Investigating treatment strategies for VEXAS syndrome: Deciphering the possibilities for therapeutic intervention

Abstract

BACKGROUND Beck et al.[1] discovered in December 2020 that VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome stems from an acquired Ubiquitin-like modifier activating enzyme 1 (UBA1) gene anomaly within hematopoietic progenitor cells. This adult-onset systemic autoinflammatory disorder arises due to somatic mutations, particularly in methionine-41 of exon 3 of the UBA1 gene. This gene encodes an enzyme crucial for ubiquitylation processes. The resulting mutation produces a truncated cytoplasmic isoform of the enzyme, which lacks catalytic activity. Consequently, ubiquitylation decreases, curbing the activation of innate immune pathways. This dysregulation contributes to heightened serum cytokine levels, triggering severe inflammatory responses. Recognizing VEXAS syndrome holds paramount importance for healthcare practitioners, as it provides a definitive diagnostic marker, facilitating the formulation of a targeted treatment approach. Notably, patients initially diagnosed with various inflammatory disorders, including relapsing polychondritis, were later found to harbor UBA1 mosaicism in their blood, underscoring the complexity of diagnosis.[2,3] CURRENT TREATMENT AND LIMITATIONS The treatment approach involves targeting both UBA1-mutated hematopoietic cell eradication and inflammation inhibition. The effectiveness of the current treatment strategy for VEXAS syndrome exhibits notable variability among individuals. This strategy encompasses the use of glucocorticoids, conventional disease-modifying antirheumatic drugs (cDMARDs) such as methotrexate, mycophenolate mofetil, and azathioprine, as well as interventions targeting interleukin (IL)-1, IL-6, and Janus kinase (JAK) inhibitors. While utilizing glucocorticoids to manage VEXAS symptoms offers benefits in the initial control of the condition, the notable occurrence of dependency on steroids and subsequent flare-ups following dosage reduction highlights the necessity for alternative strategies.[4] Although the IL-1 receptor antagonist anakinra has demonstrated its therapeutic potential in stabilizing symptoms over 1-2 years, it is linked to severe dermatologic reactions at the injection sites.[1] Although the combination of cyclosporin A and anakinra effectively prevented paradoxical skin flares, it was accompanied by the notable drawback of inducing significant neutropenia as a side effect.[5] For individuals without severe hematologic abnormalities in VEXAS syndrome, a treatment strategy involving Tocilizumab alongside low-dosage glucocorticoids may be considered, given the elevated IL-6 levels observed in these patients.[1] A combined regimen of Tocilizumab and methotrexate has demonstrated advantages in suppressing IL-6.[6] Conversely, some patients who do not respond effectively[7] to this approach have reported tocilizumab-related neutropenia, infections by the herpes zoster virus, and significant gastrointestinal complications.[6] The JAK inhibitors are another option but reported discrepancies toward curbing the inflammations. Ruxolitinib, which inhibits JAK1 and JAK2, worked more effectivity compared with other JAK inhibitors in the clinical setup for half of the patients within a month and in more than 80% of patients at the 3-month evaluation. Conversely, Tofacitinib, Baricitinib, and Upadacitinib showed poor clinical outcomes.[8] The major drawback of the JAK inhibitors is that they do not significantly affect peripheral cytopenia.[7] EMERGING THERAPIES AND THEIR BENEFITS Although mortality risks are associated, allogeneic hematopoietic stem cell transplantation (ASCT) treats VEXAS syndrome well for severe inflammatory symptoms or myelodysplastic syndromes (MDS). A series of cases showing successful treatment courses with ASCT rejuvenating the immune system by ASCT may be an ideal treatment. Still, looking at its complexity and other therapeutic options, clinical trials are strongly recommended for further confirmation.[2] Azacitidine is used to treat MDS and has also been mentioned as a potential treatment option for VEXAS syndrome.[9] Long-term data on treatment results are limited, and there needs to be a consensus on the best treatment strategy for VEXAS syndrome, which requires further study. Azacitidine and decitabine, potent DNA methyltransferase inhibitors used for MDS, have shown efficacy in the pretreatment before ASCT in MDS-associated inflammation.[10] In 46% of the patients, inflammatory symptoms exhibited improvement, coinciding with reduced reliance on steroids. Additionally, two of five patients demonstrated enhanced hematological responses lasting over a median of more than 1 year.[9] A clinically effective outcome was observed in a study where three of four MDS patients who had undergone 4–5 months of therapy showed better median time for the successive treatment contrasting anticytokine agents, methotrexate, and cyclosporine.[7] CONCLUSION To summarize, the therapeutic arsenal for VEXAS syndrome encompasses glucocorticoids, cDMARDs, and customized medications. While JAK inhibitors exhibit promise in addressing this condition, further research is imperative. Prospective avenues like ASCT and azacitidine have demonstrated potential as well. Nevertheless, the optimal treatment approach for VEXAS syndrome remains ambiguous, and the substantial mortality rate associated with this disorder raises apprehensions. Collaborating with leading research institutions worldwide through clinical trials and multicenter initiatives is paramount to formulating effective and dependable treatment strategies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.