likely has the disease and when genetic testing should be considered (See FIGURE).

FIGURE. Decision tree algorithm for the identification of VEXAS Syndrome

MCV = mean corpuscular volume; VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic; VEXAS RP = VEXAS with relapsing polychondritis
Source: Ferrada MA, Sikora KA, Luo Y, et al. Arthritis & Rheumatology, October 2021.

“Now, we know that VEXAS syndrome represents approximately 8% of patients with relapsing polychondritis,” Dr. Grayson said. He added, “This is a relatively rare disease, but it’s probably not as rare as one would think for a newly described disorder.”

The jury is still out on the estimated prevalence of the disorder, according to Peng Li, MD, PhD, medical director of hematopathology at ARUP Laboratories and assistant professor at the University of Utah School of Medicine.

“It’s too early to know the actual prevalence and incidence of this disorder,” Dr. Li said. “We need systematic genetic screening and larger studies in an unselected adult patient population.”

Currently, the NIH has a cohort of approximately 100 patients with VEXAS syndrome. The cohort is growing as clinicians receive additional referrals, thanks to increasing awareness of the disorder. Other international centers have also reported patient cohorts, including Mayo Clinic.⁵

At ACR Convergence 2021, the annual meeting of the American College of Rheumatology, Dr. Grayson and his colleagues showed that among 83 men recently diagnosed with VEXAS syndrome, and after a follow-up period of up to 18 years, the median survival time from disease onset for all patients was 10 years.⁶ The researchers also found a genotype-phenotype relationship: among three UBA1 variants, one had a lower survival rate and each variant was associated with specific clinical diagnoses.

Shortly after the NEJM report on VEXAS syndrome, Dr. Tantravahi encountered a patient in his 50s with recurrent pneumonitis, thrombocytopenia, anemia, and a recurrent rash, who became dependent on corticosteroid therapy for symptom control. He was referred to Dr. Tantravahi’s clinic for cytopenia evaluation.

“I read the NEJM paper and immediately thought to test this patient for VEXAS syndrome,” Dr. Tantravahi said.

Following genetic testing at the NIH in collaboration with Dr. Beck, the patient was confirmed to harbor a UBA1 mutation and was diagnosed with VEXAS syndrome.

“We also analyzed his bone marrow sample and identified the characteristic bone marrow vacuolization in myeloid and erythroid precursor cells, a characteristic morphologic feature of VEXAS,” Dr. Tantravahi said. “These cells are undergoing cell death have vacuoles and disordered organelles.”

Since then, Dr. Tantra­vahi and his colleagues have diagnosed several more men with the disorder.

“Many of these men also demonstrate cytopenias, mostly anemia and thrombocytopenia. Recognizing the characteristic constellation of systemic autoimmune manifestations, cytopenias, and vacuolization of the erythroid and myeloid progenitors in the marrow is critical for the diagnosis of VEXAS and genetic testing should be performed to confirm the diagnosis,” he added.

ARUP Laboratories intends to incorporate the UBA1 gene into its myeloid malignancy next-­generation sequencing panel by mid-2022.

“I think it is warranted for clinicians to send peripheral blood or bone marrow specimens of older male patients with a refractory autoimmune disorder and those with a cytopenia of an unknown cause to ARUP or other reference laboratories to screen for any underlying hematologic neoplasm and secondly, to screen for VEXAS syndrome,” Dr. Li said.

Potential Treatments

Dr. Terriou and his colleagues found that an allogeneic hematopoietic cell transplantation can cure some patients with VEXAS syndrome.^7,8

“That a hematopoi­e­tic transplant can essentially cure some of these patients we only found out by serendipity,” Dr. Terriou said. “The patients underwent transplantation because they had life-threatening autoinflammatory symptoms refractory to other therapies. We only tested them for a UBA1 mutation after the transplant.”

Of the six patients with VEXAS syndrome who received a transplant, three have been in durable complete remission for at least 32 months, two additional patients have been in complete remission for at least three months, and one patient died after transplantation.

“We cannot transplant all patients, unfortunately, because some are older and have comorbidities. We need prospective trials to test which subgroup of pa­tients benefits most from transplant,” Dr. Terriou said.

Furthermore, he said, several agents currently used for hematologic malignancies, including JAK inhibitors and IL-6 inhibitors, should be tested in prospective clinical trials in this patient population. Dr. Terriou and his colleagues from the French VEXAS registry group are also working on a draft treatment guideline and hope to initiate an international consortium to provide an up-to-date guideline for the care of patients with VEXAS syndrome.

At the NIH, hematologists have developed a phase II clinical trial to test the efficacy of allogeneic transplantation in 37 patients with VEXAS syndrome.⁹ The investigators aim to complete the study by July of 2025. Dr. Tantravahi had previously treated a man who initially presented with recurrent neutrophilic dermatitis and anemia with a combination of a proteasome inhibitor, cyclophosphamide, and dexamethasone. The patient had a transient response, but symptoms recurred promptly when the treatment was discontinued. The man was confirmed to have VEXAS syndrome.

“Many biologic agents were used to treat the systemic autoimmune illness in men with VEXAS, but none have shown any efficacy except for corticosteroids,” Dr. Tantravahi said. “Spe­cific inflammatory cytokines are elevated in these patients and identifying key players may predict response to a specific biologic agent. Therapeutic approaches such as targeting the UBA1 mutated hematopoietic progenitor cells requires further advances in our understanding of the pathophysiology of this disease.”

As therapy trials are in the works, clinicians are actively educating the clinical community about the disorder.

“We are going around the country to raise awareness about VEXAS syndrome,” Dr. Grayson said. “Every time we speak about the disease, there are clinicians – rheumatologists, dermatologists, and hematologists – in the audience for whom the lightbulb goes off and they realize they have patients that likely have this disorder. It’s amazing.”

Aside from being featured at medical conferences, the disorder has made it to primetime TV. Two months after the initial NEJM publication, the NBC drama Chicago Med featured a patient who was diagnosed with VEXAS syndrome. With time and additional research, hematologists who treat patients with this disorder may have a much clearer treatment plan at their disposal.

—By Anna Azvolinsky

References

1. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383:2628-2638.
2. Poulter JA, Collins JC, Cargo C, et al. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood. 2021;137(26):3676-3681.
3. Bourbon E, Heiblig M, Valentin G, et al. Therapeutic options in VEXAS syndrome: insights from a retrospective series. Blood. 2021;137(26):3682-3684.
4. Ferrada MA, Sikora KA, Luo Y, et al. Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS. Arthritis Rheumatol. 2021;73(10):1886-1895.
5. Koster MJ, Kourelis T, Reichard KK, et al. Clinical heterogeneity of the VEXAS syndrome: a case series. Mayo Clin Proc. 2021;96(10):2653-2659.
6. Ferrada M, Savic, S, Alessi H, et al. Genotype and transfusion dependence predicts mortality in VEXAS syndrome, a newly described disease with overlap inflammatory and hematologic features. Abstract 1426. American College of Rheumatology 2021 Annual Meeting, November 8, 2021.
7. Diarra A, Duployez N, Fournier E, et al. Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a two center experience [published online ahead of print, 2021 Oct 29]. Blood Adv. doi: 10.1182/bloodadvances.2021004749.
8. Diarra A, Duployez N, Terriou L. Mutant UBA1 and severe adult-onset auto­inflammatory disease. N Engl J Med. 2021;384(22):2163-2164.
9. A phase II study of allogeneic hematopoietic stem cell transplant for subjects with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. NCT05027945.