Short-term cyclophosphamide therapy in a cohort of over 200 Patients

Investigators: Alexandra Villa-Forte, M.D. and Gary S. Hoffman, M.D.
Location: Center for Vasculitis Care and Research, Cleveland Clinic Foundation Cleveland, Ohio

Timeline: February 1, 2002 – February 28, 2003

Abstract
Background: Cyclophosphamide (CP) is the most effective therapy for Wegener’s Granulomatosis (WG). Drug toxicity limits long-term CP therapy. Dr. Hoffman and others have stressed the limitations of CP. Since becoming Chairman of Rheumatic and Immunologic Diseases (1992) at the Cleveland Clinic Foundation (CCF), Dr. Hoffman has provided care for over 200 patients with WG. The protocol employed for severe WG has included induction of remission with CP, followed by maintenance therapy with either Methotrexate (MTX) or Azathioprine (Aza).

Objective
To utilize a single practitioner’s large patient cohort to determine whether short-term CP therapy, followed by either MTX or Aza, provides less morbidity and mortality than conventional approaches for WG.

Specific aims
1. Determine efficacy and toxicity of short-term (3-6 months) CP, followed by an alternate remission-maintenance therapy. Comparisons with conventional therapy will be facilitated because of the senior investigator’s (GSH) role as the principal investigator for the NIH WG-CP and MTX protocols.

2. Determine whether different initial clinical presentations of WG correlate with ong-term prognosis.

3. To test the hypothesis that sustained lymphopenia is associated with increased treatment effectiveness. The finding of a significant association between the presence of lymphopenia and efficacy would result in new guidelines for monitoring and modifying drug therapy.

 

What this means for patients

This study will help determine answers to the following questions:

1. Will the milder agent, MTX, be associated with fewer long-term remissions?

2. If relapses are more common after MTX has been started, will patients still do better because of fewer side effects from less prolonged use of CP (3-6 months vs. 18 or more months)?
Treatment and outcomes-related data gathered from this study will be compared to results that have been obtained by others, who have utilized similar and dissimilar treatment approaches.

3. Will only certain patients with specific types (subsets) of WG benefit from this approach? A related goal in this analysis is to determine whether certain initial features (or combinations of features) of disease, such as persistent sinusitis vs. joint, muscle, skin, lung or kidney disease, are associated with different ultimate outcomes.

4. Does the effect of therapy on reducing the numbers of certain types of white blood cells (lymphocytes) determine the likelihood of staying in remission?

It is known that one of the most striking effects of CP, MTX or other “chemotherapy”-type drugs is in reducing lymphocyte counts and suppressing lymphocyte functions. These effects may persist more than 1 year after the treatment has been discontinued. It is very possible that the risk of WG relapse is increased if the lymphocyte count is never adequately reduced or if a patient’s counts return to normal soon after remission.

Depending on the answers, the knowledge derived may change and improve therapy.

Host-microbial interactions in Wegener’s Granulomatosis: The role of ANCA and S. aureus persistence

Investigator: Robert D. Inman, M.D.
Location: University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Timeline: September 1, 2002 – August 31, 2003 (extended to Spring 2004)

Abstract
There is compelling circumstantial evidence to implicate a role for infection in the pathogenesis of Wegener’s Granulomatosis (WG). Recently there has been confirmation of a higher nasal carriage of Staphylococcus aureus in WG patients. Yet it is not known whether this finding is a cause or an effect of the disease process. Secondly, there continues to be mounting evidence of the efficacy of antibiotic therapy for WG. It is unresolved however whether agents such as ulfonamide or trimethoprim function as antibiotics or by an alternative mechanism. Third, neutrophils represent the first line of defense against bacterial pathogens. The ANCA antibody response that is the hallmark of WG may influence host defenses against such infections in a fundamental way.
Specific Aims
The aims of the proposed project are to analyze the relationship between ANCA and clearance of pathogens. This will shed new light on the relationship between infection and autoantibody formation. This is one of the fundamental problems in all autoimmune disease, and the insights from this study will have important implications for other chronic inflammatory conditions, which may have an infectious trigger.

1. To define the impact of ANCA on the internalization and intracellular killing of S. aureus by neutrophils and by endothelial cells.
2. To examine the impact of ANCA on the parameters of innate immunity, particularly TLR2 and TLR4 signaling and activation of NFkB, as marker of gene transcription and cytokine production.

What this means for patients
There is compelling reason to resolve the possible role of infection in WG:
1. As has just been confirmed, WG patients have a higher prevalence of nasal carriage in S. aureus. The reason for this microbial persistence has not been resolved.
2. Antibiotics form an important part of the treatment regimen of WG, and it has been assumed that the primary mode of action of these agents is their antimicrobial effect.
3. Since the neutrophil functions as a first line of defense against pathogens such as S. aureus, it is important to resolve whether ANCA may be significantly impairing host defenses against infection by altering neutrophil function.

The role of shear stress in neutrophil proteinase-3 expression and its importance in vascular injury sites in WG

Investigator: Deborah J. Stearns-Kurosawa, Ph.D.
Location: Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
Timeline: March 1, 2003 – February 29, 2004 (extended to June 2004)

Abstract
Vascular inflammation is a hallmark of Wegener’s Granulomatosis (WG) and other primary systemic vasculitides. Vascular inflammation is also characteristic of atherosclerosis, and WG patients have increased intimal thickening, more frequent cardiovascular disease and accelerated atherosclerosis. The concurrent endothelial dysfunction and altered flow hemodynamics will induce homing and transmigration of pro-inflammatory cells, including neutrophils.

Enzymes, cytokines and receptors expressed by emigrating neutrophils contribute to the ongoing inflammation. Neutrophils express proteinase-3, an enzyme located in neutrophil granules and recognized by the autoantibody in WG patients (PR3-ANCA). In vitro experiments have demonstrated that this PR3-autoantibody interaction induces a myriad of neutrophil inflammatory events. The in vivo importance of PR3-ANCA remains controversial in part because it is not clear how PR3 becomes accessible to the autoantibodies on largely unactivated neutrophils.

However, few investigators have considered potential contributions from flow-induced shear stress. The current data demonstrate that low level shear stress results in unique surface expression of PR3 on neutrophils; other neutrophil granule markers are largely unaffected.

Our hypothesis is that low shear stress levels are important for expression of neutrophil PR3, so that it becomes accessible to pro-inflammatory PR3-ANCA. We also hypothesize that this low level shear-induced neutrophil PR3 expression plays a major role in the localization of endothelial injury, since Wegener’s granulomatosis selectively affects small-to-medium sized vessels. Experiments also are proposed to identify shear-induced signaling mechanisms to provide mechanistic insight into PR3 expression under rheologic conditions.

Collectively, these events would bring neutrophils and their expressed PR3 and PR3/PR3-ANCA complexes in close proximity to endothelial cells, providing all the players to initiate or propagate inflammatory events.

Results from proposed studies will form the foundation of future studies identifying the molecular mechanisms underlying this unique influence of shear stress on neutrophil PR3 expression.

Specific aims
These aims are designed as a 1 year project to identify the rheologic conditions that result in surface PR3 expression on neutrophils exposed to laminar shear forces and on neutrophils rolling on endothelial cells under flow. Signaling mechanisms relevant to shear-induced neutrophil PR3 expression will be explored. Additionally, the ability of macromolecules known to bind to neutrophil PR3 under static conditions, including PR3-ANCA, will be determined under flow conditions.

1. Define the laminar flow conditions that result in neutrophil PR3 expression. Neutrophils will be exposed to varying levels of laminar shear stress in a parallel plate flow chamber. Surface PR3 expression will be evaluated by flow cytometry using anti-PR3 monoclonal antibodies and patient PR3-ANCA. These results will give insight into the influence of shear stress on PR3 expression and accessibility. Other granule markers will be evaluated concurrently. The binding of molecules known to interact with PR3 (e.g., alpha 1-antitrypsin, soluble endothelial protein C receptor) will be determined similarly under flow conditions for comparison with known static systems.
2. Evaluate the impact of shear stress and activated endothelium on PR3 expression on rolling neutrophils. Neutrophils will be rolled over TNF-α activated endothelial cells at varying physiological flow velocities and PR3 expression quantitated by flow cytometry.
3. The influence of modulators (patient PR3-ANCA, a1-antitrypsin, etc.) on adhesion, rolling velocities and transmigration will be determined. Neutrophils will be harvested for evaluation of signaling events using western blotting and ribonuclease protection assays. These studies provide a physiological context in which to evaluate the influence of laminar flow forces on PR3 expression, PR3 accessibility to PR3-ANCAs, and subsequent neutrophil adhesion events.

What it means for patients
No analysis of the type proposed has ever been attempted and a body of important new information will be developed as a result of this study. The approaches described in this proposal are new and unique ways to look at the fundamental mechanisms underlying the pathogenesis of WG and related vasculitides. The long-term consequences are impossible to predict, but knowledge of mechanisms regulating our response to inflammation may provide insight into novel therapies.

Analysis of NKG2D expression on CD28

Investigators: Peter Lamprecht, M.D. and Wolfgang L. Gross, M.D.

Location: Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck and Rheumaklinik Bad Bramstedt Luebeck and Bad Bramstedt, Germany

Timeline: January 1, 2004 – December 31, 2004

Abstract
Wegener’s Granulomatosis (WG) is a chronic inflammatory disease characterized by granulomatous lesions and an autoimmune vasculitis. Previously we have shown that circulating Th1-type so-called “late” differentiated or “effector memory” cells lacking the co-stimulatory molecule CD28 are expanded. Expansion of CD28 ¯ T-cells starts early during the disease process and correlates with organ involvement. In granulomatous lesions T-cells also generally lack CD28. Moreover, CD28¯ T-cells are the Th1-type cytokine producing T-cell population within these lesions. Data from in vitro studies suggest that CD28¯ T-cells express the co-stimulatory activating receptor NKG2D under inflammatory conditions. NKG2D interacts with the ligands MICA and MICB which are non-classical MHC-class I antigens expressed on antigen-presenting cells upon infection and cellular distress.
We hypothesize that in WG CD28¯ T-cells express NKG2D and interact with MICA and MICB expressed on antigen-presenting within granulomatous lesions. Therefore we want to determine the expression of NKG2D on peripheral blood CD28¯ T-cells by flow cytometry (n=25) and on CD28¯ T-cells within granulomatous lesions by immunohistochemistry (n=5). MICA and MICB expression on antigen-presenting cells within granulomatous lesions will be shown by immunohistochemistry (n=5).
Detection of NKG2D+CD28¯ T-cells interacting with MICA+MICB+ cells would shed new light on the nature of T-cell activation in WG and allow future detailed analysis of possible antigens involved in this process. The analysis might reveal new potential targets for a more specific therapy, for instance DAP 10, which is an adaptor protein necessary for NKG2D signaling.
What this means for patients
We see an expansion of a population of specialized, proinflammatory immune cells in WG. These specialized, proinflammatory immune cells are coined CD28¯ T-cells, because they lack a molecule, namely CD28, on their cell surface. We want to analyze whether these CD28¯ T-cells express another molecule, NKG2D, on their cell surface. The NKG2D molecule is important for the activation of CD28¯ T-cells and enables them to sense cellular distress and/or infection on surrounding cells. In that case the surrounding cells express the NKG2D ligands (counterparts) MICA and MICB on their cell surface to communicate with the CD28¯ T-cells. We want to analyze whether peripheral blood CD28¯ T-cells and CD28¯ T-cells within inflammatory lesions in nasal tissue express the NKG2D molecule on their surface and whether their ligands MICA and MICB are expressed on the cell surface of surrounding cells.
The proposed analysis will shed new light on the nature of the activation of proinflammatory immune cells in WG and might also reveal new potential targets for a more specific therapy.

Identification of Novel Wegener’s Granulomatosis Susceptibility Genes

Investigator: Katherine A. Siminovitch, M.D.

Location: Mount Sinai Hospital, Toronto, Ontario, Canada

Timeline: March 1, 2004 – ongoing

PATIENTS MAY STILL ENROLL IN STUDY.

For more information please contact:

Jennifer or Stephanie, Clinical Research Coordinators

Phone: 416-946-4501 x. 3297

Fax: 416-946-4531

Email: clinicalgenet.research@gmail.com

Abstract
Wegener’s granulomatosis (WG) is a multisystem, necrotizing, granulomatous vasculitis that affects about 3 in every 100,000 people in the United States and is equally prevalent in males and females. Diagnosis of WG is difficult, and many physicians are unfamiliar with the condition. Thus, there is a significant unmet medical need for improved diagnostic tests. Development of new diagnostic and therapeutic approaches to WG has been substantially impeded by lack of understanding of the causes of WG.

