Wegener's granulomatosis and microscopic polyangiitis are rare (combined prevalence <200,000 in U.S.), multi-system diseases commonly referred to as anti-neutrophil cytoplasm antibody (ANCA) -associated vasculitis (AAV). AAV, although rare, is almost universally fatal if left untreated. Modern treatment strategies utilize potent immunosuppressive medications and high doses of glucocorticoids (GC). While treatment has resulted in improved survival for patients with AAV, severe forms are still associated with unacceptably high rates of poor outcomes with up to 40% of patients reaching end-stage renal disease (ESRD) or death within 5 years of diagnosis. Poor outcomes in patients with AAV appear due to both inadequate disease control and as a result of treatment related toxicities and adverse events. The broad aim of this research is to improve ESRD and mortality rates for patients with AAV by improving the efficacy of treatment while reducing treatment-related adverse events. Plasma exchange, a method of removing potentially pathogenic antibodies, coagulation factors and inflammatory mediators has shown promise in improving outcomes for patients with AAV. High-dose GC during early treatment is associated with increased rates of serious infections, a principle cause of death in patients with AAV. This research will be achieved through two specific aims: 1) to conduct a multi-national randomized clinical trial comparing the use of adjunctive plasma exchange to standard treatment alone for AAV and 2) to conduct a multi-national randomized clinical trial of a low-dose GC regimen to a standard dose GC regimen for AAV. The addition of adjunctive plasma exchange is hypothesized to improve the efficacy of treatment in patients with AAV while the reduction in GC dose is hypothesized to reduce treatment related adverse events.
These aims will be achieved in the context of a large, multinational, two-by-two factorial design randomized control trial in which investigators will be blinded to the GC regimen of patients. 500 will be recruited over 5 years and randomized in a 1:1 fashion to each intervention and followed for a minimum of 2 years (maximum 7) for the development of the primary outcome of ESRD or death. This application seeks funding to support 5 study sties in the United States and combine resources with funding from the United Kingdom.

Public Health Relevance

This research will determine the best therapeutic strategy for patients with AAV, a rare (orphan) disease with very high morbidity using available treatments. Improvements in the treatment of AAV will directly result in less chronic kidney disease and improved survival for patients with AAV.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZFD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code