VEXAS Syndrome Often Misdiagnosed as Pyoderma Gangrenosum

Some cases traditionally identified as pyoderma gangrenosum (PG) in patients with certain blood diseases may actually be another rare autoimmune condition, suggest researchers.

Publishing their findings in Journal of the American Academy of Dermatology, the researchers offer insight into considerations for screening for VEXAS syndrome, a syndrome first described just 4 years ago, in certain cases of suspected or confirmed PG.¹

“Although the pathogenesis of PG is not fully elucidated, associations with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have been reported,” explained the researchers. “Our understanding of these associations has evolved with the recognition of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, a condition identified by Beck et al, arising from somatic mutations in the UBA1 gene.”

The discovery of VEXAS syndrome was reported in 2020, in which Beck et al characterized the rare, often life-threatening syndrome. The group identified 25 men with somatic mutations affecting methionine-41 in UBA1. Symptoms occurring among these men included recurring fevers, lung involvement, skin manifestations, and macrocytic anemia. Notably 40% of the men died from disease-related causes or from complications related to treatment.²

In the recently published systematic review, the researchers determined that the syndrome typically presents in men, with atypical morphology, and with systemic symptoms. These findings, suggest the researchers, call for an increased diligence for identifying cases of VEXAS syndrome when patients with PG present with atypical findings and have MDS or CMML. The group also suggested consideration for genetic testing for these UBA1 mutations for these patients.

The group compiled studies from various online databases, analyzing patient data to determine if PG cases previously identified in patients with MDS or CMML may actually be cases of VEXAS syndrome. Previous data have suggested that VEXAS is more common than historically expected. In another paper by Beck et al, researchers analyzed data from more than 163,000 patients in Geisinger’s electronic health records between 1996 and 2022. The analysis suggested that 1 in 13,591 people have UBA1 pathogenic variants.³

Researchers in this newly published systematic review analyzed data from 46 identified studies, comprising 53 patients with PG and concurrent MDS or CMML. Of these patients, the researchers pinpointed 29 as having key indicators of VEXAS syndrome.

All 29 of these patients were men, with a median age of 57.1 years, and 44.8% had an unknown subtype of PG. PG involvement was commonly observed in the trunk (48.3%), upper extremity (37.9%), and head/neck (34.5%). Most patients presented with fever (86.2%). Other symptoms included inflammatory arthritis (51.7%), chondritis (44.8%), pulmonary infiltrates (27.6%), and vasculitis (24.1%). Skin symptoms included neutrophilic dermatoses (34.5%) and nodules (17.2%).

The researchers observed that a notable number of patients were refractory to treatment, with more than 1 in 3 (41.4%) patients having no response to glucocorticoids, cyclosporine, and/or chemotherapy.

“The absence of genetic data in earlier reports presents an inherent limitation, precluding definitive diagnoses of VEXAS syndrome; however, we employed a detailed comprehensive review of all cases, aligning clinical and laboratory findings with established characteristics of VEXAS syndrome,” described the researchers. “Despite the retrospective nature of our data and possibility of publication bias, our review highlights that PG in the setting of MDS and CMML may have, historically, represented syndromic disease states including Sweet syndrome and VEXAS, presenting with neutrophilic dermatoses and PG-like manifestations.”

References

1. Croitoru DO, Huang RS, McMullen EP, et al. Investigating historic cases of pyoderma gangrenosum in myelodysplastic syndrome and chronic myelomonocytic leukemia for possible VEXAS syndrome: a systematic review. J Am Acad Dermatol. Published online June 19, 2024. doi:10.1016/j.jaad.2024.05.086

2. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383(27):2628-2638. doi: 10.1056/NEJMoa2026834

3. Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. 2023;329(4):318-324. doi:10.1001/jama.2022.24836