Many lines of evidence suggest that a major cause of WG is infectious insult of genetically susceptible individuals. A handful of susceptibility genes have been examined as possible etiologic factors, but to date both the genetic and infectious factors underlying WG remain unknown. Identification of WG susceptibility genes would, however, provide a very promising avenue to the development of improved diagnostic and prognostic tests as well as new targets for therapeutic management. Although technologies for disease gene discovery are radically improving, the application of such technologies is highly dependent on the availability of collections of DNA samples from affected individuals and their family members.

This proposal describes a strategy to collect blood samples and prepare DNA from individuals with WG and their immediate family members, and to conduct comprehensive clinical chart review in order to obtain powerful data for results stratification and analysis. The obtained samples and clinical information will lay the foundation, and be absolutely required for, future studies to identify WG susceptibility genes.

Specific aims and goals contained within this grant:
a) To collect blood samples for DNA analysis from 500 WG patients and family members where available;
b) To review and document clinical data from these WG patients, including demographic data;
c) To prepare DNA samples for banking from the blood samples;
d) To lay the groundwork for future genetic analysis of the WG patient/family cohort

Larger goals within the framework of our WG research program (anticipated to be funded by additional national granting programs)
e) To understand the fundamental causes of WG by using genetic association and family-based linkage studies (where possible) to focus on identification of the full complement of WG susceptibility genes;
f) To develop gene-based (DNA) diagnostic assays for early identification of susceptible individuals, in conjunction with established ANCA blood testing and other diagnostic procedures;
g) To elucidate the molecular pathophysiology of WG and the nature of environmental-genetic interactions that trigger disease, and;
h) To design improved strategies for prevention and treatment of WG, including the diagnostic applications mentioned above.

Relevance to WG:
The exact cause(s) of WG are unknown, but it is generally thought to result from infection of individuals with an underlying genetic susceptibility. A variety of gene variants have been shown to be associated with WG susceptibility, including the immunologically relevant IL-10 (Interlukin 10), transforming growth factor-beta (TGFB) and the cytoxic T lymphocyte associated antigen-4 (CTLA-4) genes. Additionally, some other genes have been associated with WG, including those for the angiotensin-converting enzyme (ACE), proteinase-3 and alpha-1-antitrypsin. The tendency to relapse among WG patients has also been associated with variants of the Fcgamma receptor gene. Despite these data, the molecular and biochemical pathways underlying WG onset and progression remain largely uncharacterized.

Recent studies of the genetics of Crohn’s Disease, an inflammatory disease of the gastrointestinal tract, and of the rare Blau syndrome, have demonstrated an association with variants of the NOD2 gene bacterial species. Because both Crohn’s Disease and Blau syndrome are associated with granuloma development, and because granulomatous disease in Crohn’s Disease patients are specifically associated with NOD2 gene variants, we recently undertook a genetic study in WG patients (Newman et al. (2003)., J. Rheuma. 30(2):305-7. While we did not detect any association between WG and the NOD2 gene, our results illustrate our general strategy in examining candidate genes that may be involved in WG, and further emphasize the necessity of much larger, family-based genetic studies in research into the genetic underpinnings of this disease. Accordingly, we propose to greatly expand our current collection of DNA samples from WG patients and their family members, in order to lend greater power to future genetic association and family-based linkage studies. We anticipate working closely with the WGA to achieve these goals.

Long-range objective:
The long-range goal of our WG research program is to identify genes that confer susceptibility to WG.

Progress to date:
Over the past three years, our group has focused on collection of patient and family samples required to map and isolate genes that cause and/or modulate WG. To date, patients have been ascertained mainly from the Canadian Wegener’s Granulomatosis Support Group (WGSG), and the relevant family members have been ascertained via telephone contact initiated with the probands’ consent. To allow for case-control and family-based association as well as linkage analysis, we have collected the following types of materials: individual patients for whom no other family members are available (singletons) and who can be used for case-control association studies; patients and their parents and/or unaffected siblings (trio families), who can be used for family-based association studies; and multicase families such as affected siblings and their parents (sib-pair family) or patient and affected as well as unaffected parent (relative-pair family), who can be used for linkage analysis.
Collection involves obtaining blood samples for DNA and lymphoblastoid cell line preparation and detailed demographic data on all study participants and detailed clinical data on all affected individuals.

Research Plan
The objective of this proposal is to collect sufficient numbers of WG patients and family members to lay the groundwork for identifying WG susceptibility genes. This proposal is therefore entirely focused on patient recruitment. However, in the future we will use these patient materials to carry out a genome wide scan of WG families and to examine and analyze any other genes that are discovered in the future to be associated with granulomatous disease and/or granuloma formation. Data from these studies will provide the framework for further studies aimed at identifying candidate and ultimately the relevant WG susceptibility genes.

As noted above, the patient collections possible in eastern Canada are largely completed. However, significant additional patient sample resources are required to ensure that sufficient clinical materials are available, for example, for large-scale case-control association and linkage analyses. We propose to work closely with, and seek the assistance of, the WGA in ascertaining and recruiting volunteer patients and family members interested in participating in this study.

To allow for the use of several complementary methods for WG gene identification, we will continue to collect WG patients/families of varying pedigree structures. These include:

• Multicase families: These families, which will be used for linkage analysis, contain a minimum of two affected siblings and their parents (sib-pair family) or an affected parent-child combination and an unaffected parent and/or sibling (relative-pair family).
• Trio families: These families include patients and their parents (or minimally, a patient and a single parent) as well as patients and unaffected siblings.
• Singletons: Individual patients, for whom family members cannot be recruited are also being collected and will be used for case-control association studies to facilitate candidate gene analysis once chromosomal regions of interest are identified. As most of the patients collected represent singletons, we anticipate that at least 500 such individuals will be recruited to the study by the end of year 1 and these individuals, together with any individuals drawn from the trio and multicase families, will provide a substantive resource for analysis of the association between selected SNPs/genes and WG.

Conclusion:
The identification of disease susceptibility genes has attracted considerable interest in recent years, an interest that builds upon the wealth of genetic information and improved genotyping technologies emanating from the Human Genome Project research. Definition of WG susceptibility genes will not only elucidate the combination of genes which influence disease progression, severity and response to treatment, but will also pave the way for identifying individuals at risk, delineating the specific environmental factors which help convert genetic susceptibility to disease, and designing strategies for intervention and disease prevention. Even in advance of development of new therapeutic drugs, our investigations should provide DNA-based diagnostic tools that will complement and enhance current ANCA and other clinical testing procedures, resulting in earlier diagnosis of WG and the opportunity to widen the opportunity for therapy.

Environmental Factors in the Pathogenesis of Wegener’s Granulomatosis

Investigator: Daniel A. Albert, M.D., Professor of Medicine

Location: University of Pennsylvania, School of Medicine, Division of Rheumatology, Philadelphia, Pennsylvania

Timeline: January 1, 2005 – December 31, 2005

Abstract
Wegener’s Granulomatosis (WG) is an autoimmune inflammatory disease of the sinus pulmonary tract and other organs of unknown etiology. Both allergic (sinusitis) and infectious (staphylococcus aureus) factors are thought to play a role, but other factors remain to be elucidated. Previous studies have focused on environmental exposures that might provide further stimulation for this autoimmune process. These studies suggest that exposure to heavy metals (mercury and possibly lead), aromatic hydrocarbons, and silica may precede the onset of Wegener’s and that one possible source is through contaminated ground water in wells. This study will assess these risk factors in greater detail through a questionnaire survey of patients with Wegener’s versus controls with either gout or osteoarthritis. In addition, we will directly measure heavy metal exposure through a blood test that will quantify body burden of lead, mercury, cadmium, and arsenic and other heavy metals. These data will provide new information regarding environmental exposures that may be casually linked to Wegener’s Granulomatosis.

This is a pilot study that will provide preliminary data necessary to justify an RO1 application. We plan to utilize this data to support a proposal to examine the role of these factors in animal models of vasculitis and in future studies on patients with Wegener’s Granulomatosis.

Localized Wegener’s Granulomatosis: Epidemiological, clinical and histopathological characteristics

Investigators: Peer Malte Aries, M.D. and Wolfgang L. Gross, M.D.

Location: Department of Rheumatology, University Hospital of Schleswig- Holstein, Campus Lübeck and Rheumaklinik Bad Bramstedt, Germany

Timeline: January 1, 2005 – December 31, 2005

Abstract
The existence of different clinical phenotypes within Wegener’s granulomatosis (WG) has been recognized for several decades. So far, it is unknown why some patients remain in the early, localized phase of the disease with the predominance of granulomatous lesions of the upper and/or lower respiratory tract, whereas in most patients disease progresses to early systemic or generalized WG.

Specific aim
The aim of this study is to examine the clinical, histological and immunological (phenotypes of leukocytes subsets, activation markers, proteinase 3-expression and Th1/Th2 cytokine profile) features of localized compared to generalized WG. We hypothesize, that a Th1-type cytokine expression in serum, together with a lower PR3 expression on T cells will help us to distinguish localized from generalized WG. These findings may help us to establish diagnosis of WG earlier, even if symptoms are restricted to the upper and/or lower respiratory tract like in localized WG.

Detection of distinguishing features of localized WG will give us the opportunity to start treatment early in the course of disease; even before major organ involvement has been established. Apart from diagnostical assistance the analysis might reveal new potential targets for a more specific and stage adopted therapy.

Funding for the proposed project will enable us to get a closer insight into the mechanisms of the initial course of the disease -also called localized WG- and give us new support in the clinical management of those patients. Early disease detection and prevention of disease progression is a major interest of the WGA. This data are essential and necessary for the following application for a larger grant funded by the Deutsche Forschungsgemeinschaft (German Research Society – the NIH equivalent in Germany) to further support.

The ultimate goal of this research is to identify immunological and histological features distinguishing the early granulomatous phase of WG from its subsequent generalized vasculitic stage. A closer understanding of the immunological characteristics distinguishing localized versus generalized WG will help us to develop a more stage related therapy that may prevent further progression to the generalized vasculitic disease.

Wegener’s Granulomatosis and Microscopic Polyarteritis Case Control Study in Western Montana

Investigators: Helen Emery, M.D., Andrew Zeft, M.D. and Peggy Schlesinger, M.D.

Location: University of Washington, Children's Hospital and Regional Medical Center, Section of Rheumatology, Seattle, Washington

Timeline: August 1, 2004 – July 30, 2005

Abstract
Etiologic factors for Wegener’s Granulomatosis (WG) and Microscopic Polyarteritis (MPA) have not been identified, although it is possible that specific environmental exposures may trigger disease onset in a susceptible host. Previous studies have shown an increased risk of these disorders in patients with certain environmental exposures, the clearest association being with occupational silica.
In the last ten years, the Montana rheumatology community has observed an increased incidence and case clustering of both WGA and MPA in certain counties of western Montana. The mining industry and areas with known high heavy metal concentrations make this region unique.

Specific aim
To evaluate the relative risk of Wegener’s Granulomatosis and Microscopic Polyarteritis in a defined population in Western Montana, focusing on residential and occupational exposure to silica, heavy metals, and pesticides.

We will identify and characterize all WG and MPA cases in western Montana onset from January 1993 to June 2004 by case report from Montana rheumatologists, pulmonologists, nephrologists, and otolaryngology physicians. Using hospital records, we will identify two controls matched by age, gender, race, and distance to the hospital of index WG or MPA cases. We will interview index and control cases for residential and occupational exposures to silica, heavy metals, and pesticides.

Development of a Measure to Assess Patients’ Adherence to Vasculitis Treatment Regimens

Investigator: Robert F. DeVellis, Ph.D.

Location: Arthritis Multidisciplinary Clinical Research Center, Department of Health Behavior & Health Education, School of Public Health, Department of Psychology, University of North Carolina at Chapel Hill, North Carolina

Timeline: September 1, 2004 – August 31, 2005

Abstract
Individuals who are diagnosed with Wegener’s Granulomatosis (WG) and other forms of ANCA-associated systemic vasculitis (AASV) face a daunting array of psychosocial challenges. One challenge not previously studied is patients’ adherence to treatment regimens. The lack of research is troublesome, given that non-adherence to treatment regimens is common across all chronic illnesses, and could lead to ineffective treatment, serious complications, and even death in patients with these illnesses.
Complicating the study of treatment non-adherence in these patients is the lack of an existing self-report measure that can reliably, validly, and conveniently measure adherence to the self-care behaviors specifically recommended by physicians to AASV patients.

