Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused upon two rarer forms of vasculitis: drug-induced vasculitis and large vessel vasculitis (LVV). In terms of drug-induced vasculitis, we have focused on levamsiole, an anti-helminth drug that has recently been implicated in cases of drug-induced autoimmunity in humans exposed to cocaine adulterated with levamisole for profit. The United States Drug Enforcement Agency estimates that >75% of cocaine within the US has been contaminated with levamisole. We discovered that levamisole induces neutrophil extracellular trap (NET) formation through engagement of muscarinic receptors on the surface of neutrophils. Through animal models we defined that the M3 muscarinic receptor specifically is triggered by levamisole. In collaboration with colleagues from the National Institute of Drug Abuse and colleagues from the University of San Francisco, we studied sera from cohorts of patients actively using cocaine contaminated with levamisole was used to identify novel autoantibodies against NET components. We also studied the effect that levamisole and NETs on vascular endothelial cells and found that levamisole-induced NETs were toxic to endothelial cells in vitro and in aortic myogram models. These data suggest that NETs are a source of autoantigens in levamisole-induced autoimmunity, contribute to vascular damage, and that heretofore uncharacterized interactions between the cholinergic nervous system and neutrophils may play a causal role in autoantibody formation and autoimmune disease. Abstracts related to this work have presented at the 2015 American College of Rheumatology Annual Meeting and the 2016 EULAR League Against Rheumatism Annual meeting as oral presentations. A manuscript of this work is currently under revision. In terms of LVV, we continue to recruit patients with these rare diseases. To date, we have performed whole body PET scans and angiography on 60 patients with LVV. We have discovered vascular abnormalities on PET scans suggestive of ongoing subclinical vascular inflammation in a subset of patients with LVV (approximately 50%) whom clinically were thought to be in disease remission. These findings are intriguing because a subset of patients with LVV are known to develop life-threatening vascular complications including aortic aneurysms and dissections late into the course of disease. We are investigating potential serologic and clinical predictors of abnormal PET scans in our cohort and to study PET scan findings in association with corresponding angiography. Preliminary findings from the clinical analyses have been presented at the 2016 DC Rheumatism Research Conference and were accepted for presentation at the 2016 American College of Rheumatology Annual Meeting. An image from our cohort and accompanying article was accepted as the cover art for Arthritis & Rheumatology May 2015. Preliminary findings from in vitro studies indicate that metabolism is altered in specific immune cell populations in association with PET scan findings in patients with LVV> Additionally, in a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We plan to perform RNA sequencing experiments on the different cell populations and analyze subsequent findings in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets.
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