The VF Board of Directors is pleased to announce it has selected three new research studies for funding in 2018. The studies were chosen from a selection of 20 applications submitted by investigators world-wide. Every year the VF receives proposals for very high-quality research from investigators who have a wealth of experience and we are pleased to support their efforts.
To date, the Vasculitis Foundation has funded more than $2.5 million dollars for 49 individual research studies including the three funded this year. It is amazing to see how much vasculitis research has grown. We would like to thank all the researchers for their dedication to understanding these devastating diseases.
Your Donations Fuel VF-Funded Vasculitis Research
In 2017 we saw exciting developments in vasculitis which are a direct result of generous funding to VF-funded research. In 2009, the Vasculitis Foundation funded $99,738.00 for two years to the Diagnostic and Classification Criteria in Vasculitis (DCVAS) study. This is the largest study in vasculitis including centers throughout the world. As a result of their work, the DCVAS group presented a new set of classification criteria for ANCA-associated vasculitis in November 2017 at the American College of Rheumatology Annual Meeting. These criteria will be critical for use in future research studies.
Also in 2017, the Vasculitis Foundation provided funding to A Randomized Multicenter Study for Isolated Skin Vasculitis (ARAMIS). This is the first randomized clinical trial to compare treatment options for skin limited vasculitis. The study is now recruiting at multiple vasculitis centers across North America.
Additionally, during 2017, the Vasculitis Patient-Powered Network (V-PPRN) provided the structure to support multiple studies including JOURNEY, V-PREG, VascWork and AAV-PRO. We want to thank everyone who has enrolled, and participated, in the V-PPRN. We encourage everyone to join the V-PPRN.
This is an exciting era in vasculitis research. Many advancements in vasculitis research have been a result of funding provided by the Vasculitis Foundation. We are grateful for our many generous donors who have made this a reality.
Study Title: Endothelial Cell Inflammasomes in ANCA-Associated Vasculitis
Investigator: Dan Jane-Wit, MD, PhD
Co-investigator: Caodi Fang, MS
Institution: Yale University
Award: One-year, $50,000
ANCA-associated vasculopathy (AAV) are inflammatory disorders that include Granulomatosis with polyangiitis (formerly Wegener’s), microscopic polyangitis, and EGPA/Churg Strauss. These conditions are characterized by chronic inflammation leading to blockages of blood vessels and diminished blood flow to vital organs like the kidney. How inflammation causes these blockages to form is unknown.
The researchers will study how interactions between two immune mechanisms, complement and CD4+ T cells, lead to blockages in blood vessels in AAV. Complement are immune proteins that circulate in the blood. During AAV, complement proteins are activated and self-assemble to form membrane attack complexes (MAC). MAC are pore-like structures that insert into the cell membranes of endothelial cells (EC), the cells that line blood vessels. When this occurs, the researchers found that MAC causes EC to release IL-1beta, a secreted protein that enhances the activation of CD4+ T cells. IL-1beta enhanced activation of CD4+ T cells that went on to release a factor called IFN-gamma that led to blood vessel blockages. Thus, MAC deposition on EC led to EC release of IL-1beta which then enhanced activation of CD4+ T cells that released IFN-gamma to cause blood vessel blockages in AAV.
Using human biospecimens to increase the likelihood that their findings will be relevant to patients, the researchers will study how a protein structure called the inflammasome is activated by MAC on EC to allow IL-1beta secretion. The researchers will then examine the significance of the inflammasome in human coronary arteries in a humanized mouse model, and will further test the clinical relevance of the inflammasome by analyzing its expression in AAV patient tissues. Their studies will lead to novel insights into how AAV causes blood vessel blockages and may lead to new therapies to prevent this from occurring.
Study Title: Metabolic Dysregulation of Pro-inflammatory Responses in DADA2 Vasculitis
Investigator: Sonia Sharma, PhD
Co-investigators: Rekha Dhanwani, PhD; Mohit Jain, MD, PhD
Institution: La Jolla Institute for Allergy and Immunology, California
Award: One-year, $50,000
Vasculitis is an auto-immune condition characterized by inflammation and damage to the blood vessels, which precipitates multi-organ damage due to restricted blood flow to affected tissues. Many vasculitis diseases are rare genetic syndromes, and unraveling the biological basis of these debilitating condition is absolutely critical for developing effective therapeutic treatments. Understanding vascular inflammation is also broadly useful for understanding chronic inflammatory conditions where vasculitis is often a key clinical complication. The lab recently generated data showing that the metabolic enzyme Adenosine Deaminase 2 (ADA2), which is mutated in DADA2 vasculitis, directly controls inflammatory immune responses. Our studies provide an important new link between vasculitis and pro-inflammatory immune responses, and would also be the first to establish vascular inflammation as a metabolic disorder. By exploiting this new-found knowledge, we aim to explore new treatments for vascular inflammation aimed at dampening pro-inflammatory immune responses in DADA2 and other similar vasculitis syndromes by correcting the metabolic defect caused by low ADA2 activity.
Study Title: Long Term Patient Follow-up of ANCA-associated Vasculitis
An International Inception Cohort Study by the European Vasculitis Society (EUVAS)
Research team: Ingeborg Bajema, MD, Mikkel Fauschou, MD, PhD, Thomas Hauser, MD, Peter Hoglund, MD, PhD, David Jayne, MD, Alfred Mahr, MD, MPH, PhD, Laura Moi, MD, Raashid Luqmani, DM FRCP, (E) and Kerstin Westman, MD
Award: One-year, $62,000
There is a paucity of information on the long term outcome of patients with ANCA associated vasculitis (AAV) and factors predictive for adverse outcomes. The European Vasculitis Society (EUVAS) has conducted nine randomized controlled trials in AAV recruiting over 900 patients from diagnosis between 1995 and 2010.
In 2007, EUVAS examined five-year follow-up of 500 patients and reported on mortality, malignancy, cardiovascular events, safety, relapse and renal outcomes. Up-to-date data on 85% of the original cohorts was obtained. This data has helped shape current attitudes to AAV but further study is now required to assess change with more recent studies and longer term follow-up of older studies. Exemplar topics relevant to current practice include the cancer risks associated with cyclophosphamide, the impact of relapse on damage accrual and health related quality of life.
There is limited data regarding long term outcomes in forms of ANCA-associated vasculitis and factors that prevent adverse outcomes. These researchers are developing a large database using the information collected as part of ANCA trials from 1995 to 2010. The team is examining factors such as survival, long term kidney function, co-morbidities, relapse status, vasculitis-related damage, drug exposure, mortality, cancer rates, cardiovascular events, drug safety, relapse rate and other kidney-related outcomes.
Dr. Laura Moi, a fellow supported by the grant and a member of the EUVAS Council, will manage the project.