This study will characterize the behavioral demands of WG treatment regimens and the barriers individuals face in trying to follow them, develop and evaluate a self-report measure of WG treatment adherence, and describe the tendencies of patients to adhere to the different behavioral recommendations in WG treatment regimens.

Toward this end, we will survey a total of 335 adults living with WG or other forms of AASV. In Phase 1, we will interview 20 patients about the self-care behaviors required by their treatment regimens and the barriers and facilitators they experience in trying to perform them. The Phase 1 data will help inform the development of a self-report adherence measure to be piloted with clinical experts and 15 patients in Phase 2. In Phase 3, 300 patients will complete a revised draft of the adherence measure and their data will be analyzed to determine the measure’s psychometric properties.

What this means for patients
Through this research, we hope to gain insight into the challenges that patients face in trying to adhere to their treatment regimens, and facilitate future investigations by developing a convenient measure of treatment adherence specific to WG and related disorders.

A Pilot Project towards Establishment of a US/Canadian Diagnostic Registry of Children with WG and Related Vasculitides

Investigator: David A. Cabral, MBBS

Location: BC Children’s Hospital and University of British Columbia, Vancouver, Canada

Timeline: March 1, 2005 – February 28, 2006

Abstract
The presentation and natural history of pediatric Wegener’s Granulomatosis (pWG) may differ significantly from adult disease; and pWG may be more difficult to distinguish from other related types of chronic vasculitis. One-third of pWG does not fulfill adult-derived classification criteria and two-thirds of chronic vasculitis in children is unclassifiable. Because study of pWG is limited by rarity of the disease, we propose to set up a pilot pediatric registry of all chronic small-medium vessel vasculitis to determine the validity, and specificity of adult classification criteria for use in pWG; feasibility of establishing an international (US/Canada) registry will thus be assessed during operation of the pilot registry and by survey of potential physician participants. In the long term, a registry will permit detailed characterization of pWG and identify homogeneous subgroups of patients to enhance pathophysiological understanding and treatment of the disease.

The first phase of the study will electronically survey pediatric rheumatologists throughout US/Canada who are members of CARRA (Childhood Arthritis and Rheumatology Research Alliance) to determine feasibility of establishing and maintaining an international registry for the short or long term; assessment will include estimates of patient numbers, local resources and commitment to participation.

Secondly, by Delphi survey of the membership we will determine optimal diagnostic features and disease markers for pWG, to be included in the pilot, and proposed international registry; this is a well established consensus formation methodology to assimilate ‘expert’ opinion (weighted for experience) through the use of sequential, iterative questionnaires rationalized by interim analysis.

Finally, information on all cases of pWG and related vasculitides over the preceding five years will be collected from CARRA centers in the Pacific-Northwest, entered into the ‘electronic’ pilot registry, and analyzed against adult-derived criteria. Demands on participating centers will be simultaneously evaluated as part of the feasibility assessment.

Specific aim
The ultimate aim of this project is to identify the need and feasibility for a valid, secure, web-based international (US/Canadian) registry of children with Wegener’s Granulomatosis and related small-medium vessel chronic vasculitis that has the ongoing commitment of all pediatric rheumatology centers to ensure reliable collection of diagnostic and monitoring data.

Renal transplantation in WG: mortality, allograft outcomes, and incidence of malignancies from the United States

Investigator: Nadine D. Tanenbaum, M.D.

Location: School of Medicine, Duke University Medical Center, Durham, North Carolina

Timeline: July 1, 2005 - July 1, 2006

Abstract
Background: Wegener's Granulomatosis (WG) is a rare systemic vasculitis that can affect almost any organ. Renal involvement occurs in at least 80% of patients. Kidney transplantation is a treatment option for those who reach end-stage renal disease. Small studies have demonstrated the success of transplantation in this population. Multiple aspects, however, regarding the long-term course of WG patients who undergo renal transplantation remain unknown. Information on the long-term allograft and patient survival in large numbers of patients, as well as on the incidences of acute allograft rejection and posttransplant malignancies, is lacking.
Hypotheses:
1. Patient and allograft survival may be different between WG transplant recipients and transplant recipients without WG.
2. WG transplant recipients and transplant recipients without WG may have different incidences of acute allograft rejection.
3. Patients with WG may be at greater risk than patients without WG for the development of posttransplant malignancies.
4. Specific risk factors can be identified that predispose certain WG transplant recipients to poorer outcomes.

Methods and Aims: Data will be extracted from the United Network for Organ Sharing database on 883 patients with WG who have undergone a total of 929 renal transplantations from January 1, 1988 through February 28, 2005. A group of 2787 patients matched for age, ethnicity, history of prior transplant, time of transplant, and center will serve as the control group. The aims of this study are to compare long-term patient and allograft survival rates, as well as to compare the incidences of acute allograft rejection and posttransplant malignancies between these two groups. Another aim is to identify predictors of adverse outcomes in the WG cohort.

Significance: Characterizing the course of WG transplant recipients and identifying risk factors for adverse outcomes may help us better define how to care for this population of patients.
The goal of this study is to examine the clinical course of a large population of patients with Wegener's granulomatosis (WG) who have undergone renal transplantation. In a preliminary data search on the United Network for Organ Sharing (UNOS) website, 883 WG patients in the United States from January 1, 1988 through February 28, 2005 have been identified who have received a total of 929 kidney transplants.
Specific aims
1. To compare long-term patient and renal allograft survival in renal transplant recipients with and without WG.
2. To compare the incidence of acute allograft rejection in renal transplant recipients with and without WG.
3. To determine the incidence and types of posttransplant malignancies in WG transplant recipients and to evaluate whether this risk is elevated compared to transplant recipients without WG.
4. To identify predictors for patient and renal allograft death, malignancy, and WG allograft recurrence in WG transplant recipients.

Characterizing the clinical course of WG transplant recipients and identifying risk factors for adverse outcomes may help us better define how to follow and care for this population of patients.

Methods
WG is a rare systemic anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis that can affect almost any organ. Untreated, the one year mortality rate is 80% [1]. Renal involvement, characterized by a pauci-immune necrotizing crescentic glomerulonephritis (GN), occurs in at least 80% of patients at some point in their course [2-4]. Between 11-43% of patients with WG or ANCA-associated GN develop end-stage renal disease (ESRD) and require chronic hemodialysis [3,5-8]. Among patients with ANCA-associated GN, the need for dialysis at diagnosis is a predictor of mortality with a significant difference in 5-year survival rates between patients with ESRD (61%) and those with preserved renal function (87%) [7].

In WG patients who reach ESRD, renal transplantation is treatment option. Case reports and small observational studies have demonstrated the success of transplantation in this population [9-13]. Multiple important aspects, however, regarding the course of WG patients who undergo renal transplantation remain unknown. Information is lacking regarding the long-term renal and patient survival in large numbers of patients, the risk of posttransplant malignancies, and the optimal immunosuppressive regimens. A better characterization of the incidence of disease recurrence and acute allograft rejection in this population is also needed.

Patient and renal allograft survival
One aim of this study is to compare differences in mortality and allograft survival between WG patients and patients without WG who receive a kidney transplant. The age of transplant recipients in this country is increasing. Patients older than 50 year now receive 47% of cadaveric transplants [14]. It is therefore likely that in the future clinicians will be confronted more frequently with the decision of whether renal transplantation in the often elderly WG patient is appropriate and whether WG patients will fare as well as patients without vasculitis. In the general transplant recipient population among patients age 60-74 years old, the estimate of additional years of life gained with a transplant compared to dialysis is about four years [15]. Small studies with fairly short follow-up in both WG patients and in patients with other types of vasculitides such as lupus suggest similar patient and graft survival when compared to patients without vasculitis [16-21]. In a group of 115 WG patients transplanted between 1982-1990, patient and allograft survival at 3 years of follow-up was similar between those with and without WG, although there was a trend towards a lower survival in the WG group [16]. Smaller studies that have followed patients up to 5 years have shown similar equivalent results [17-19]. However, the latter studies have consisted of less than 20 patients with either microscopic polyangiitis or WG [17-19]. Given its large cohort size and long length of follow-up, the proposed investigation is uniquely suited to address this issue in more detail. Furthermore, unlike most prior studies, this proposal includes patients only with WG. The course of renal disease in WG may differ from that associated with microscopic polyangiitis (MPA) or renal-limited vasculitis (RLV) [7].

Acute allograft rejection
Another aim of this study is to evaluate whether WG patients are at increased risk for acute allograft rejection. Acute allograft rejection is a major risk factor for chronic allograft nephropathy and ultimate graft loss [22-24]. Established risk factors for acute allograft rejection are the following: Black race, cadaveric transplant, second transplant recipients, elevated panel-reactive antibodies, increasing degree of HLA antigen mismatches, and possibly viral infections most notably CMV [25]. It is possible that ANCAs may cause subclinical neutrophil activation in WG transplant recipients, causing subsequent elevated levels of cytokines that might augment allograft rejection. Alternatively, the occurrence of rejection may predispose to recurrent allograft WG by cytokine-induced priming of ANCA antigens in the allograft. Demonstrating that WG transplant recipients have an elevated risk of acute allograft rejection in adjusted analyses would lend support to the idea that ANCA antibodies might be pathogenic in the rejection process and further studies, such as ANCA titer monitoring, could be proposed.

Malignancy in transplantation and WG
Patients with WG and ANCA-associated vasculitis are at increased risk for malignancies, especially bladder, skin, hematological, and possibly renal cell malignancies [26-33]. Much of this risk has been attributed to cyclophosphamide use. Of 1065 WG patients from a Swedish registry, 13% of deaths were secondary to a malignancy [27]. In some studies, the risk of bladder cancer in patients treated with cyclophosphamide has been about 30-fold greater than expected [26,31]. Other studies without available history on cyclophosphamide use have reported a 5-fold increase in bladder cancer risk [28]. The link between vasculitis and malignancies in general is incompletely understood. WG patients not treated with cyclophosphamide may also be at increased risk for malignancies. For example, Tatsis et. al. reported either preceding or concurrent diagnosis of malignancy in 23 patients also diagnosed with WG [32]. It is conceivable that there is a common genetic susceptibility for development of both WG and malignancy. It is also possible that the chronic immune stimulation of vasculitis predisposes to malignancy or inversely, that neoantigen exposure in malignancy may trigger the development of WG.

Malignancy is more common in all renal transplant recipients compared to age- and gender-matched controls, in large part secondary to the intensity of the immunosuppressive regimen. Skin cancers, particularly squamous cell skin cancers, are most common. There is also an increased risk of lymphomas, especially non-Hodgkin’s lymphomas, as well as renal cell carcinomas, Kaposi sarcoma, anogenital and hepatocellular carcinomas. Interestingly, there is only a mild increase in the risk of more common cancers such as lung, prostate, and colorectal cancers [34,35]. Clear risk factors for the development of malignancies after transplantation are sun exposure (for skin cancers), history of pretransplant malignancies, increasing age, Epstein Barr virus (EBV) negative to positive seroconversion at the time of transplantation and exposure to antilymphocytic therapy (the latter two are risk factors mainly for lymphomas) [34,35]. Higher maintenance levels of cyclosporine and tacrolimus, lower CD4 counts (for skin cancer) and increasing length of dialysis pretransplant have also been implicated as risk factors [34,35]. Recent studies have suggested that the immunosuppressive medicine sirolimus, which binds to FK binding protein and modulates the mammalian target of rapamycin (mTOR) resulting in eventual cell cycle arrest in the G1-S phase, has antiproliferative properties and has been associated with less posttransplant malignancies. Unlike tacrolimus and cyclosporine, sirolimus blocks cytokine-driven T- and B-cell activation [36-38].

Understanding the risk of posttransplant malignancy in WG transplant recipients is another goal of this study. It is important to define this risk in order to identify whether specific posttransplant screening is warranted in this population. To the best of the principal investigator's knowledge, only one prior study with 8 WG and 7 MPA transplant recipients has investigated whether patients with ANCA-associated vasculitis are more prone to malignancies [39]. The results of this study suggest that the incidence of malignancy may be elevated. Risks of malignancies in patients with other types with vasculitis who may have received cyclophosphamide (eg. systemic lupus erythematosus (SLE) patients) have not been specifically investigated in the transplant setting.

