No Longer as Vexing: The Role of Somatic Mutations in Rheumatic Diseases

CHICAGO—Not long ago, somatic mutations were recognized almost exclusively as the cause of malignant conditions. This created an intellectual atmosphere in which rheumatologists felt they need not concern themselves too much with the subject of somatic mutations when thinking about autoinflammatory and autoimmune diseases. However, the discovery of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020 shifted this paradigm, and the conversations happening now about genetics and rheumatology are immensely thought-provoking.¹ At ACR Convergence 2025, the session Somatic Mutations in “Benign” Disease: What Every Rheumatologist Should Know explored this relatively new and exciting topic.

The first speaker was David Beck, MD, PhD, assistant professor in the Department of Medicine and the Department of Biochemistry and Molecular Pharmacology, New York University (NYU) Grossman School of Medicine, New York. Dr. Beck is one of the co-discoverers of VEXAS and has established the NYU Autoimmune and Autoinflammatory Genetic Diseases Program, which is dedicated to identifying new genetic disorders and providing precision therapy for patients with genetic diagnoses. In his talk, Dr. Beck explained that VEXAS, which arises from myeloid-restricted somatic mutations in the UBA1 gene, is now believed to be as common as about one in every 4,000 males older than the age of 50 in the U.S.² Females can be affected as well, but because the disease is X-linked, the prevalence in females is lower, about one in every 26,000 females in the U.S. older than the age of 50.²

VEXAS Syndrome

Dr. Beck explained that VEXAS is often severe, includes inflammatory and hematologic manifestations and can be quite heterogeneous in its clinical presentation. Patients with VEXAS often meet criteria for other known, well-established conditions, including relapsing polychondritis; vasculitis, such as polyarteritis nodosa or giant cell arteritis (GCA); and rheumatoid arthritis, yet testing for somatic mutations in UBA1 should be considered when patients do not fit neatly into these other diagnostic boxes. The predisposition to hematologic conditions, such as myelodysplastic syndrome (MDS; seen in 30–40% of patients), myeloproliferative neoplasms, plasma cell dyscrasias and recurrent thrombosis, is a common feature of VEXAS and helps distinguish it from other clinical rheumatic syndromes.³

In a systematic review of 720 patients with VEXAS, the most common clinical features of the disease were cutaneous involvement (seen in 82% of patients), such as neutrophilic dermatoses, followed by constitutional symptoms like fevers, weight loss, night sweats and fatigue (69% of patients) and respiratory disease (61% of patients), including pulmonary infiltrates, ground glass opacities and pleural effusions.⁴

The Search for Effective Treatments

Dr. Beck pointed out that VEXAS is a progressive disease that often leads to worsening anemia and macrocytosis, a sign of bone marrow failure. For this reason, finding effective treatments for the condition has been high on the list of priorities for researchers. In a multicenter retrospective study from Hadjadj et al., the authors looked at 110 patients with VEXAS who received a total of 194 courses of targeted therapy. At three months, the overall response rate (complete or partial) was 24% for patients who were treated with Janus kinase (JAK) inhibitors, 32% for those treated with interleukin-6 (IL-6) inhibitors, 9% for those on IL-1 inhibitors and 0% for tumor necrosis factor alpha (TNFα) inhibitors or other targeted agents.⁵ At six months, response rates were 30% for JAK inhibitors and 26% for IL-6 inhibitors. Although the authors of the study conclude that JAK inhibitor and IL-6 inhibitor therapies show some benefit, Dr. Beck noted that these treatments are still insufficient for a large number of patients with VEXAS.

On that topic, Dr. Beck discussed research on azacitidine, a cytosine analogue and antineoplastic agent used in the therapy of myelodysplastic syndromes, as a treatment for VEXAS. In a multicenter retrospective study of 88 patients with VEXAS, most of whom (80%) met criteria for MDS, inflammatory response rates to azacitidine were 41% at six months and 54% at 12 months, regardless of MDS status. Among responders, relapse-free survival was 90% at one year and 85% at five years, although relapse was common after discontinuation. A molecular response, which was defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was seen in 65% of patients and correlated with clinical response. This last finding was highlighted by Dr. Beck, who said such results imply that UBA1 mutation burden could potentially be used as a biomarker of response to azacitidine in patients with VEXAS.

