Notice of an article in Nature rolled into my inbox and stopped me up short. It alerted me to a study published in January 2023 on VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic). I’m going to have to stop saying that something has “blown my mind,” for fear of overusing it. Never had I ever heard of this. Turns out, it was discovered in 2020 that variants on the gene ubiquitin like modifier activating enzyme 1 (UBA1) cause autoimmune and hematologic (blood) disease. The 2023 study uses data from a Whole Exome Sequencing project in Pennsylvania. Study subjects are individuals in the Geisinger healthcare system who agreed to have their exomes sequenced for a variety of research purposes. The Whole Exome Sequencing study is called “MyCode Community Initiative.”
There, right in my inbox is the stunning example of what I’ve been learning and writing about since September. First, it’s spectacular to have data on a subject population that’s this large. It’s so uncharacteristically large for studies on autoimmune disease. Second, it perfectly illustrates how Whole Exome Sequencing is one of the fundamental solutions to accurate autoimmune disease diagnosis, and research on treatments. Unrelated to this study, the first 3 patients identified as having VEXAS syndrome were found through sequencing their genome. Subsequent “ascertainment,” as the researchers call it, was made using signs and symptoms of the disease, not sequencing. Not surprisingly, no diagnostic criteria for VEXAS syndrome exists.
To find out more, the researchers use the exome data as a way to study the prevalence of UBA1 disease-causing variants in the MyCode Community Initiative population. The researchers scoured patient medical records between January 1, 1996 through January 1, 2022 to determine which participants with disease-causing UBA1 variations showed signs and symptoms of VEXAS. They found that what was previously considered an exceptionally rare disease actually had a prevalence in their participant population of 1 in 13,591. That’s actually an incredible finding when you consider that the better known Systemic Lupus Erythematosus is thought to have an approximate prevalence rate in the United States of 15 in 10,000 (I will always choose the higher number when reporting prevalence ranges because it is my belief that autoimmune disease is under-diagnosed).
The research findings are particularly relevant to studying treatment because UBA1 disease-causing variants are not something participants are born with. They are acquired and occur later in life. This suggests that there may be a way to revert UBA1 gene expression to non-disease causing expression. So, that explosive feeling in my brain after reading that piece of information…wow! What other autoimmune disease causing variants occur with advancing age? The participants in this study with disease-causing variants carried
a variety of clinical diagnoses, including polyarteritis nodosa, relapsing polychondritis, giant cell arteritis, Sweet syndrome, and myelodysplastic syndrome (MDS).
So, why am I vexed? It’s a little bit because after titling this post I found an earlier article using the same word similarities that I did. It’s also because VEXAS is x-linked, so it more commonly occurs in men. I am not against advances in autoimmune disease discoveries in males, but considering high prevalence rates among females, I can’t help a little disappointment. Still, this is fascinating, fits well into Organized Autoimmunity, and elucidates so much about how autoimmune disease may work, in both males and females, possible treatment avenues, and more effective ways to understand prevalence.
My next posts will review the 2023 VEXAS study in more depth. I apologize for missing my post last Friday and that this one is late today. Our community has serious school board drama that has consumed a lot of my free time. Going forward, I plan to post once per week on Fridays. Once I’ve finished posting about the elucidating VEXAS syndrome, I plan to focus posts on what I find out while researching individual diagnosis descriptions. I need to focus more of my time on filling in important information on my List of Autoimmune Disorders to test my theory of Organized Autoimmunity. I also find it very annoying when the thing I most want to look up on a list is blank or “coming soon.” I imagine others do too, so I need to spend time fixing that. As always, I really appreciate your readership, and find it kind of amazing that you want to go on a deep dive with me.
References
Beck DB, Bodian DL, Shah V, et al. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. 2023;329(4):318–324. doi:10.1001/jama.2022.24836