In addition to strong recruitment efforts over the last year, two important papers have been published in Arthritis & Rheumatology from research conducted within the VTRP. These papers highlight our approach to use whole genome gene expression profiling to identify potential biomarkers in AAV. One paper describes a neutrophil transcriptional signature that predicts treatment response in granulomatosis with polyangiitis (GPA) and demonstrates functional correlates of this transcriptional signature with elevated levels of low-density neutrophils that undergo NETosis. A second paper published in A&R focuses on transcriptional abnormalities in the nasal passages of patients with GPA, which may allow development of novel biomarkers for disease activity, something badly needed in this area. 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. In collaboration with colleagues from the National Institute of Drug Abuse, sera from a cohort of patients actively using cocaine contaminated with levamisole was used to identify novel autoantibodies against NET components. These data suggest that NETs are a source of autoantigens in levamisole-induced autoimmunity and that heretofore uncharacterized interactions between the cholinergic nervous system and neutrophils may play a causal role in autoantibody formation and autoimmune disease. An abstract entitled Levamisole Triggers Neutrophil Extracellular Trap Formation through Muscarinic Receptors in Patients with Drug-Induced Vasculitis was recently accepted as an oral presentation at the upcoming 2015 American College of Rheumatology meeting in San Francisco and a manuscript is in preparation. In terms of LVV, we are actively growing a unique cohort of patients with these diseases. To date, we have performed whole body PET scans and angiography on 30 patients with LVV. We have discovered vascular abnormalities on PET scans suggestive of ongoing subclinical vascular inflammation in a subset of patients with LVV 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 plan to identify serologic and clinical predictors of abnormal PET scans in our cohort and to study PET scan findings in association with corresponding angiography. Additionally, in a subset of patients with LVV in our cohort, we 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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