Predictors of adverse outcomes: patient and renal allograft death, WG recurrent allograft disease, and malignancy
A final aim is to identify independent clinical predictors of four specific outcomes (patient and renal allograft death, WG recurrent allograft disease, and malignancy) in the group of WG transplant recipients. While many of these predictors are likely to be the same as in the general transplant population at large, attention here is drawn to several specific questions. In nontransplanted WG patients with newly-diagnosed GN, serum creatinine at diagnosis of renal dysfunction is the single most important predictor of renal outcome [40-42]. Presumably, this is true as well in the transplant population. Therefore, it is important to identify risk factors for WG allograft recurrence in this population in order to highlight those at risk so that an early diagnosis can be made. Recurrent disease in the allograft has been estimated to be 16%, with 40% of these cases resulting in graft failure [43]. Recurrence has been described up to 13 years after transplantation [44]. ANCA titers at transplant have not been shown to be predictive of allograft outcome or disease relapse [19,21,45]. Whether ANCA monitoring in a high risk subgroup is not known. It is conceivable but unproven that different immunosuppressive regimens may affect disease relapse rates. In one of the largest studies of 127 WG renal transplant recipients, Nachman et. al. reported a roughly 20% systemic disease relapse rate which was similar between patients treated with cyclosporine and without cyclosporine [45].

Whether disease relapse rates are lower in the era of tacrolimus, mycophenalate mofetil, and sirolimus use has not been studied. We intend to examine what is the incidence of recurrent allograft disease and whether certain immunosuppressive regimens may be associated with lower rates of recurrence. We also intend to examine whether occurrence of acute allograft rejection is an independent risk factor for recurrent disease (see also section above entitled acute allograft rejection).

Significance
• It is important to determine in a large study with long follow-up whether WG transplant recipients have equivalent patient and allograft survival to patients without WG in order to make the most appropriate decisions regarding transplantation.
• If WG is shown to be a risk factor for acute allograft rejection, this would lend support to the idea that ANCA antibodies might be pathogenic in the rejection process.
• As the age of patients receiving transplants increases and improving allograft survival necessitates longer duration of chronic immunosuppresion, it is essential to understand what, if any, the increased risk over others WG patients are at for the development of posttransplant malignancy.
• Finally, identifying independent predictors of poor outcomes in WG transplant recipients could be helpful in developing future predictive models to assist with patient care decisions.

Identification and characterization of immunodominant, conformational epitopes of anti-neutrophil cytoplasmic antibodies

Investigators: Antje Mueller, Ph.D., Elena Csernok, Ph.D. and Prof. Peter Lamprecht, M.D.

Location: Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck, and Rheumaklinik Bad Bramstedt, Germany

Timeline: January 1, 2006 – December 31, 2006

Abstract
Autoantibodies against human neutrophilic cytoplasmic antigens (ANCA) have been a major diagnostic hallmark for small vessel vasculitides such as Wegener`s granulomatosis (WG) since their discovery more than 20 years ago. Animal models demonstrated that ANCA targeting either myeloperoxidase or proteinase 3 (PR3 = “Wegener`s autoantigen”) induce vasculitis. Binding of ANCA to an exposed epitope of the autoantigen PR3 is one of the determining steps in their mechanism of action. Therefore, knowledge of binding epitopes on the autoantigen is necessary to understand subsequent pathologic events and develop inhibitory strategies. The aim of this study is to identify and characterize immunodominant, conformational epitopes binding to ANCA directed against proteinase 3 and/or related molecules such as other neutrophilic enzymes and complementary PR3 (cPR3). A random peptide (12-mers) library expressed in E. coli will be employed to screen for antigen-antibody interactions. We hypothesize that by screening immunoglobulin G (IgG) preparations of patients with PR3-ANCA+ WG we will find and characterize novel antigenic peptide molecules with homologies to PR3 and/or other antigens, e.g. cross-reactive antigens. This approach differs from previous experiments, because the ANCA antibodies can bind conformational, i.e. non-linear epitopes. We shall isolate peptide clones that bind to PR3-ANCA-IgG pooled from WG patients (n=25) and synthesize and further characterize such peptides. The analysis allows to detect immunodominant, conformationally expressed antigenic peptide epitopes of PR3. Blocking such epitopes and thereby subsequent events might provide a future therapeutic approach of selective intervention in WG.

Specific aims
The aim of the study is to identify and characterize immunodominant, conformational epitopes binding to anti-neutrophil cytoplasmic antibodies in WG. Such an analysis will also disclose cross-reactive antigens and related molecules (cPR3), respectively. The study might generate new tools for the detection of disease-inducing epitopes and therapeutic intervention. The study will also provide new clues for the analysis of the impact of PR3-specific T cells (reacting with linear peptides) in the pathogenesis of WG.

1. Rationale of proposal and relevance to Wegener’s Granulomatosis.
a) Background

Several linear antigenic epitopes/areas of PR3 and, recently, complementary PR3 (cPR3) binding to antibodies have been characterized, mainly by looking at proliferative responses.

b) Own studies

As inferred by renowned immunologist R.M. Zinkernagel, many autoimmune diseases display lymphoid tissue-like structures in their inflamed target organs, where autoantigen recognition and presentation is thought to be maintained. We have shown that PR3+ cells, B cells, plasma cells, T cells and potential autoantigen-presenting cells are seen in granulomatous lesions of WG patients (11,12,13), thus permitting and sustaining an ongoing (auto)immune response.

Further, we know that monoclonal antibodies directed against PR3, like WGM2, generated by our group (14), recognize conformational epitopes of PR3. In contrast, T cells recognize linear peptide sequences as shown by incubation with four linear HLA-restricted PR3 peptides resulting in the detection of TNFα-producing PR3-specific T cells in WG (15). To detect conformational epitopes binding to PR3-ANCA+ IgG we searched for an approach that allows for antibody binding to non-linear epitopes (16). By now, we have established a random peptide library screening, which can identify binding to linear and/or non-linear antigenic epitopes. Preliminary findings yielded a potentially PR3-ANCA-binding epitope that shows some consensus sequence to PR3 (depicted in bold), “SVSTVHNHETVR” (one-letter-code of amino acids). When compared to the crystal structure of PR3 (17), the contiguous area seems to be accessible for antibody binding (Fig. 2). These findings warrant further analyses of a larger patient group.
The necessity and the potential of finding relevant ANCA-binding epitopes is also supported by a study showing that the interaction of PR3 and PR3-ANCA can be targeted in an interventional approach by inhibition of PR3-ANCA binding and destruction of ANCA-producing B cells by a fusion molecule of PR3 with a toxin (18).

c) Rationale and relevance

The pathogenetic role and relevance of a PR3-specific immune response in WG is still not fully elucidated. One major open question relates to (an) antigenic motif(s) on PR3 or other potential antigens, which via binding to ANCA induce(s) the well-described chain of inflammatory events leading eventually to subsequent endothelial destruction and full-blown small vessel vasculitis, i.e. WG (19). Once this question is answered, a more precise examination of a corresponding PR3-specific T cell response should be possible, as well as a monitoring of a potential epitope change. For systemic sclerosis, the use of a random peptide library not only led to the detection of an immunodominant epitope with homologies to a viral protein as well as to an autoantigen, but this recognition also initiated a potential pathologic mechanism, namely apoptosis of endothelial cells (20). Therefore, we hypothesize that such an approach will allow us to confirm known and identify still unknown immunodominant antigenic epitopes binding to ANCA IgG. Thus, the rationale of this proposed study is to obtain information about WG-relevant and less-WG-relevant peptide epitopes binding to ANCA, which could then be used for elucidating (auto)antigen presentation and antigenic T cell responses in WG and even for PR3-PR3-ANCA binding inhibition experiments in search for specific therapeutic agents.

2. Research methods and procedures including, if applicable, proposed statistical analysis.

IgG from PR3-ANCA+ sera of WG patients (n=25) will be purified by protein G column liquid chromatography. IgG preparations will be examined for PR3-ANCA titer (U/ml) by ELISA. Screening of potentially ANCA binding epitopes will be done employing a commercially available random peptide library, based upon a fusion protein consisting of a flagellar protein and thioredoxin, which is expressed at the surface of E. coli. In brief, the pooled IgG preparations will be coated onto a tissue culture plate at 20 µg/ml and then an incubation with the peptide-expressing E. coli will follow. After washing the bound bacteria are eluted, multiplied and incubated again with the IgG preparation to select for frequent epitopes. Following each so-called panning step the bound bacteria are seeded on agar plates as well to identify single clones. These clones are then grown in liquid culture and the plasmid DNA is isolated, purified and subjected to sequencing. Follwowing sequencing, data will be analysed using appropriate alignment and structure tools from NCBI (Blast etc., 21) to identify potential peptides, i.e. if mimics can be found. Then, a number of peptides will be synthesized and tested for binding to the patient’s IgG in ELISA, in comparison to PR3. Statistics will be analyzed using the SPSS software (Munich, Germany).

An Investigation of the Role of the Innate Immune Response in Kawasaki Disease

Investigator: Neil Edward Bowles, M.D.

Location: University of Utah School of Medicine, Salt Lake City, Utah

Timeline: January 1, 2008 - December 31, 2008

Abstract

Kawasaki disease (KD) is the most common systemic vasculitis syndrome particularly affecting the coronary artery, but the etiology remains unknown. It is widely believed that KD is due to one or more common infectious agent(s), which evoke an abnormal immunological response in genetically susceptible individuals. Most patients respond to treatment, although 25-45% will develop coronary artery lesions (CAL). The role of the innate immune response has been widely investigated in a number of infectious diseases, with data showing that variants (mutations or polymorphisms) in genes encoding proteins of innate immune response signaling pathways can result in worse outcomes following infections with bacteria or viruses. We hypothesize that variations in genes encoding proteins involved in the innate immune response will be associated with the development of KD and/or with the development of CAL. In order to test this hypothesis we propose the following aims.

1)         To enroll patients with KD (with or without CAL), collect blood samples and isolate DNA for genetic analyses.

2)         To use Taqman technology to determine the frequency of non-synonymous single nucleotide polymorphisms (SNPs) in genes encoding proteins of the innate immune response The frequency of SNPs in patients with and without CAL will be compared with the frequencies in the normal population.

3)         To perform mutation analysis of a group of these genes by analysis of amplified gene products using Lightscanner technology and direct DNA sequencing.

            Identification of defects in these signaling pathways could be significant. In the era of pharmacogenetics, interventions tailored to bolster the innate immune response may offer novel therapeutic options for the treatment of KD-associated vasculitis. Identifying variations in a specific component could also shed light on the etiologies of KD, since variations in TLR2 would implicate bacteria, while variations in TLR3 would implicate RNA viruses.

 

Lay Person Summary 

Kawasaki disease (KD) is a common disease in children, who experience a fever for more than 5 days, along with other symptoms, including swelling and rashes.  While most children recover after treatment, up to 20% will develop problems in the blood vessels of their hearts. It is believed that KD is caused by infection with an unknown virus or bacteria. It also appears that some people are more susceptible to develop KD and heart problems.  This is probably because they have changes in genes which make key proteins that protect them from bacterial or viral infections. We believe that changes in the proteins that are involved in the initial defense of the body against bacteria and viruses may cause these individuals to be at greater risk.  To investigate this we propose to collect blood samples from KD patients and to isolate DNA, which is the chemical that makes up genes.  We will look for changes in the DNA structure (known as the DNA or gene sequence).  Initially, we will look for changes that are already known to exist in some people to see if these changes occur more frequently in KD patients than in normal people. Then we will investigate some of these genes in detail to look for changes that have not been seen before and that do not occur in normal people. If we find any changes this may mean that the protein made by this gene is important in protecting people against the virus or bacteria that causes KD. In the future, these studies may allow us to identify which individuals are more likely to develop KD, which KD patients are more likely to develop heart problems, and could provide clues as to which viruses or bacteria cause KD.

ANCA Vasculitis: Autoimmune B Cell Dysregulation and its Clinical Impact

Investigator: Patrick H. Nachman, M.D.

Location: University of North Carolina at Chapel Hill, North Carolina

Timeline: January 1, 2007 - December 31, 2007

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA), directed against myeloperoxidase and proteinase 3 are found in patients with small vessel vasculitis, and play an important role in their pathogenesis. However, the mechanisms of loss of tolerance that allow production of these autoantibodies are poorly understood.  Imbalances in positive and negative regulation of B cells, and changes in their phenotypic distribution have been implicated in autoimmunity. 