Somatic Mosaicism

The second speaker in the session was Michelle Robinette, MD, PhD, instructor in medicine at Brigham and Women’s Hospital, Boston, and a postdoctoral fellow at Dana Farber Cancer Institute, Boston. Dr. Robinette began her talk by discussing the general topic of somatic mosaicism, a state in which two or more groups of cells possess different genetic compositions. This phenomenon can, at times, manifest quite visibly. Proteus syndrome, for example, is a disease in which a gene mutates in some—but not all—cells, leading to overgrowth of portions of the body. (It is believed that Joseph Merrick, the 19th-century Englishman who became known as the Elephant Man due to his pachydermatous deformities, suffered from this condition.)⁶

Dr. Robinette explained that next-generation sequencing has revealed that somatic mutations are ubiquitous across the tissues of the body; this is one reason that the National Institutes of Health (NIH) has funded the Somatic Mosaicism across Human Tissues (SMaHT) Network, which aims to create an atlas of somatic mutations in different organs.⁷

Clonal Hematopoiesis

In particular, the study of clonal hematopoiesis (CH), the phenomenon of clonally expanded hematopoietic stem and progenitor cells that have acquired a selective growth advantage, has led to a better understanding of somatic genetic variation and outcomes for patients with malignant and nonmalignant diseases. Dr. Robinette explained that CH is now understood as a precursor to hematologic malignancies (especially myeloid neoplasms) and is associated with increased all-cause mortality and a higher incidence of cardiovascular disease.⁸

Of note for rheumatologists, Dr. Robinette et al. examined the sequenced exomes of more than 470,000 UK Biobank participants and found that individuals with CH had a 1.48-fold increased risk of developing GCA as compared with those without CH. The risk was highest among those individuals with cytopenias and those with mutations in TET2, a gene that is associated with the development of myeloid neoplasms. TET2 mutations were also associated with an increased risk of vision loss in patients with GCA.⁹ These findings suggest that somatic genetic testing may become important in the prognostic evaluation of patients with GCA in the future.

From both lectures it is clear that the concept of what constitutes a genetic disease and the role that genetic sequencing should play in the practice of a rheumatologist is fast-evolving. It is worth paying attention to this growing area, and only time will tell what insights will be gained by researchers willing to explore the wide world of somatic mutations.

Dr. Jason Liebowitz

Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

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 Dec 31;383(27):2628–2638.
2. Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA. 2023 Jan 24;329(4):318–324.
3. Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood. 2021 Jul 1;137(26):3591–3594.
4. Al-Hakim A, Goldberg S, Gaillard S, et al. Clinical features in VEXAS syndrome: A systematic review. Rheumatology (Oxford). 2025 Oct 1;64(10):5217–5229.
5. Hadjadj J, Nguyen Y, Mouloudj D, et al. Efficacy and safety of targeted therapies in VEXAS syndrome: Retrospective study from the FRENVEX. Ann Rheum Dis. 2024 Sep 30;83(10):1358–1367.
6. Huntley C, Hodder A, Ramachandran M. Clinical and historical aspects of the Elephant Man: Exploring the facts and the myths. Gene. 2015 Jan 15;555(1):63–65.
7.  Somatic Mosaicism across Human Tissues (SMaHT) Network. https://smaht.org/.
8. Evans MA, Sano S, Walsh K. Cardiovascular disease, aging, and clonal hematopoiesis. Annu Rev Pathol. 2020 Jan 24;15:419–438.
9. Robinette ML, Weeks LD, Kramer RJ, et al. Association of somatic TET2 mutations with giant cell arteritis. Arthritis Rheumatol. 2024 Mar;76(3):438–443.