VEXAS syndrome and its vexing presentations: Is VEXAS still under-recognized in India?

INTRODUCTION

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare and newly recognized autoinflammatory condition that has confounded doctors since its identification in 2020. Initially mistaken for long COVID due to its timing around the pandemic and its complex presentation, which predominantly affects males. This syndrome presents with a distinctive, confusing constellation of symptoms, including persistent high-grade fever and other varied manifestations, masking as hematological and rheumatological manifestations with widespread systemic inflammation affecting multiple organs. The presentations vary from mild symptoms, ranging from skin rashes to severe pulmonary and vascular complications, which, despite treatment, resulted in mortality. The underlying cause of VEXAS syndrome is a somatic or mosaic mutation in the UBA1 gene, which encodes the primary E1 activating enzyme, which is essential for initiating all cellular ubiquitin signaling. This mutation disrupts the function of the E1 enzyme, a crucial component of the ubiquitin- proteasome system, leading to the accumulation of dysfunctional proteins and widespread inflammation.¹ What makes VEXAS particularly fascinating is the way it mimics more common disorders, leaving clinicians puzzled as they vigorously search for answers. Widespread and chronic inflammation is the hallmark of this syndrome, and understanding VEXAS offers both a fascinating glimpse into the complexity of our immune systems and opens new challenges for medical research. This article aims to understand the little-known medical mystery that has emerged recently, with its vexing systemic presentations and current available treatment options.

EPIDEMIOLOGY

Initial estimates suggested that VEXAS was exceedingly rare. However, large-scale population genomic studies have significantly revised this understanding. For instance, a U.S.-based exome sequencing study involving over 163,000 participants found that ∼1 in 4,000 males aged >50 years harbored pathogenic UBA1 mutations, implying that thousands of undiagnosed cases may exist globally.²

While most cases occur in males, rare instances have been reported in females with Turner syndrome, skewed X-inactivation, or clonal hematopoiesis.³ The exact incidence is still being defined due to under-recognition and limited availability of genetic testing. The median age of onset is between 60 and 75 years.⁴ More than 90% of reported cases are in males, although female cases have emerged as awareness and genetic testing improve.³ Ethnically, most data have come from North American and European cohorts, but case reports from Asia, including Japan, China, and India, indicate a global distribution.^5,6 VEXAS syndrome is associated with substantial morbidity and mortality. In one of the original cohorts, the 5-year survival rate was ∼63%, with death often due to progressive inflammation, infections, or thromboembolic events.¹ Co-existing hematological malignancies, such as myelodysplastic syndrome (MDS) or multiple organ involvement, further worsen the prognosis.⁴ Misdiagnosis or delayed diagnosis is common, as patients are often initially classified under relapsing polychondritis, Sweet syndrome, or unclassified inflammatory conditions.^1,4 A recent comprehensive systematic review adhering to PRISMA guidelines analyzed all genetically confirmed cases of VEXAS syndrome reported since its initial description in 2020. Data from 720 patients across 33 case reports and 21 case series spanning 32 countries were evaluated to delineate the full clinical spectrum of the disease. Cutaneous involvement emerged as the most frequent manifestation, followed by constitutional symptoms, musculoskeletal involvement, and respiratory disease. Ocular involvement and venous thromboembolism were also commonly observed. Hematological associations were prominent, with myelodysplastic syndrome reported in over 1/3 of patients. Importantly, the review highlighted several under-recognized but clinically significant manifestations, including cardiovascular, renal, and central nervous system involvement, underscoring the multisystemic and heterogeneous nature of VEXAS syndrome and the need for heightened clinical awareness.⁷

In India, documented cases remain few but are gradually increasing. The first reported case in Eastern India described a 67-year-old male with inflammatory arthritis, macrocytic anemia, and elevated inflammatory markers, ultimately diagnosed with VEXAS after targeted genetic testing.⁶ Another case from PGIMER Chandigarh reported coexisting systemic lupus erythematosus (SLE) and VEXAS syndrome.⁸ Limited access to next-generation sequencing in many parts of India may contribute to underdiagnosis, but awareness among rheumatologists and hematologists is increasing.

PATHOGENESIS

VEXAS syndrome is caused by a somatic mutation in the UBA1 gene, located on the X chromosome, which encodes the ubiquitin-activating enzyme E1. Most commonly, this mutation affects methionine-41 (p.Met41), impairing the cytoplasmic isoform (UBA1b), which is crucial for initiating ubiquitination, a process essential for protein degradation and regulation of inflammatory pathways.¹ This mutation arises later in life, explaining the syndrome’s late-onset, and predominantly affects men, though rare female cases with Turner syndrome or skewed X-inactivation have been reported.^2,3 The defective ubiquitination process leads to the accumulation of misfolded proteins, triggering endoplasmic reticulum (ER) stress and the unfolded protein response, which in turn activates proinflammatory cytokine signaling such as interleukin (IL-6), tumor necrosis factor (TNF-α), and type I interferons.^1-4 This chronic activation of the innate immune system causes the hallmark systemic inflammation seen in VEXAS, including fever, skin rashes, and arthritis, often mimicking autoimmune diseases but lacking classic autoantibodies. In the hematopoietic system, the UBA1 mutation causes clonal expansion of mutated progenitor cells, resulting in macrocytic anemia, cytopenias, and characteristic bone marrow vacuolization in myeloid and erythroid precursors.^1-5 Some patients may develop MDS or exhibit coexisting mutations in genes like Tet methylcytosine dioxygenase (TET2) or DNA methyltransferase 3 alpha (DNMT3A), indicating overlap with clonal hematopoiesis. These clonal alterations contribute to both the inflammatory and hematologic phenotypes of VEXAS.