The objective of this proposal is to investigate perturbations of B cells phenotypes in patients with ANCA vasculitis and their clinical impact on the course of disease.  Based on our preliminary findings, we hypothesize that patients with ANCA vasculitis have subsets of autoreactive B cells characterized by an increased likelihood of activation by antigen, and are associated with more severe manifestations of disease and/or a higher frequency of relapse.  Specifically, we will test the hypotheses that, compared to healthy controls, patients with ANCA vasculitis: (1) demonstrate the presence of B cell subsets that are activated, or are “poised for activation” based on their increased expression of the activation-related markers CD19, CD 86, CD40 and HLA-II, and decreased expression of down-regulatory molecules CD5 and CD21; and (2) have alterations in memory B cells (based on the expression of IgD and CD27) that are associated with a higher state of disease activity. 

We will further evaluate the impact of these alterations in B cell phenotypes on the clinical course of patients with vasculitis. We suggest that the observed B cell changes affect the response to treatment and the severity of subsequent disease activity.  We will examine B cell phenotypes in patients presenting with active vasculitis, and prospectively thereafter.  We will specifically evaluate whether the observed B cell alterations: (1) correlate with the response to initial therapy; (2) “normalize” with response to therapy and (3) predict the subsequent severity of disease.

LAY PERSON SUMMARY

 

 

Anti-neutrophil cytoplasmic autoantibodies (ANCA), are found in patients with small vessel vasculitis, and play an important role in causing the disease. However, the mechanisms that allow for the production by B lymphocytes of these antibodies directed against “self” are poorly understood.  B lymphocytes undergo an elaborate maturation process which commits them to various sub-types, such as “antibody producing cells” or “memory” cells.  Under normal circumstances, self-reacting B cells are either deleted or neutralized.  Conversely, breakdown in regulation allows self-reacting B cells to remain active.  Changes in the distribution of B cells among their various sub-types have been found in some autoimmune diseases.

The objective of this proposal is to investigate alterations of B cells sub-types in patients with ANCA vasculitis and their clinical impact on the course of disease.  Based on our preliminary findings, we hypothesize that patients with ANCA vasculitis have subsets of self-reactive B cells that are more easily activated, and are associated with more severe disease or a higher frequency of relapse.  Specifically, we will test the hypotheses that, compared to healthy controls, patients with ANCA vasculitis: (1) have B cell subsets that are activated or are “poised for activation” based on their expression of cell-surface markers; and (2) have alterations in memory B cells that are associated with increased disease activity. 

We will further evaluate whether these alterations in B cell sub-types affect the response to treatment and the severity of the subsequent course of disease.  We will specifically assess whether the observed B cell changes: (1) show a relationship with the response to initial treatment; (2) “normalize” with therapy and (3) predict the subsequent severity of disease.  We believe that understanding these B cell perturbations can lead to better monitoring of disease activity and tailoring treatment to each patient’s individual needs.

RESEARCH ACTIVITIES (of the PI for the past 3 years)

 

Over the last three years Dr. Nachman has continued his clinical and laboratory research endeavors in the field of anti-neutrophil cytoplasmic autoantibodies (ANCA). 

 

Clinical research activities were based upon, and contributed to the large cohort of patients with anti-neutrophil cytoplasmic autoantibodies-associated vasculitis followed in the University of North Carolina Vasculitis and Glomerular Disease clinic in collaboration with Doctors Ronald J. Falk, Susan L. Hogan and Mary Ann Dooley (rheumatology). 

1- Study of clinical and serologic predictors of disease resistance and relapse based on the analysis of a prospective cohort of 350 patients.  This work has published in November 2005 in the Annals of Internal Medicine (Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC, Nachman PH.  Predictors of Relapse and Treatment Resistance in ANCA Small Vessel Vasculitis.  Annals Internal Med. 2005;143(9):621-31.  See attached copy of the manuscript).  Research aimed at improving our understanding of predictors of clinical course and outcomes of patients with ANCA vasculitis bears direct clinical impact as it can help tailoring the long-term immunosuppressive therapy to the needs of each individual patient based on his or her risk profile for relapse.  This research is currently ongoing with a validation study in collaboration with Doctors Loic Guillevin and Christian Pagnoux in Paris, France, with an abstract submitted for the upcoming meeting of the American Society of Nephrology and a manuscript in preparation.  This work was supported in part by a grant from the NIDDK (P01-DK58335).     

2- Efforts to expand collaboration with other North American centers with expertise in vasculitis have led to the formation of the Glomerular Disease Trials Consortium under the leadership of Dr. Ronald J. Falk.  This Consortium aims to design and implement multicentric, collaborative trials in vasculitis and glomerulonephritis, and has led to several NIH grant submissions in these fields.  These efforts have led to the establishment of an electronic, secure, web-based registry of patients with ANCA vasculitis which is currently operational.  This expanded registry is aimed at facilitating epidemiologic studies of patients with vasculitis, and serve as a necessary infrastructure for the implementation of future clinical trials.  The web-based registry is funded by a granted from Aspreva Pharmaceuticals. 

3- Pilot study on the use of mycophenolate mofetil in the treatment of resistant or relapsing ANCA vasculitis. (Joy MS, Hogan SL, Jennette JC, Falk RJ, Nachman PH.  A Pilot Study Using Mycophenolate Mofetil in Relapsing ANCA Small Vessel Vasculitis.  Nephrol Dial Transplantation. 2005;20(12):2725-32.).  This study was funded by a grant from Roche. 

Dr Nachman clinical research also includes participation in a number of multicentric trials notably in lupus nephritis, and focal segmental glomerulosclerosis.

 

Laboratory research activities have likewise focused on ANCA vasculitis, and specifically the study of the regulation of the B cell response in this autoimmune disease.  Dr. Nachman is the PI for the following 3 projects:

1-            Study of the immunodominant epitopes of anti-myeloperoxidase autoantibodies (MPO-ANCA) using a model of mouse-human chimeric molecules.  This work was recently published in Kidney International (Erdbrugger U, Hellmark T, Bunch DO, Alcorta DA, Jennette JC, Falk RJ, Nachman PH.  Mapping of myeloperoxidase epitopes recognized by MPO-ANCA using human-mouse MPO chimers. Kidney Int. 2006 May;69(10):1799-805.). 

2-            The study of B cell regulation in ANCA vasculitis was started based on an animal model of transgenic mice that express an anti-MPO immunoglobulin light chain (manuscript in preparation). 

This work is now fully focused on studying the dysregulation of B cells in patients with ANCA vasculitis as is reflected in this grant proposal.        

 

Expression and activation of p38 MAPK isoforms in ANCA-associated renal vasculitis

Investigator: Jochen Zwerina, M.D.

Location: University of Erlangen, Germany

Timeline: February 1, 2007 - February 1, 2008

Abstract

Crescentic glomerulonephritis is a potentially devastating and outcome-limiting manifestation of ANCA-associated vasculitides. Upon unknown stimuli, infiltration of the glomerulum with inflammatory cells and glomerular crescent formation rapidly proceeds until irreversible organ damage.

Activation of p38 mitogen-activated protein kinases (p38MAPK) is a key signal transduction step in acute and chronic inflammatory disorders. Inhibition of p38MAPK has proven to be of therapeutic benefit in various animal models of inflammatory and autoimmune diseases including crescentic GN. However, early phase clinical trials in humans have been confronted with unfavorable safety profile of p38MAPK inhibitors. This might be related to the fact that four different isoforms of p38MAPK exist, expression and activation of which are differentially regulated.

In this project, expression and activation of p38MAPK isoforms will be analyzed in ANCA associated renal vasculitis (AARV) and in healthy donors (from living kidney transplantation donors) by immunohistochemical analysis of kidney biopsies. Further, the specific cell types expressing p38MAPK isoforms will be determined. Moreover, immortalized human podocytes will be used to confirm these findings. In vitro kinase assays are planned to determine, whether relevant pro-inflammatory cytokines for ANCA-associated nephritis are able to activate specific p38MAPK isoforms in vitro.

These results will add to our knowledge on tissue specific expression, localization and activation of p38MAPK and hence potentially allow development of more selective small-molecule p38MAPK inhibitors for AARV.

LAY PERSON SUMMARY

Vasculitis is an inflammation of the vessel wall. Certain forms of vasculitis, called ANCA- positive vasculitides are life-threatening diseases because they can destroy the architecture of the vessel walls and result in organ dysfunction. The kidney is key target organ of ANCA-positive vasculitides, which leads to rapid deterioration of organ function and often results in chronic renal failure. Inflammation in the context with vasculitis is triggered by proteins, which fuel the disease by facilitating the recruitment inflammatory cells and production of enzymes, which destroy the vessel wall. These inflammatory proteins are controlled by intracellular enzymes, which regulate their synthesis within the inflamed tissue. These enzymes, one of the most important ones is p38MAPK, are therefore considered as an interesting therapeutic target for new anti-inflammatory drug therapies. However, there are four different p38MAPK proteins and it is currently unknown which of them is the most important one for driving vasculitis. This project aims to define the nature of p38MAPK enzymes involved in human ANCA-positive vasculitis. To address this question it is planned to assess the expression and regulation of all 4 p38MAPK enzymes in kidney biopsy samples from patients with ANCA-positive vasculitis.

RESEARCH ACTIVITIES (of the PI for the past 3 years)

Since his thesis in 2003, Jochen Zwerina investigated the pathogenesis of experimental rheumatoid arthritis in the research group of Georg Schett. Within the three major pathologies of experimental and human rheumatoid arthritis (RA), he is predominantly interested in why arthritis causes major damage to the bone. There he explored the potential of different cytokines such as TNF, IL-1 and RANKL to drive bone damage. He could show that combined blockade of different cytokines is more effective than single blockade and that there is a hierarchy between different cytokines by using selective cytokine blockers (Zwerina et al, A&R 2004). Consequently, he pursued a research project on the role of IL-1 in TNF-mediated bone destruction by using gene-knockout mice. The results establish an important role for IL-1 in TNF-mediated bone destruction.

Additionally, he is interested in the role of iron-regulatory enzymes in the differentiation of osteoclasts. Heme oxygenase 1, an anti-inflammatory acting iron-regulating enzyme, inhibits generation of bone-resorbing osteoclasts. Interestingly, this enzyme can be up-regulated by anti-rheumatic drugs and is found in vivo in joint sections of RA patients thus representing a potential pharmacological target in RA (Zwerina et al, FASEBJ 2005).

Moreover, Jochen Zwerina is involved in research projects regarding the role of certain mitogen activated protein kinases (MAPK) in chronic inflammatory diseases. MAPK are activated upon extracellular stress (e.g. pro-inflammatory cytokines) and in turn activate themselves deleterious signaling cascades leading to perpetuation of inflammation and tissue destruction. Experimental and human RA are two examples, where MAPK are heavily activated and thought to drive the disease (Schett et al, A&R 2000; Gortz et al, Arthritis Research 2004). By using selective p38 MAPK inhibitors, he could demonstrate a marked amelioration of inflammation, cartilage and bone damage in experimental RA (Zwerina et al, A&R 2006). Currently, he investigates the role of p38 MAPK in different human inflammatory disorders including ANCA-associated diseases.

Gene Expression Profile of Temporal Arteritis in Giant Cell Arteritis

Investigators: Rula, A. Hajj-Ali, M.D. and Gary S. Hoffman, M.D.

Location: Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, Ohio

Timeline: March 1, 2006 - February 28, 2007

Abstract

Giant cell arteritis (GCA) is the most common type of vasculitis and affects people with mean age of about 70.Complications include ischemic–occlusive disease leading to blindness, strokes, neurologic dysfunction, and lesions in major arteries. The pathogenesis of vasculitis is incompletely understood. It is uncertain whether selective injury to specific vascular sites is due to primary abnormalities of immune function or abnormalities that first appear within the once normal vessel that “invites” an immunoinflammatory response. Observations in man and experimental models indicate that the vessel wall is not a passive participant in the process of injury, and injured sites are not randomly selected. We hypothesize that the tissue substrate (vessel wall) in GCA plays an important role in disease vulnerability and pathogenesis and that gene expression profile of uninvolved segments of temporal arteries from patients with GCA, will reveal the initial changes that predispose to vasculitis, before overt inflammation occur. Our goals are to characterize the molecular signature that defines vessel targeting and susceptibility for different vascular disease and to identify pathogenic mechanisms in giant cell arteritis. We propose to use microarray techniques to specifically aim to identify differential gene expression patterns of uninvolved segments of temporal arteries from patients with GCA compared to age-, gender and ethnicity- matched control specimens, to validate the data obtained from microarray analysis by using Real Time Quantitative PCR and to Identify the microenvironment where the genes of interest are expressed using RNA in situ hybridization techniques. Differences in gene expression that we identify in the temporal arteries of GCA-affected vs. control temporal arteries should lead to a better understanding of pathogenesis of GCA. These findings will aid to understanding qualities of vascular substrate that influence susceptibilities to other type of systemic vasculitis including Wegener Granulomatosis.

