Towards treatments for VEXAS

Abstract

VEXAS is a new hematologic disease. VEXAS is an acronym from the syndrome’s key characteristics: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. As an acquired genetic defect of the hematopoietic stem cell, VEXAS is analogous in its pathophysiology to paroxysmal nocturnal hemoglobinuria, and to other diseases familiar to hematologists in which somatic mutations are etiologic.1 VEXAS was identified using a genotype-first approach to screen DNA from patients with rheumatologic disease: highly localized mutations in the X-linked UBA1 gene, resulting in loss of function of the E1 enzyme of the ubiquitinoylation pathway, were found in 25 men with severe systemic inflammation, and also a predisposition to hematologic malignancies.2 One implication of its molecular discovery is that archived tissue can be easily subjected to rapid screening for the specific mutation. Since the original publication, several groups have reported heterogenous clinical phenotypes but also a high frequency of refractoriness to available treatments.3-5 Glucocorticoids are effective but almost always require sustained treatment at high doses, with breakthrough inflammatory flares and marked drug toxicities.5 Cytopenia, particularly macrocytic anemia, and cytoplasmic vacuoles in marrow are nearly universal, and myelodysplastic features in the marrow are common in VEXAS.6 Myelodysplastic syndrome (MDS) is diagnosed in 40–50% of cases, most lower-risk.6-8 Therefore, many patients have received treatment directed towards MDS. In the short but timely retrospective report by Dr. Comont et al., the efficacy and safety of azacytidine in 11 VEXAS patients with MDS with a particular focus on the response to inflammatory manifestations are reported. Azacytidine, a derivative of the nucleoside cytidine, is a hypomethylating agent widely used for the treatment of MDS. While all included patients treated with azacytidine in this cohort met the criteria for MDS based on WHO 2016, the indication for treatment was uncontrolled inflammation despite chronic corticosteroid therapy in 8/11 cases. With relatively long median follow-up of 32 months, there was improvement of inflammatory symptoms, major and minor responses, in 46% (n = 5) of treated patients after 4 cycles of azacytidine. This clinical observation raises multiple questions about the disease course and azacytidine as a therapy: How does azacytidine act to improve inflammation? Does treatment alter UBA1 clone size or affect the function of mutated cells? Could azacytidine in the inflammatory phase of VEXAS decrease the high risk of MDS later in the disease course? There are two major approaches to therapeutics in VEXAS: to target and eradicate the etiologic UBA1 clone and/or inhibit inflammatory pathways and cytokines. In VEXAS, inflammation is believed to be primarily driven by myeloid cells, especially neutrophils.2 Up-regulation of an inflammatory gene signature was observed in a zebrafish model with engineered loss of uba1. Ongoing efforts to develop a mouse model and sophisticated single cell experiments will further characterize the biological effects of UBA1 mutations. Perhaps azacytidine interrupts this pro-inflammatory pathway. Recent evidence suggests direct effects of hypomethylating agents on immune cells9 and pre-clinical models have shown its effectiveness in other systemic autoimmune diseases.10 For instance, azacytidine reduced pulmonary inflammation in a murine model of acute lung injury, with reduction in neutrophil numbers and decreased cytokines and chemokines.11 In addition, hematopoietic stem and progenitor cells with UBA1 mutations may be differentially susceptible to azacytidine. VEXAS is a heterogenous disease in its clinical manifestations, with multi-organ involvement and variable marrow dysfunction: responses to therapy will need to be carefully categorized across organ systems. The authors in the current report used objective measures of inflammatory markers and reduction in steroid dose, which are appropriate for immunomodulatory therapy. However, changes in the UBA1 clone size and immune cell phenotyping will be useful in future studies. Of importance, few VEXAS cases have co-occurring myeloid neoplasm gene mutations2, 12 and their role in disease is not entirely clear at the moment. Two responding patients in the current report had concurrent DNMT3A. VEXAS results in high morbidity and mortality. Effective therapeutics and development of a treatment algorithm are immediate goals.13 In addition to azacytidine, anti-IL6 (tocilizumab),14 JAK inhibitors (ruxolitinib),4 and hematopoietic stem cell transplantation15 have been effective in small cohorts and case reports. The current article describes three patients who showed hematologic improvement without improved inflammatory symptoms, indicating that azacytidine might also serve as a bridge to hematopoietic stem cell transplant in VEXAS. As more is learned about this new disease, many available immune therapies can be repurposed. While HSCT should be curative, it may not be ideal for all patients, who are older, at high risk of infections (due to lymphopenia, monocytopenia, and prolonged glucocorticoid use), and may have decreased performance status. Tolerability of treatment should be prioritized. Careful clinical observations and publications, as in the current work, and ultimately prospective clinical trials will suggest and prove the value of treatments, and patients in hematology and rheumatology clinics should be strongly encouraged to participate in research.

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