The sustained inflammatory environment also leads to vasculitic features, endothelial injury, and a high risk of thrombosis, explaining the frequent presence of cutaneous vasculitis, pulmonary infiltrates, and vascular complications in these patients. Thus, VEXAS represents a novel interface between autoinflammation, clonal hematopoiesis, and immune dysregulation, requiring high clinical suspicion for diagnosis.

Systemic presentations of VEXAS syndrome:

• 1.

  Hematological manifestations: VEXAS syndrome is almost universally associated with hematologic abnormalities, especially macrocytic anemia, often refractory to treatment.¹ Other findings include thrombocytopenia, leukopenia, and bone marrow vacuolization, a hallmark feature of the syndrome seen in myeloid and erythroid precursors.² Many patients develop clonal hematopoiesis, and some progress to MDS.³

• 2.

  Rheumatological manifestations: Patients often present with treatment-resistant arthritis, relapsing polychondritis, or vasculitis-like symptoms, mimicking diseases like granulomatosis with polyangiitis or Behçet’s disease.⁴ These manifestations often precede the hematologic abnormalities, leading to initial misclassification as autoimmune rheumatic disorders.

• 3.

  Pulmonary manifestations: Pulmonary involvement includes recurrent pneumonitis, interstitial lung disease, and pleural effusions. Lung biopsies may reveal non-specific inflammation or organizing pneumonia.⁵ These findings can resemble other autoimmune lung diseases, complicating the diagnosis.

• 4.

  Dermatological manifestations: Cutaneous signs include neutrophilic dermatoses such as Sweet syndrome and leukocytoclastic vasculitis.⁶ Skin biopsies often show intense neutrophilic infiltration without infection, and lesions may appear on the limbs or trunk, often in association with systemic flares.

• 5.

  Gastrointestinal and hepatic manifestations: Some patients experience abdominal pain, nausea, or transaminitis, and liver biopsies can show non-specific inflammation or portal tract infiltrates.⁸ Though less common, gastrointestinal symptoms may be misleading and can result in investigations for inflammatory bowel disease or hepatic vasculitis.

• 6.

  Neurological manifestations: Neurological symptoms such as peripheral neuropathy, sensorineural hearing loss, and even stroke-like episodes have been reported.¹ These are thought to result from vasculitic or thrombotic complications due to the underlying autoinflammatory state and hypercoagulability.⁹

• 7.

  Renal and genitourinary manifestations: Renal involvement is infrequent but has been documented in the form of proteinuria, microscopic hematuria, and, in some cases, tubulointerstitial nephritis and renal failure. Genitourinary manifestations are rare and nonspecific, with occasional reports of orchitis or lower urinary tract symptoms, though these are not well characterized.¹

• 8.

  Ocular manifestations: ocular symptoms are uncommon but may present as episcleritis, scleritis, or uveitis. These conditions reflect the systemic autoinflammatory nature of the disease and may occur alongside other constitutional and vasculitic features. Prompt recognition is important to prevent and preserve visual functions.¹⁰

• 9.

  VEXAS syndrome in females: Although VEXAS syndrome is predominantly described in males due to its X-linked pathogenesis, rare cases in females have been reported. These cases are typically associated with X-chromosome monosomy, skewed X-inactivation, or acquired somatic mosaicism involving the UBA1 gene. Female patients described in the literature exhibit clinical features broadly like those seen in males, including systemic inflammation, cytopenias, and steroid-refractory disease. However, diagnostic delays may be more pronounced due to the perceived rarity of the condition in females. Awareness of VEXAS syndrome in women with compatible clinical and hematologic features is essential to avoid under-diagnosis and ensure timely genetic evaluation.^1-7

CONCLUSION

VEXAS syndrome stands at the intersection of genomics, inflammation, and hematology, a stark reminder that not all systemic illnesses fit the conventional autoimmune picture. Caused by a somatic mutation in the UBA1 gene, it presents with a constellation of features: fevers, cytopenias, chondritis, vasculitis, and vacuolated myeloid precursors to other systemic involvements. While global awareness is rising, recognition in India remains limited, often leading to misdiagnosis as refractory autoimmune disorders or even tuberculosis, especially in geriatrics. With the growing accessibility of next-generation sequencing and a rising index of suspicion, Indian clinicians must begin to think beyond the infectious-autoimmune binary, particularly when standard therapies fail. In an era of precision medicine, VEXAS challenges us to bring genomic thinking to the forefront of clinical practice in India.

Authors’ contributions

AKS: Design, definition of intellectual content, literature search, manuscript preparation, manuscript editing and review; HS: Conceptualization, literature review, manuscript drafting, manuscript editing, data collection and interpretation, and final approval of the manuscript.

Ethical approval

Institutional Review Board approval is not required.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.