Specific AimsTo determine whether acquired abnormalities within the vessel wall precede and are required for inflammatory injury (i.e. vasculitis) in giant cell arteritis (GCA) of the elderly.

Relevance to Wegener's Granulomatosis

It is uncertain whether selective injury to specific vascular sites is due to primary abnormalities of immune function or abnormalities that first appear within the once normal vessel that “invites” an immunoinflammatory response. The fact that giant cell arteritis affects patients >50 years of age (mean 74) suggests that acquired abnormalities of either the targeted vessels and/or of immune function play a role in pathogenesis. Observations in man and experimental models indicate that the vessel wall is not a passive participant in the process of injury, and injured sites are not randomly elected. For example, GCA has a predilection for the aortic arch, its primary branches, and the cranial vessels that originate from the external carotid artery (e.g. temporal, occipital, maxillary and facial arteries). In contrast, the abdominal aorta and its distal branches are rarely involved. These observations about site predilection argue most strongly for initial change in tissue substrate playing an important role in pathogenesis.

However such patterns and onset in the elderly would not eliminate a role for genetic factors. Indications of genetic factors playing a role in GCA include the observations that women are affected 2-3 times more often than men and individuals of Northern European decent are more commonly affected than others, such as African Americans and Asians, among whom GCA is rare. Patients with GCA also have an ncreased requency of HLA-DR4 alleles. Prior studies, that have evaluated the pathogenesis of GCA, have primarily focused mostly on description of the inflammatory events within the vessel wall. These studies have added a great insight to understanding cell populations and cytokine profiles that play a role in injury. However, the question of why selective vessel targeting occurs or what acquired vessel changes lead to triggering disease in specific vessels has not been addressed. Knowledge of gene expression patterns within the vessel wall in GCA will enhance our understanding of the initial events in the pathogenesis of GCA and will have implications in the pathogenesis of not only of giant cell vasculitis but also in different systemic vasculitides including Wegener Granulomatosis.

Future Plans

The pathophysiology of GCA is poorly understood and efforts to understand this disease are highly appreciated. We are proposing to study the pathophysiology of giant cell arteries in a novel way that address the organ targeting and challenge the long standing paradigm that the initial insult in GCA is immune mediated. The advent of new methodologies like the microarray provide unprecedented opportunities to study the wall of vessels affected by GCA in a comprehensive manner. In addition, complementing these studies with In situ hybridization will reveal the topography of the identified genes. Such methods have not been applied previously in studying this disease. We expect to find differential gene expression profile at initial stage of the disease and complement the data in the future by the differential protein profile which will add a great insight into the understanding of the functional role of the expressed genes. We have taken a careful step in analyzing the data, to include ways to check for PI Name: Hajj-Ali , Rula, A. reproducibility, validity and reliability of the measurements, in order to interpret the results in a meaningful way. In this design we aimed to further validate the data and most importantly to localize the microenvironment of the genes of interest. This proposal represents a pilot study of our future research plans. Once the differentially expressed genes have been identified and organized into functional groups or “clusters”, the implications of these gene expression changes need to be addressed. The second tier of studies will allow us to determine whether the gene expression changes identified are initial triggering events, secondary changes or late compensatory changes. We will employ functional proteomic analysis to investigate proteins that interacts with specific genes of interest.

The localization of the cellular microenvironment or structure where the differentially expressed genes will emerge will serve as the basis for specific evaluation of this structure or cellular element in the pathogenesis of GCA.

Investigating the role of the novel Th17 cells in the pathogenesis of ANCA associated vasculitis...

Title: Investigating the role of the novel TH17 cells in the pathogenesis of the ANCA associated vasculitis and their potential for immunomodulation.

Investigator: Alan David Salama, M.D.

Location: Hammersmith Hospital, London, UK

Abstract

ANCA-associated vasculitides (AAV) are relapsing remitting diseases in which an autoimmune response to certain leukocyte proteins is generated. Despite current immunotherapeutic strategies disease relapses are common in up to 50% of patients. There is evidence that T cell immune responses to the autoantigens are critical to disease pathogenesis, with T cells being found in the biopsies of affected tissues, identified in peripheral blood and involved in both granuloma formation and class switching of ANCA-IgG. Recently a novel T cell phenotype has been described as being fundamental for autoimmune disease, in which cells are characterized by the production of Interleukin-17(IL-17). We hypothesize that an auto-reactive antigen-specific Th17 cell population is present in AAV, impairs the generation of regulatory T cells, promotes tissue damage and underlies disease relapses. Moreover, these may be relatively resistant to conventional treatment and may be best targeted using more appropriate biological (anti-cytokine) agents which are currently being trialed in other autoimmune disease settings. This hypothesis will be tested by studying Th17 cells in human disease and in a recently described experimental model of ANCA associated glomerulonephritis, in which tolerance is broken to the autoantigen and disease localized to the kidney following neutrophil recruitment.

IL-17 levels in patient samples will be compared to that in controls and correlated to disease severity. The cytokine responses of PBMC to antigen stimulation will be characterized and renal biopsies examined for Th17 cells. Using an experimental model of ANCA-induced glomerulonephritis, the role of IL-17 and gamma-interferon in disease will be compared. We will investigate whether certain clinical strategies could be applied to treat disease, based on preventing the generation/expansion of Th17 cells by blockade of IL-6, IL-23 or IL-1. Using this more targeted approach, to prevent Th17 cell generation, relapse of disease might be prevented.

Lay Person Summary

Auto-immune diseases are those caused by the body’s own immune system. A group of these are characterized by an antibody called anti-neutrophil cytoplasmic antibody (ANCA). They cause inflammation of blood vessels (vasculitis) which result in significant health problems such as kidney failure and lung disease. Like other autoimmune diseases, they often relapse, requiring repeated treatment with drugs that suppress the immune system but have serious side-effects. In patients with frequent relapses this treatment may be required for life, while even in patients who initially respond to therapy, one in five patients with kidney involvement will go on and develop end stage kidney disease, and ultimately up to half the patients will undergo some form of disease relapse. These relapses represent a significant challenge to treatment regimens, especially for patients with Wegener’s granulomatosis or those with Proteinase 3(PR3)-ANCA in whom relapse is more common.

Although we understand some of the events which perpetuate inflammation in the kidneys and lungs of

patients who have disease, little is known about what initially causes it and why it relapses. Based on published evidence, it is suggested that a newly recognized, but little understood immune pathway, involving specialist white blood cells releasing a chemical called interleukin-17, might underlie both the trigger for disease initiation and relapse. In this project, we will study the role of this pathway in ANCA-related kidney disease using patients and newly established experimental model systems. As we understand more about this pathway it should be possible to specifically target these cells, treat the disease more effectively and potentially prevent the development of disease relapse.

RESEARCH ACTIVITIES (of the PI for the past 3 years)

Following my postdoctoral research at Harvard University, Boston USA, I returned to the UK in 2003 and took up a post as a PI and Senior Lecturer in the Renal Unit at Imperial College, Hammersmith Hospital. Over the last 3 years I have established a laboratory in which we have been investigating immune mechanisms underlying vasculitis and glomerulonephritis. The main aims of our research are to understand how the autoimmune process is initiated and develop strategies that may allow us to reestablish immunological tolerance and hence ultimately negate the need for long term immunosuppression. In addition I have helped run the vasculitis clinic and have introduced a number of novel strategies for difficult to treat patients, in close collaboration with ENT and ophthalmological colleagues. We have been studying the impact of these novel therapies and continue to investigate the basis of therapeutic efficacy, in patients with ANCA disease. I am the PI of a large, multicentre, randomized, double blinded trial of CTLA4Ig in ANCA vasculitis, for which I have received an educational grant from Bristol Myers Squibb. This will begin recruiting in September 2007.

We have established significant laboratory and clinical links with a number of other investigators, especially the units in Birmingham and Cambridge, UK.

Vasculitic T Cells in Giant Cell Arteritis

Investigator: Cornelia M. Weyand, M.D.Cornelia Weyland, MD

Location: Emory University, Atlanta, GA

Timeline: July 1, 2008 - June 30, 2010

Abstract

Giant cell arteritis is a granulomatous vasculitis with T cell-macrophage infiltrates attacking medium-sized and large arteries. Multiple lines of evidence assign a key disease-promoting role to T cells. GCA is an HLA class II-associated disease; clonally related T cells expand in distinct regions of affected arteries, T cell clones from vascular lesions respond to tissue antigens and depletion of T-cell instructing dendritic cells strongly suppresses vasculitis. However, mechanisms through which CD4 T cells promote vessel-damaging immune responses are poorly understood. This proposal is designed to discover T cell effector functions promoting vessel wall inflammation. We will use two experimental models which recapitulate vasculitic immune responses: SCID mouse chimeras engrafted with human arteries and bioengineered human macrovessels. Specific Aim 1 is based on preliminary data that GCA-affected arteries contain IL-17, a T cell cytokine recently discovered as a major driver of autoimmune disease. We will examine IL-17 production in vasculitic T cell clones from GCA patients and investigate whether TH17 cells (T cells committed to IL-17 production) drive vascular inflammation in the vasculitis models. Specific Aim 2 focuses on an alternate T effector function, T-cell mediated cytotoxicity. We will examine whether GCA patients possess CD4 T cells that kill vascular smooth muscle cells and will test how such cytolytic T cells affect inflammation in and integrity of the vessel wall. Finally, in Specific Aim 3 we will search for novel GCA-relevant T effector pathways. We will apply gene expression profiling analyzing vascular T cell infiltrates in bioartificial arteries to find pathways relevant in the disease-promoting functions of such T cells; e.g. wall infiltration, control of pro-inflammatory macrophages, involvement in maladaptive healing responses, etc. The ultimate goal of this project is to define T cell-dependent disease pathways that can be therapeutically targeted to improve management of this devastating vasculitic syndrome.

Lay Person Summary 

Patients with giant cell arteritis/temporal arteritis (GCA) are threatened by vision loss, stroke and aortic aneurysm. Laboratory tests show intense inflammation; blood vessel biopsies reveal clusters of inflammatory cells in the walls of arteries. Such inflammatory clusters are composed of T lymphocytes and macrophages, cells of the immune system, which react to yet unknown instigators and attack vessel walls. T lymphocytes are highly sophisticated cells, equipped with a large array of receptors and the ability to release local hormone-like substances (called cytokines) to drive inflammation and tissue injury. Over the last decade T lymphocytes have emerged as key regulators causing GCA. However, little is known about how they facilitate blood vessel damage. This proposal is designed to find out how T lymphocytes communicate with other immune cells and cells of the arterial wall to promote disease. The experiments are made possible because we have generated two experimental models in which we can study blood vessel wall inflammation: we engraft human arteries into mice or we generate human arteries through bioengineering. First, we will examine whether vasculitis is caused by T lymphocytes specialized in producing IL-17, a cytokine recently implicated in driving autoimmune disease. We will then explore whether T lymphocytes in GCA patients can kill essential cells, in particular vascular smooth muscle cells that form the scaffold of the blood vessel. We already have preliminary data that such killer T cells are circulating in the blood of GCA patients. Finally, we will use state-of-the-art techniques to discover new pathways through which lymphocytes damage the blood vessel structure. These experiments involve gene expression profiling and sophisticated bioinformatics methods to identify pathways of interest.

The ultimate goal is to overcome our current limitations in treating GCA by opening new avenues for novel therapeutic and diagnostic approaches urgently needed for affected patients.

