As an example of the implications of this intricate network, a recent case report revealed the development of VEXAS syndrome, one of the newly discovered autoinflammatory conditions, after SARS-CoV-2 infection in a patient with both NOD2 and UBA1 gene mutations.13 The mechanisms responsible for this presentation are not well defined but appear to involve loss of the normal ubiquitination of the NOD2 sensor by genes such as UBA1, further enhanced by SARS-CoV-2’s innate deubiquitinating enzymes. An additional component to the pathogenesis lies in the fact that ssRNA of SARS-CoV-2 is itself a target for activation of the NOD2 sensor.
Given that our patient presented with symptoms of her disease before her SARSCoV-2 infection, it is possible the timing of her COVID-19 illness and subsequent increased frequency of her symptoms are merely related through synchronicity. We wonder, however, if COVID-19 may have played a more direct rather than contributory role as described in other case reports because it appears to be involved in a key mechanistic pathway between cytosolic immune sensing and a dysfunctional inflammatory response.
As our understanding of autoinflammatory disease grows, we need to be aware of the possibility that a patient may harbor more than one genetic mutation, with possible phenotypic and therapeutic implications on their disease. Lastly, it is possible that infections may augment the course of these diseases and help unravel the mechanisms associated with pathogenesis.
Saud Abaalkhail, MD, is a rheumatology fellow at Larkin Community Hospital, Miami. He completed his internal medicine residency training at Saint Vincent Hospital in Massachusetts.
Muhammed Umair Javaid, DO, is a recent graduate of the rheumatology fellowship program at Larkin Community Hospital, Miami, and is now an assistant professor of medicine in the rheumatology department at Augusta University, Georgia.
Amarie Negron Rodriguez, MD, is a private practice rheumatologist in Fort Lauderdale, Fla., and is actively involved in the education and training of future rheumatologists.
Acknowledgment
The authors thank Qingping Yao, MD, PhD, both for his contributions to this article, and for expanding our knowledge and understanding of this rare condition.
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