Disease Trajectories and Glucocorticoid Exposure in VEXAS Syndrome Treated with Cytokine-Directed Therapies

Benjamin A Turturice; Alice Fike; Bhavisha A Patel; Emma M Groarke; Fernanda Gutierrez-Rodriguez; Karyssa Stonick; Hannah Berrett; Shanni Liu; Ivana Darden; Kaitlin A Quinn; Neal S Young; Peter C Grayson

doi:10.1016/j.ard.2025.05.021

Disease Trajectories and Glucocorticoid Exposure in VEXAS Syndrome Treated with Cytokine-Directed Therapies

Ann Rheum Dis. 2025 Jun 27:S0003-4967(25)01039-8. doi: 10.1016/j.ard.2025.05.021. Online ahead of print.

Affiliations

¹ National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
² National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
³ National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: peter.grayson@nih.gov.

PMID: 40581580
DOI: 10.1016/j.ard.2025.05.021

Abstract

Objectives: To establish the long-term impact of cytokine-directed therapies on glucocorticoid use and clinical outcomes in Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS).

Methods: Patients with VEXAS were prospectively followed for events of transfusion dependence, haematopoietic stem cell transplantation or death. Laboratory results, glucocorticoid exposure and clinical measures were retrospectively assessed in relationship to treatment initiation with interleukin-6-directed therapies (anti-IL6R) or Janus kinase inhibitors (JAKi). Patients were stratified by UBA1 variants and presence of typical clonal haematopoiesis with variant allele fraction ≥ 10% (CH^V^AF^≥^10%).

Results: In 71 VEXAS patients (81.7% with anti-IL6R or JAKi exposure), event-free survival differed by genotype and presence of concomitant CH^V^AF^≥^10%: p.M41V (HR [95% confidence interval (CI)]: 5.7 [1.5-20.4]) or p.M41L/T with CH^V^AF^≥^10% (hazard ratio [HR]: 5.7 [1.6-20.8]) compared to p.M41L. No association between event rates and exposure to anti-IL6R or JAKi was observed. The p.M41V genotype had the highest risk of anaemia, elevated C-reactive protein (CRP) levels, and monocytopenia. Over a median follow-up of 4.8 (interquartile range [IQR] 3.0, 8.1) years, the patients' mean glucocorticoid dose was >15 mg/day prednisone regardless of variant or disease duration. At prospective visits, clinical remission on ≤10 mg/day prednisone was observed in only 2.7% of visits. Treatment with anti-IL6R or JAKi showed no clinically meaningful reduction (<5 mg/day difference) in steroid exposure at 1 year post-treatment. No attenuation in the progression of anaemia was observed in response to anti-IL6R and JAKi.

Conclusions: Cytokine-directed therapies alone do not alter the risk of haematologic disease progression or significantly reduce glucocorticoid exposure in VEXAS. These data provide benchmarks for future interventional studies.

Published by Elsevier B.V.