Concurrent Pilot Studies in Giant Cell Arteritis and Takayasu's Arteritis to Examine the Safety, Efficacy, and Immunologic Effec

Study Status: Recruiting Summary: Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate. Background Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are diseases that cause redness and swelling of blood vessels (vasculitis). These diseases are likely to affect the large sized blood vessels that supply blood to different parts of the body including the brain, eyes, arms, legs, lungs, kidneys, intestines, heart, and other parts. The purpose of this study is to determine if the medication abatacept is safe and effective in giant cell arteritis or Takayasu's arteritis. About this Study In the beginning of this study, all subjects will receive abatacept (by vein) combined with standard doses of prednisone. If there is no sign of GCA or TAK at month 3, you will be assigned by chance (like flipping a coin) to continue abatacept or switch to a placebo (fake treatment or inactive look-a-like) for the rest of the study. Your total time on the study will range from 12 to 48 months (1-4 years). About 66 people will take part in this study (33 with GCA and 33 with TAK) across 4 medical centers. You will be examined by the following: ·         Medical history review ·         Physical exam ·         Imaging (x-rays, MRI) ·         Blood/urine tests ·         Lung function tests ·         Study questionnaires ·         Skin test Target Enrollment: To be eligible to participate, you must: 1.     have a diagnosis of GCA or TAK 2.     have presence of GCA or TAK within the past 2 months 3.     be 18 years of age or older 4.     be willing and able to follow treatment and follow-up procedures 5.     be willing to use an effective means of birth control during this study 6.     be willing and able to give written informed consent You are not eligible to participate if: 1.     you have signs of an infection 2.     you are pregnant or breast feeding 3.     you are infected with HIV, hepatitis C, or hepatitis B 4.     you are not able to follow study guidelines 5.     you are not able to give informed consent 6.     you have a reduced number of blood cells 7.     you have a poor kidney(s) How to Participate: In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.   ·  Cleveland Clinic Foundation (VCRC) Cleveland, Ohio Principal Investigator: Carol Langford, MD, MHS Contact Person: Katherine Tuthill, RN, MSN, CNP Office: 216-444-9606 Email: TUTHILLK@ccf.org   Participation in research studies is voluntary. Deciding not to participate in a research study does not affect your ability to receive care at any of our Clinical Centers or from other physicians.

Update your contact information! We want to keep you informed with the latest news and information. Keeping your contact information up to date can be done quickly and easily on the Web: Click Here to Update Your Information About the VCRC The Vasculitis Clinical Research Consortium (VCRC) is an integrated group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research in different forms of vasculitis and improving the care of patients with vasculitis. The Vasculitis Clinical Research Consortium is part of the National Institutes of Health's Rare Diseases Clinical Research Network. The VCRC continues to grow and is working on several new research projects concerning vasculitis. Check back with the VCRC website regularly for updates: w

Defining Mechanisms of atherosclerosis in Wegener’ Granulomatosis:

This study looks at causes of atherosclerosis (hardening of the blood vessels) in patients with Wegener’s Granulomatosis. The study entails collection of clinical information, and blood samples. In addition all patients with Wegener’s Granulomatosis will undergo ultrasound of the carotid arteries to assess for hardening of these vessels located in the neck.  By correlating clinical information with findings from the research blood and ultrasound, scientists may be able to study the reasons of atherosclerosis (hardening of the vessels) in Wegener’s Granulomatosis.

 

Population needed:  Patients older than 18 years of age with Wegener’s Granulomatosis patients who are in remission with no previous diagnosis of heart failure, blockage of the arteries (heart or leg arteries), or stroke are welcome to participate.  Candidates will be screened with a history and physical examination, blood tests for research purposes and for lipids and fasting sugar measurements and ultrasound of the carotids. Patients or their third party payers will not be responsible for any cost which is out of the standard care. 

 

WHO CAN PARTICIPATE IN THIS RESEARCH STUDY?

• Age >18 years old.
• An established diagnosis of Wegener Granulomatosis, currently in remission.
• The ability to understand and sign informed consent.
• Normal kidney function.

 

YOU MAY NOT PARTICIPATE IN THIS STUDY IF YOU HAVE:

• Diagnosis of heart disease, stroke, or blockage of arteries in the legs.
• Recent infection.
• Diagnosis of chronic inflammatory diseases other than Wegener Granulomatosis.
• Diagnosis of Cancer or clotting tendency.

 

WHAT IS INVOLVED?

• One visit is required. An interview with physician for medical history and measurement of waist to hip length.
• Blood samples will be drawn and ultrasound of the neck vessels will be performed.
• Stop Aspirin and other Non-steroidal anti-inflammatory medication for a week prior to the enrollment.

 

 If you are interested in participating please contact Rula Hajj-Ali, MD at 216.444.9643

Cleveland Clinic Center for Vasculitis Care and Research

Rituxan in Churg Strauss Syndrome - Pilot Study at Mayo

The Mayo Clinic Nephrology Collaborative Group (MNCG) announces a new pilot study on the use of Rituximab in the treatment of Churg Strauss Syndrome with renal involvement.

The plan is to enroll five patients in the open label study using four weekly doses of Rituximab. Patients will be followed for one year after beginning of the remission induction regimen. Disease relapses, as defined in the protocol will be treated according to the standard of practice for patients with this disease.

To learn more:
Study Coordinators:
Lori Riess, 507.266.1047
Shirley Jennison, 507.255.0231
Email: MNCG@mayo.edu

Rituximab (Anti-CD20) for the Treatment of Hepatitis C Associated Cryoglobulinemic Vasculitis

Summary: This study will examine the safety and effectiveness of the drug Rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis.

About 5 percent of patients with hepatitis C develop cryoglobulinemic vasculitis. This syndrome, characterized by inflammation of blood vessels (vasculitis), may involve the skin, joints, kidneys, nerves and other sites, and cause skin rashes, joint pain, weakness, fatigue, and numbness.

About 10 to 30 percent of patients develop kidney disease, which, in some cases, can lead to kidney failure. Although the cause of cryoglobulinemic vasculitis is not known, a critical component is the presence of cryoglobulins-abnormal proteins that white blood cells called B lymphocytes produce in response to the chronic hepatitis C infection. Rituximab decreases the number of B cells.

The Food and Drug Administration approved Rituximab in 1997 for the treatment of B-cell non-Hodgkin's lymphoma.

Patients between 18 and 75 years of age with hepatitis C and signs and symptoms of cryoglobulinemic vasculitis may be eligible for this study. They must have failed, or been unable to tolerate, treatment with IFN-a and ribavirin. Candidates will be screened with a history and physical examination, electrocardiogram (ECG), blood and urine tests, 24-hour urine collection and chest X-ray, if clinically indicated.

Participants will be randomly assigned to receive Rituximab upon entering the study or 6 months after entering the study. Those whose treatment is delayed 6 months will be followed once a month at NIH for disease evaluation and blood tests during that time.

Patients will be given Rituximab intravenously (through a vein) once a week for 4 weeks. For the first dose, patients will be admitted to the hospital for at least 24 hours after the infusion for monitoring. Subsequent infusions will be given on an inpatient or outpatient basis, depending on how the infusion is tolerated. The day before each infusion they will have a history and physical examination, blood work, and other tests, such as X-rays, as clinically indicated. After the four infusions, patients will be followed for drug side effects and response to treatment. They will have blood tests every week for 4 weeks and will then return to NIH for 1 day every month for 12 months for a physical examination, blood tests, and X-rays, if medically indicated. Visits may be more frequent, if necessary, and patients may be asked to stay longer than a day if test findings require further investigation.

Patients whose cryoglobulinemic vasculitis improves and remains inactive for 12 months after completing Rituximab therapy will have completed the study. Those who benefit from treatment but have a later worsening of disease may receive a second course of four infusions, with follow-up for 12 months after the last infusion. Patients who do not respond to treatment and whose disease worsens will be advised of other treatment options, but will be asked to return to NIH monthly for 12 months for follow-up.

Sponsoring Institute: National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail Type: Participants currently recruited/enrolled

Gender: Male & Female Referral Letter Required: No Population Exclusion(s): Children Eligibility Criteria:

INCLUSION CRITERIA

Diagnosis of HCV-CV: must have all of the following HCV infection documented by serology and/or plasma HCV RNA.

One or more organ system with objective evidence of active vasculitis such as: Palpable purpura; Glomerulonephritis (defined by the presence of glomerular hematuria and/or new or worsening proteinuria); Acute peripheral neuropathy. Detectable cryoglobulins and/or RF.

Failure of treatment with IFN-alpha and ribavirin to control manifestations of HCV-CV OR intolerance to IFN-alpha/ribavirin regimen.

Patients must have a personal physician responsible for the care of their HCV.

Ages of 18 and 75 years

Willingness to use effective contraception during and for 12 months following Rituximab treatment. Effective contraception methods include abstinence, surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap or sponge, or hormonal contraception.

EXCLUSION CRITERIA

Recent (within 4 weeks) initiation of or increase in immunosuppressive therapy.

Active systemic infection (other than hepatitis C).

Pregnancy or breast feeding.

Prior treatment with Rituximab.

Known allergy to murine proteins.

Significant renal insufficiency (creatinine clearance less than 30 ml/min).

Presence of life-threatening HCV-CV; defined as rapidly progressive glomerulonephritis (defined as a doubling of the serum creatinine over a 3 month period), CNS vasculitis, cardiac disease due to active vasculitis, or GI vasculitis (defined by ischemic bowel, perforation, or infarction).

Significant hepatic insufficiency as manifested by Child-Pugh classification of B or C.

History of variceal bleeding, encephalopathy.

History of liver transplantation.

Co-infection with either HBV or HIV.

Any underlying medical condition that in the judgment of the investigator would put the patient at increased risk for serious infusion-related adverse events. Special Instructions: Currently Not Provided Keywords: Hepatitis Vasculitis Rituximab Cryoglobulinemia Recruitment Keyword(s): Hepatitis C Vasculitis HcV-cV Cryoglobulinemic Vasculitis Cryoglobulinemia Condition(s): Hepatitis C

Vasculitis Investigational Drug(s): Rituximab Investigational Device(s): None Intervention(s): Drug: Rituximab Supporting Site: National Institute of Allergy and Infectious Diseases

Contact:

National Institutes of Health Building 10 Room 8C416 10 Center Drive

Bethesda, Maryland 20892

Phone: 1-(800) 411-1222

Uveitis Study Needs Participants

Patients, both male and female, between the ages of 18 and 25, with non-infectious acute anterior uveitis and any previous episodes of acute anterior ileitis occurring at least four weeks before starting the study are being invited to enroll in a safety and efficacy study of iontophoresis and dexamethasone phosphate to treat anterior uveitis.  The study is being sponsored by EyeGate Pharmaceutical.

 

This is a randomized, double-masked exploratory study of four doses of iontophoretic delivery of dexamethasone phosphate ophthalmic solution in patients with non-infectious acute anterior segment uveitis. The current study will evaluate the safety, tolerability, and efficacy of the technology at the four dose levels to determine a safe, effective dose that is appropriate for future trials.

 

Five centers currently enrolling patients are located in Cambridge and Boston, MA; New York, NY; Norfolk, VA; and Columbus, OH.

 

For more information or to enroll, go to www.clinicaltrials.gov(study#NCT00694135); or contact Debbie Chmielewski at 887-334-0050 (a Texas number) or e-mail debbie.chmielewski@pleiad.com 

 

Source: EyeGate Pharmaceuticals, Waltham, MA

Autoimmune Diseases Association, InFocus, Vol. 16 No. 3, September 2008

VCRC Concurrent Pilot Studies in Giant Cell Arteritis and Takayasu’s Arteritis .....

5523:  Concurrent Pilot Studies in Giant Cell Arteritis and Takayasu’s Arteritis to Examine the Safety, Efficacy, and Immunologic Effects of Abatacept (CTLA4-Ig) in Large Vessel Vasculitis (AGATA)

Status: Recruiting

Summary:

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are diseases that cause redness and swelling of blood vessels (vasculitis). These diseases are likely to affect the large sized blood vessels that supply blood to different parts of the body including the brain, eyes, arms, legs, lungs, kidneys, intestines, heart, and other parts. The purpose of this study is to determine if the medication abatacept is safe and effective in giant cell arteritis or Takayasu's arteritis.

