Our goal in this section is to provide summaries as well as the text of medical articles so that you understand the significance of major articles and how their findings build on the base of knowledge about VEXAS syndrome and effective treatments. We begin with three of the fundamental articles about VEXAS.

Article

Beck, D.B. et al., “Somatic Mutations I UBA1 and Severe Adult-Onset Autoinflammatory Disease,” New England Journal of Medicine, 383:27; December 31, 2020, https://doi.org/10.1056/NEJMoa2026834

Summary

This study highlights the role of somatic mutations in adult-onset inflammatory diseases. VEXAS syndrome represents a new category of autoinflammatory disease driven by myeloid-restricted UBA1 mutations. 

  • Adult-onset inflammatory syndromes often have overlapping clinical features. 

  • Somatic mutations in ubiquitin-related genes, particularly UBA1, were identified as a cause of a new disorder. 

  • UBA1 encodes the E1 enzyme essential for ubiquitylation, a process regulating cellular functions. 

Methods

  • Peripheral-blood exome sequencing was used to identify mutations in ubiquitin-related genes. 

  • Functional studies included Sanger sequencing, immunoblotting, flow cytometry, transcriptome profiling, and CRISPR-Cas9 zebrafish models. 

Key Findings

Discovery of VEXAS Syndrome:

  • Identified somatic mutations in UBA1 affecting methionine-41 (p.Met41) in 25 men. 

  • Named the disorder VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. 

  • Symptoms include fevers, cytopenias, vacuoles in myeloid and erythroid precursor cells, neutrophilic inflammation, chondritis, vasculitis, and dysplastic bone marrow. 

Genetic Features:

  • UBA1 mutations were somatic and restricted to myeloid cells, not lymphocytes or fibroblasts. 

  • Mutations led to loss of the cytoplasmic UBA1 isoform (UBA1b) and expression of a catalytically impaired isoform (UBA1c). 

Clinical Features:

  • Median age of onset: 64 years. 

  • Common symptoms: recurrent fevers (92%), skin involvement (88%), pulmonary infiltrates (72%), chondritis (64%), and macrocytic anemia (96%). 

  • High mortality rate: 40% of participants died from disease-related causes. 

  • Glucocorticoids were the only treatment consistently effective in reducing inflammation. 

Functional Studies:

  • Mutant cells showed decreased ubiquitylation and activation of innate immune pathways. 

  • Zebrafish models confirmed systemic inflammation due to loss of cytoplasmic UBA1 function. 

Implications:

  • VEXAS syndrome connects seemingly unrelated adult-onset inflammatory syndromes. 

  • Somatic mutations in UBA1 are a major cause of severe inflammatory conditions in men. 

  • Potential treatments include targeting the clonal somatic process, such as bone marrow transplantation or gene-editing therapies. 

Article

Ferrada, Marcela et al., “Translation of Cytoplasmic UBA1 Contributes to VEXAS Syndrome Pathogenesis,” Blood, Vol. 140, No. 13, September 29, 2022, https://doi.org/10.1182/blood.2022016985

Summary

This article highlights the clinical, genetic, and molecular insights into VEXAS syndrome, emphasizing the negative impact of the p.Met41Val variant and transfusion dependence on survival and disease severity.  

Vexas Syndrome Overview

  • VEXAS syndrome is an adult-onset inflammatory disease caused by somatic mutations in the UBA1 gene at p.Met41. 

  • It is characterized by systemic inflammation, hematologic abnormalities, and high mortality rates. 

  • Mutations at p.Met41 lead to reduced translation of the cytoplasmic isoform UBA1b and production of an impaired isoform, UBA1c. 

Key Findings

Survival Predictors:

  • Ear chondritis: Associated with increased survival. 

  • Transfusion dependence: Linked to decreased survival (hazard ratio: 4.47). 

  • p.Met41Val variant: Associated with the shortest survival (median: 9 years) compared to p.Met41Leu and p.Met41Thr variants. 

  • No patient with the p.Met41Val variant survived beyond 12 years after symptom onset. 

Clinical Manifestations:

  • Fever, skin involvement, arthritis, pulmonary infiltrates, and ear chondritis are common symptoms. 

  • Specific genetic variants correlate with distinct clinical features:

    • p.Met41Val: Associated with undifferentiated inflammatory syndrome and less ear chondritis. 

    • p.Met41Thr: Linked to inflammatory eye disease. 

    • p.Met41Leu: Associated with Sweet syndrome. 

Molecular Mechanism:

  • The p.Met41Val variant supports significantly less UBA1b translation compared to p.Met41Leu and p.Met41Thr. 

  • Reduced UBA1b levels correlate with increased disease severity and mortality. 

