This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, and specific Challenge Topic 03-OD (ORDR)-101*: Validating Biomarkers for Functional Outcomes in Rare Diseases. The systemic vasculitides are a group of diseases characterized by severe inflammation of blood vessels leading to arterial stenosis or occlusion, and organ damage or death if untreated. Two related vasculitides, Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), each associated with anti-neutrophil cytoplasmic antibodies (ANCA) and notable for being organ- and life-threatening and prone to relapse after periods of remission. With aggressive immunosuppressive treatment, most patients with these ANCA- associated vasculitides (AAV) survive, but subsequent disease course is variable, relapse is common, and long-term morbidity from vasculitis or its treatment is expected. There is a significant unmet need for markers of disease activity, responsiveness to therapy, risk of relapse, and long-term damage. Accurate markers would be of great benefit in detecting flares early to prevent acute and chronic morbidities, avoiding over-treatment, and measuring response to treatment in practice, early-phase proof-of-concept treatment studies, and larger trials. Two studies now offer an unprecedented opportunity to accelerate discovery of useful biomarkers in patients with AAV, due to their large and already established cohorts, comprehensive clinical data collection systems, repositories of biological specimens linked to each visit, and longitudinal nature: the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, and the Rituximab in ANCA-Associated Vasculitis (RAVE) clinical trial. The value of these repositories is evidenced by the interest that basic science investigators have expressed in collaboration. Plans are presented for ground-breaking studies on biomarkers of platelet activation, vascular inflammation and immunology, endothelial damage, and epitope-specific ANCA subsets. These studies will identify and validate markers of active vasculitis and markers predictive of future flare or remission. The work proposed is fully consistent with the goals of NIH funding through the American Recovery and Reinvestment Act of 2009: All of the materials and expertise necessary to conduct these studies are ready and available for immediate use (""""""""shovel ready"""""""") and the funds would be used quickly and efficiently to create and retain jobs in US academic medical centers. The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis.

Public Health Relevance

The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1AR058303-02
Application #
7943927
Study Section
Special Emphasis Panel (ZRG1-VH-D (58))
Program Officer
Witter, James
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$500,000
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Berti, Alvise; Warner, Roscoe; Johnson, Kent et al. (2018) Brief Report: Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol 70:1114-1121
Langford, Carol A; Monach, Paul A; Specks, Ulrich et al. (2014) An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis 73:1376-9
Hinkofer, Lisa C; Seidel, Susanne A I; Korkmaz, Brice et al. (2013) A monoclonal antibody (MCPR3-7) interfering with the activity of proteinase 3 by an allosteric mechanism. J Biol Chem 288:26635-48
Lieberthal, Jason G; Cuthbertson, David; Carette, Simon et al. (2013) urinary biomarkers in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol 40:674-83
Monach, Paul A; Warner, Roscoe L; Tomasson, Gunnar et al. (2013) Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. Ann Rheum Dis 72:1342-50
Monach, Paul A (2012) Repeating tests: different roles in research studies and clinical medicine. Biomark Med 6:691-703
Monach, Paul A; K├╝mpers, Philipp; Lukasz, Alexander et al. (2012) Circulating angiopoietin-2 as a biomarker in ANCA-associated vasculitis. PLoS One 7:e30197
Tomasson, Gunnar; Boers, Maarten; Walsh, Michael et al. (2012) Assessment of health-related quality of life as an outcome measure in granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 64:273-9
Monach, Paul A; Tomasson, Gunnar; Specks, Ulrich et al. (2011) Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 63:3988-97
Tomasson, Gunnar; Lavalley, Michael; Tanriverdi, Kahraman et al. (2011) Relationship between markers of platelet activation and inflammation with disease activity in Wegener's granulomatosis. J Rheumatol 38:1048-54

Showing the most recent 10 out of 11 publications