About this Study

In the beginning of this study, all subjects will receive abatacept (by vein) combined with standard doses of prednisone. If there is no sign of GCA or TAK at month 3, you will be assigned by chance (like flipping a coin) to continue abatacept or switch to a placebo (fake treatment or inactive look-a-like) for the rest of the study. Your total time on the study will range from 12 to 48 months (1-4 years). About 66 people will take part in this study (33 with GCA and 33 with TAK) across 4 medical centers. You will be examined by the following:

• Medical history review
• Physical exam
• Imaging (x-rays, MRI)
• Blood/urine tests
• Lung function tests
• Study questionnaires
• Skin test

Target Enrollment:

To be eligible to participate, you must:

1. have a diagnosis of GCA or TAK
2. have presence of GCA or TAK within the past 2 months
3. be 18 years of age or older
4. be willing and able to follow treatment and follow-up procedures
5. be willing to use an effective means of birth control during this study
6. be willing and able to give written informed consent

You are not eligible to participate if:

1. you have signs of an infection
2. you are pregnant or breast feeding
3. you are infected with HIV, hepatitis C, or hepatitis B
4. you are not able to follow study guidelines
5. you are not able to give informed consent
6. you have a reduced number of blood cells
7. you have a poor kidney(s)

How to Participate:

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

·  Cleveland Clinic Foundation (VCRC)

Cleveland, Ohio

Principal Investigator: Carol Langford, MD, MHS

Contact Person: Katherine Tuthill, RN, MSN, CNP

Office: 216-444-9606

Email: TUTHILLK@ccf.org

Participation in research studies is voluntary. Deciding not to participate in a research study does not affect your ability to receive care at any of our Clinical Centers or from other physicians.

VCRC Imaging Protocol for Magnetic Resonance and Positron Emission Tomography in Large Vessel Vasculitis

Study Name: 5515 - VCRC Imaging Protocol for Magnetic Resonance and Positron Emission Tomography in Large-Vessel Vasculitis (Takayasu's Arteritis): Development as clinical trial outcome measures

 

Study Status: Recruiting

For:

Takayasu's Arteritis (TAK)

Summary:

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Takayasu's arteritis is a rare disease that affects the blood vessels. Takayasu's arteritis can cause swelling of large and medium-sized blood vessels. The blood vessels that are commonly affected are the branches of the aorta (the main blood vessel that leaves the heart). The purpose of this study is to help doctors learn more about this disease by using x-ray-like tests to see if they are helpful in taking care of patients with Takayasu's arteritis.

About this Study

This is an imaging study that compares x-ray-like tests that would not be a part of your regular care (PET/CT) with x-ray-like tests that are a part of your regular care (MRI). At two visits, three months apart, patients will have a PET/CT scan performed at the same time as their MRI scan; some patients with also have a third PET/CT scan. A total of 36 people with Takayasu's arteritis at several hospitals will take part in this study. Doctors will use images from the different time points, along with information from exams and symptoms, to learn more about the disease.

Target Enrollment:

To be eligible to participate, you must:

1. Have a diagnosis of Takayasu's arteritis as defined by the VCRC Longitudinal Study #5503 and be enrolled in the VCRC Longitudinal Study #5503 at the same time.
2. Be older than 16 years of age. 
3. Have active disease occurring in combination with a disease relapse within 2 weeks before enrollment.

   Active disease will be defined by the presence of clinical features or imaging or both:

   Clinical features:

   • Constant fever higher than 38o C for longer than 1 week
   • Blood vessel pain/tenderness, scalp tenderness, or an abnormal blood vessels of the head
   • Unusual headaches
   • Limit of blood supply to the eye (retina), damage to the eye nerve, or loss of vision
   • Tongue/jaw pain and/or cramping
   • Brief limit of blood supply in the brain or stroke
   • Pain and/or cramping in body limbs
   • Muscle and bone symptoms (joint swelling or morning stiffness)
   • General feeling of being unwell and tired
   • Other symptoms/signs known by the doctor to be related Takayasu's arteritis
4. Willing and able to follow the imaging schedule and follow-up procedures
5. Willing and able to give informed consent

You are not eligible to participate if:

1. You are pregnant or breast feeding 
2. You are not able to follow study rules
3. You are not able to safely have an MRI scan

How to Participate:

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

How to Participate:

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Boston University School of Medicine

Boston, Massachusetts

Principal Investigator: Peter Merkel, MD, MPH

Contact Person: Jessica Martin

Office: 617-414-2507

Email: jmartin@bu.edu

Cleveland Clinic Foundation (VCRC)

Cleveland, Ohio

Principal Investigator: Carol Langford, MD, MHS

Contact Person: Geetha Krishnan

Office: 216-445-5930

Email: Krishng@ccf.org

 

Participation in research studies is voluntary. Deciding not to participate in a research study does not affect your ability to receive care at any of our Clinical Centers or from other physicians.

VCRC Multi-Center, Open-Label Pilot Study of Abatacept (CTLA4-Ig) in the Treatment of Mild Relapsing Wegener’s Granulomatosis

Background

Wegener's granulomatosis (WG) is an illness characterized by inflammation of blood vessels. It may involve many different parts of the body, but typically affects the upper respiratory tract (nose and sinuses), the lower respiratory tract (lungs), and kidneys. The current standard treatment for WG involves various medications and is based on disease severity. Unfortunately, more than 50% of people experience a relapse after remission, placing them at risk for additional organ damage and toxicity from medication. To prevent this, safer and more effective treatments for mild-moderate relapses are needed. We especially need to find treatments to help reduce the amount of prednisone patients need to take. The purpose of this pilot study is to determine the safety of the medication abatacept in WG and to gain information about whether abatacept may be effective in the treatment of mild relapsing WG.

 

About this Study

This is a treatment study, with a total of 20 people with WG taking part in this study at several hospitals. In this study abatacept is given intravenously at study visits on Days 1, 15, 29 and once a month thereafter. Participation in this study may last between 7 and 24 months. Study visits include the following:

• abatacept infusions
• blood tests; for clinical and for research purposes
• questionnaires to measure quality of life
• chest x-rays and CT scans of the chest and/or sinuses
• medical exam and physician assessment

 

To be eligible to participate, you must:

• Have an established diagnosis of WG
• Be experiencing a relapse of WG including one or more of the following manifestations:
• Active sinus/nasal disease
• Mouth ulcers
• New skin lesions
• Joint and/or muscle aches
• New pulmonary disease
• Eighteen years of age or older
• Willing and able to provide informed consent and comply with treatment and follow-up procedures
• Willing to use effective means of birth control while receiving treatment through this study

 

You are not eligible to participate if:

• Your relapse does not meet the criteria for mild-moderate disease
• You are taking more than 15 mg of prednisone daily
• You are being treated with cyclophosphamide (Cytoxan) at the time of enrollment
• You have been treated with rituximab within the past 12 months
• You are not able to follow study rules

 

How to Participate:

Please use the information below to inquire about participation.

Boston University School of Medicine, Boston, MA
Jessica Pettit
Study Coordinator
jlpettit@bu.edu
Phone: 617.414.2508

 

Cleveland Clinic Foundation, Cleveland, OH
Katherine Tuthill
Study Coordinator
tuthillk@ccf.org
Phone: 216.444.5257

 

Johns Hopkins Vasculitis Center, Baltimore, MD
Lourdes P. Sejismundo
Study Coordinator
lsejism1@jhmi.edu
Phone: 410.550.6818

 

Mayo Clinic College of Medicine, Rochester, MN

Kathy Mieras
Lead Study Coordinator/Project Manager
Mieras.kathleen@mayo.edu
Phone: 507.284.9187

 

University of Toronto Mount Sinai Hospital, Toronto, ON (site soon to open)
Sara Sutherland, RN BScN
Study Coordinator
SWebster2@mtsinai.on.ca

Phone: 416.586.8616

 

VCRC Longitudinal Studies and Patient Registry

Vasculitis Clinical Research Consortium (VCRC)

The VCRC was established in 2004 to address the challenges inherent in diagnosing and treating rare vasculitic diseases. Dr. Peter Merkel, of Boston University School of Medicine, is the Principal and Overall Lead Investigator for the VCRC, along with Co-Investigators from Johns Hopkins, Cleveland Clinic and the Mayo Clinic. The VCRC is conducting Longitudinal Studies (now enrolling patients) in different forms of vasculitis to identify biomarkers for disease risk, disease severity and activity, and clinical outcome. The VCRC is also planning to conduct experimental trials of new drugs for vasculitis. The VCRC Patient Contact Registry is a method for patients with vasculitis to register themselves with the VCRC so that they will be notified of new clinical research studies conducted by the VCRC. The contact registry is free of charge and anonymous, and patients can register by using a paper form, by calling a toll-free number (866-313-9879), or online by clicking “Join the VCRC Contact Registry” at http://rarediseasesnetwork.org/vcrc. By taking action, patients can help researchers develop a better understanding about vascultis. Patients who participate in research make it possible for researchers to create new studies and to find new treatments.

The Genetics Study of Systemic Vasculitis

Dear Interested Participant:

You are invited to participate in a new research study on the genetics of vasculitis. Some examples of the diseases classified as vasculitis include Wegener's granulomatosis, Takayasu's arteritis, microscopic polyangiitis, the Churg-Strauss syndrome, and polyarteritis nodosa.

Vasculitis is a group of diseases about which much remains unknown. This is particularly true about risk factors for the disease: who gets the disease and why?

We believe that genes contribute to a person's risk of getting vasculitis. This study is designed to identify some of the genes that may be important in leading to the condition of your specific form of vasculitis.

Your participation in the study would involve the following:

(1) You must have a diagnosis of vasculitis and be willing to answer a series of questions regarding your health and medications. We may also ask your doctor some questions regarding your health and test results. Before starting this study, we will have you sign a form that tells you about this study and how we plan to keep your information private during the study.

(2) You must have two living biological parents or one parent and two siblings who are also willing to participate in the study.

(3) You would provide a blood sample that could be drawn at your doctor's office using materials we send in the mail. The sample will be mailed back to us, using a pre-packaged mailing kit.

(4) After completing the consent process, your parents and/or siblings would provide a swab from inside their cheek (this can be done at home, without requiring a visit to their doctor's office or drawing blood) using materials we would send in the mail. The swab would then be mailed back to us, using a pre-packaged mailing kit.

If you are interested in participating in this study, you may contact us in one of two ways:

Telephone (on a toll-free number): 1-800-226-6023

Email: jhvc@jhmi.edu

We appreciate your interest in the study.

Sincerely,

Dr. Stuart Levine

Assistant Professor of Medicine

Co-Director, The Johns Hopkins Vasculitis Center

Johns Hopkins Bayview Medical Center

Division of Rheumatology

Rituximab for ANCA-Associated Vasculitis (RAVE) Study

Enrollment is Open: Participants Needed

Sponsored by The National Institute of Allergy and Infectious Disease and The Immune Tolerance Network

A randomized, multicenter trial for patients with severe ANCA-associated vasculitis.

Participants will be randomized to either a treatment of cyclophosphamide (CYC) and prednisone or rituximab and prednisone.

The primary objective of this trial is to determine the efficacy of rituximab and glucocorticoids in the induction of remission of ANCA-associated vasculitis.

For further detailed information: http://vasculitis.med.jhu.edu

Study Coordinators:

Lourdes Sejismundo (410) 550-6818 or

Yavette Goldsborough (410) 550-4580

Email: jhvc@jhmi.edu

Lead Investigators:

Ulrich Specks, M.D.,

Division of Pulmonary and Critical Care, Mayo Clinic

Co-directors: Philip Seo, M.D./Stuart Levine, M.D.,

The Johns Hopkins Vasculitis Center

Participating Medical Centers

Boston University

Cleveland Clinic

Duke University

Hospital for Special Surgery, New York City

Mayo Clinic

The Johns Hopkins Vasculitis Center

University of Alabama at Birmingham

Identification of Novel Wegener’s Granulomatosis Susceptibility Genes

Investigator:

Katherine A. Siminovitch, MD Location: Mount Sinai Hospital, Toronto, Ontario, Canada

Timeline: March 1, 2004 – ongoing

Dr. Katherine Siminovitch’s study “Identification of Novel Wegener’s granulomatosis Susceptibility Genes” is an ongoing project to collect blood samples from Wegener's patients and their family members.

The goal of the study is to collect blood samples and prepare DNA from 500 patients and their immediate family members, and to conduct a comprehensive clinical chart review in order to obtain powerful data for results stratification and analysis.

The study needs at least 250 more WG patients to donate samples to have sufficient data to develop definitive results. It is very easy to participate in the study. Patients enroll in the study and have a blood sample drawn at their local doctor’s office and shipped to Dr. Siminovitch with the materials provided.

For more information please contact:

Alida Pokoradi, Clinical Research Coordinator

Phone: 416-946-4501 x3297

Fax: 416-946-4531

Email: clinicalgenet.research@gmail.com

To read the complete abstract for the study:

Identification of Novel Wegener’s granulomatosis Susceptibility Genes