  • A minimum threshold of UBA1b translation is required for disease progression, and p.Met41Val produces levels below this threshold. 

Why p.Met41Val is Worse:

  • The p.Met41Val mutation results in the lowest residual translation of UBA1b among the three canonical VEXAS variants.

  • This leads to more severe disease manifestations and shorter survival. 

  • Molecular studies show a two-fold reduction in UBA1b levels compared to p.Met41Leu and p.Met41Thr, explaining its association with worse outcomes. 

Why Transfusion Dependence is Worse:

  • Transfusion dependence reflects progressive bone marrow failure, a hallmark of advanced VEXAS syndrome. 

  • Patients requiring frequent red blood cell transfusions (>3 times in 6 months) have significantly higher mortality rates. 

  • It is a time-varying predictor of death, indicating worsening hematologic dysfunction and systemic disease progression. 

Implications for Treatment:

  • Reactivating UBA1c or increasing UBA1b levels through targeted therapies could be potential strategies for managing VEXAS syndrome. 

  • Genotype-driven risk stratification may guide clinical decisions, including bone marrow transplantation. 

Study Limitations:

  • Retrospective design and modest sample size may introduce confounding factors. 

  • Findings need validation in larger cohorts and prospective studies. 

Article

Czech, Mary et al., “Opportunistic Infections, Mortality Risk, and Prevention Strategies, in Patients with VEXAS,” Open Forum Infectious Diseases, July 23, 2024, https://doi.org/10.1093/ofid/ofae405.

Summary

This study concludes that patients with VEXAS syndrome are at high risk for infections, which can worsen outcomes.  Preventive measures like prophylaxis for PJP and VZV are effective and should be prioritized.  Prophylaxis not only prevents infections but also reduces mortality risks. Careful diagnosis and a team-based approach are essential for managing this complex condition. 

Key Findings

Common Opportunistic Infections:

  • Pneumocystis jirovecii pneumonia (PJP): A fungal infection that causes severe lung inflammation, especially in immunosuppressed patients. Found in 6% of VEXAS patients. 

  • Alphaherpesviruses: Reactivation occurred in 15% of patients, with varicella zoster virus (VZV) (causes shingles) being the most common and herpes simplex virus (HSV) (causes cold sores or genital herpes) less frequent. 

  • Nontuberculous mycobacteria (NTM): Environmental bacteria that can cause skin, soft tissue, or lung infections.  Found in 10% of patients, often leading to severe complications.

Impact on Mortality: 

  • Patients with PJP or NTM infections had a significantly higher risk of death. 

  • Herpes simplex virus (HSV) reactivation also increased mortality risk, but VZV did not. 

Why Prophylaxis is Important:

  • Preventive treatment (prophylaxis) for PJP and VZV significantly reduces infection rates and improves survival outcomes. 

  • Prophylaxis for PJP had a "number needed to treat" (NNT) of 4, meaning treating 4 patients prevents 1 infection. 

  • Prophylaxis for VZV had an NNT of 7. 

  • Without prophylaxis, these infections can lead to severe complications and shorten survival.

Challenges in Diagnosis: 

  • Many patients were treated for presumed infections (e.g., pneumonia or skin infections) that were later found to be inflammation caused by VEXAS, not actual infections. 

  • This highlights the importance of careful evaluation to avoid unnecessary antibiotic use. 

Risk Factors for Infections: 

  • Advanced age, chronic use of immunosuppressive medications (like steroids), and bone marrow failure contribute to infection risk. 

  • Skin breakdown and immune dysfunction also increase susceptibility to infections like NTM. 

Recommendations:

Prophylaxis:

  • Patients with VEXAS syndrome should receive preventive treatment for PJP and VZV, especially if they are on immunosuppressive therapies. 

  • Prophylaxis is critical to reduce infection rates and improve survival. 

Careful Evaluation:

  • Distinguish between infections and inflammation caused by VEXAS to avoid overuse of antibiotics. 

  • Invasive tests (e.g., biopsies or bronchoalveolar lavage) may be needed for accurate diagnosis. 

Multidisciplinary Approach: 

  • Management of VEXAS syndrome should involve specialists in infectious diseases, rheumatology, and hematology.

Videos

VEXAS and Relapsing Polychondritis Webinar for Patients Interview with Dr. Marcela Ferrada

ERN ReCONNET. September 11, 2023

VEXAS Syndrome Interview with Dr. Emma Groarke

EBMT Trainee Pearls for Hematologists. December 4, 2021

VEXAS and Importance of Wide range of Clinical Manifestations Interview with Dr. Marcela Ferrada and Dr. David Beck

RheumNow. November 9, 2021

Clinical Heterogeneity in VEXAS Dr. Matthew Koster

Mayo Clinic. October 4, 2021