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Sharpening our "Spidey Sense" - Unravelling the Cause of Levamisole-induced Vasculitis

Dr. Lillian Barra  Featured
November 10 2015 1:14 AM ET via RheumReports RheumReports

Levamisole is an antihelminthic and immunomodulator that has been withdrawn from the market on account of severe adverse events, including vasculitis skin ulcerations. Recently, it has been reported that levamisole is frequently used to adulterate cocaine in order to increase revenues. The Drug Enforcement Agency reports that 70% of cocaine in the USA is adulterated with levamisole. This has led to an increased incidence of levamisole-induced vasculitis that mimics granulomatosis with polyangiitis (GPA), characterized predominately by ischemic skin lesions on the face, ears and limbs, arthritis and positive autoantibodies (anti-PR3, ANA, anti-MPO, etc.), but can also present with other vasculitic manifestations, including glomerulonephritis. It can coexist with cocaine-induced midline facial destructive lesions, which can further complicate diagnosis, especially since a toxicology screen for cocaine will only be positive for approximately 3 days. Treatment involves stopping the exposure, and may require immunosuppression.

The mechanism behind levamisole-induced vasculitis is unknown. In a series of elegant experiments, Grayson et al. are unraveling the cause of this disease, which may have implications for other types of drug-induced vasculitis. They are studying Neutrophilic Extracellular Traps (NETs), which are spiderweb-like structures excreted by neutrophils that are hypothesized to trap infectious agents to assist with the immune response. NETs have been implicated in various autoimmune diseases including RA, where citrullinated peptides trapped within the NETs are thought to promote breaks in immune tolerance.

Grayson's group showed that neutrophils exposed to levamisole produced large amounts of NETs (abstract #1085). In addition, cells isolated from patients with levamisole-induced vasculitis produced NETs in vitro whereas neutrophils from normal subjects did not. The cells in a given individual stopped producing NETs when the patient stopped using cocaine. Furthermore, NET production was found to be dependent on muscarinic receptors.

This study provides insight into the mechanisms of drug-induced vasculitis and could potentially lead to new diagnostic biomarkers or therapeutics that may apply to other types of vasculitis. However, from a cohort of cocaine users in which all were exposed to levamisole, only a small proportion (<5%) developed vasculitis. Clearly there are other factors at play that are important in inducing vasculitis.


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About the Author

Dr. Lillian Barra
Dr. Lillian Barra

Lillian Barra is an Assistant Professor at Western University. Her research interests include autoimmune vascular disease and the role of autoantibodies in rheumatoid arthritis.

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