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 on four forms of vasculitis: large vessel vasculitis (LVV), deficiency of adenosine deaminase 2 (DADA2), relapsing polychondritis (RP), and ANCA-associated vasculitis (AAV). 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 approximately 100 patients with LVV. We recently published two full-length original reports focused on the role of vascular imaging in LVV. The first report, 18F-FDG-PET as an Imaging Biomarker in a Prospective Longitudinal Cohort of Patients with Large Vessel Vasculitis, was published in Arthritis & Rheumatology in March 2018 and an image from the study was selected for the journal cover. In this paper, we demonstrated that the majority of patients with LVV who were studied during a time of apparent clinical remission have FDG-PET findings suggestive of active vasculitis. We showed that degree of PET activity during remission predicted clinical relapse. The second paper, Comparison of MRA and 18F-FDG-PET in large-vessel vasculitis, was published in the Annals of the Rheumatic Diseases in August 2018. In this paper, we show fair agreement between MRA and PET to detect vascular inflammation, while PET more closely aligns with clinical impression of disease activity. Interestingly, more than half of patients in remission had what appears to be active vasculitis detected by both MRA and PET. Three other imaging-based publications are currently under review, and three imaging abstracts from this cohort were recently accepted to the 2018 American College of Rheumatology (ACR) Annual Meeting. In the lab, we are studying the immunology of subclinical vascular inflammation in LVV. 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. In a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We are analyzing data from RNA sequencing experiments on the different cell populations in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets. In terms of RP, we have recruited >70 patients with this rare disease over the last year and half. We are currently developing classification criteria for this disease and defining an optimal clinical approach to assessment and treatment of this condition. As part of these efforts, we have formed the first International Working Group in Relapsing Polychondritis, dedicated to collaborative clinical and translational research in this disease. We recently published data from a patient-based online survey assessing burden of disease in RP. An abstract detailing evaluation of the airway in patients with RP was accepted for oral presentation at the 2018 ACR annual meeting. In terms of DADA2, we have characterized the effect of ADA2 loss-of-functions mutations on neutrophil biology. We have shown that adenosine mediates neutrophil extracellular trap formation in DADA2 and this effect is reduced by ADA2. We also demonstrated that NETs from patients with DADA2 stimulate production of inflammatory cytokines by macrophages. We characterized the pathways of adenosine-medaled NET formation, including the role of specific adenosine subtype receptors. Work from this project has been presented at two international meetings and is currently under scientific review for publication. Ultimately, work from this study could lead to the development of novel therapeutics in DADA2 and in a broad range of inflammatory diseases that are mediated in part by adenosine. In terms of AAV, we continue to pursue genomic approaches to discover novel biomarkers and identify potential novel therapeutic pathways involved in the disease. In collaboration with the VCRC, we studied micro-dissected renal tissue from patients with AAV, nephrotic syndrome, and healthy living donors. We identified mRNA signatures of immunometabolism within vasculitis kidney biopsy samples and validated these signatures at the protein level in renal tissue from patients. We identified that the pentose phosphate pathway is activated in renal biopsy tissue, that macrophages are likely the cellular source of the signature, and that pentose phosphate pathway expression is tightly linked to expression of inflammatory cytokines. This work was published in the Annals of the Rheumatic Diseases in August 2018. We also contributed to a study coordinated by the University of Pennsylvania to characterize the nasal microbiota in patients with AAV, with a report recently accepted for publication in the Annals of the Rheumatic Diseases. Finally, we published a brief report in Arthritis & Rheumatology on the pathogenic role of various drugs that have been implicated in drug-induced forms of AAV. We characterized the pro-inflammatory effects of hydralazine and procainamide on neutrophils and showed the diverging pathways of drug-induced NET formation with these different drug stimuli. Novel aspects of drug-induced autoimmunity based on our work were detailed in a review article that we helped write entitled Drug-induced lupus: traditional and new concepts.
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