Active clinical trials for "Granulomatosis with Polyangiitis"

Overview: This open label, randomized, multi-centre study will enroll and treat 24 patients with refractory AAV. Aims: To determine the clinical response and severe adverse event rates associated with alemtuzumab therapy among patients with relapsing or refractory ANCA associated vasculitis (AAV). Hypothesis: Treatment with alemtuzumab induces sustained remission in AAV and will reduce immunosuppressive and steroid exposure.

OBJECTIVES: I. Determine whether there is prompt engraftment after autologous peripheral blood stem cell transplantation using filgrastim (G-CSF) mobilization in patients with life threatening autoimmune diseases. II. Determine the kinetics of T- and B-cell immune reconstitution after a combination of timed plasmapheresis, high dose cyclophosphamide and total lymphoid irradiation, and posttransplant immunosuppression with cyclosporine in these patients. III. Determine whether this treatment regimen beneficially influences the clinical course of these patients.

Anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis are rare diseases characterized by inflammation of blood vessels. Among the numerous cell types that play a role in vasculitis, one of the key actors is the neutrophil. Neutrophils are equipped with very powerful molecules that they use to destroy the invading microbes. Therefore, the mechanisms controlling neutrophil activation should be tightly controlled. If that is not the case, neutrophils may destroy the tissues of the host. This is what happens during chronic inflammation in vasculitis. Autoantibodies directed against neutrophils, ANCA, produced thus demonstrating that neutrophils are also targets of the immune system in these diseases. In addition, molecular studies provided evidence that genes normally silenced in mature neutrophils under normal conditions can be re-expressed in neutrophils from patients with ANCA-associated vasculitis thus strongly suggesting a profound deregulation of neutrophil functions in these conditions. Notably, the investigators have preliminary data showing that neutrophils from patients with granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), an ANCA-associated vasculitis, interfere with the normal phase of resolution of inflammation. The objective of the investigators' study is to understand the mechanisms underlying this increased activation state and determine if neutrophils could be used to define prognostic markers by clinicians to optimize patients' care. Therefore, the investigators plan to study the expression of proteins implicated in GPA pathophysiology at the membrane of neutrophils when they undergo apoptosis. The investigators will also study the deregulation of protein expression in neutrophils. This point will be the molecular translation of neutrophil deregulation. This technique is powerful and well adapted to identify by mass spectrometry the proteins that will be differentially expressed between the control and the disease state. After identification of proteins differentially expressed in patients with GPA, the investigators will further investigate whether their expression is modulated during the disease course and/or modified by the treatment. The investigators believe that understanding these neutrophil perturbations can lead to better monitoring of disease activity. Ultimately, the investigators may propose more targeted anti-inflammatory therapies which would be better tolerated by patients. the investigators also can identify new markers for disease activity which allow clinicians to define a better therapeutic strategy.

The investigators recently showed an abnormal expansion of NK-like CD4+ T cells in Wegener's granulomatosis (WG), mainly in the diffuse vasculitis presentation. These cells expressed an assortment of activating NK cell receptors and their signaling partners, in particular DAP12. The investigators hypothesize that DAP12, or a downstream signaling target of DAP12, is the missing link between the different cell components involved in WG (neutrophils, macrophages, CD4 T cells).

This study will evaluate the safety and effectiveness of a staged approach to therapy for Wegener's granulomatosis and other systemic vasculitides using prednisone plus cyclophosphamide followed by methotrexate. Vasculitides involve inflammation of blood vessels (vasculitis) that may affect the brain, nerves, eyes, sinuses, lungs, kidneys, intestinal tract, skin, joints, heart and other sites. Standard treatment with prednisone and cyclophosphamide is very effective, but has significant toxicity (adverse side effects). Methotrexate is also an effective treatment and is less toxic, but it is associated with a higher rate of disease recurrence and has not been used in patients with severe lung or kidney disease. Staged therapy using cyclophosphamide first and then methotrexate may provide better results for overall safety and effectiveness. Patients 10 to 80 years of age with active Wegener's granulomatosis, polyarteritis nodosa or a related systemic vasculitis may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood and urine tests, chest X-ray, electrocardiogram (EKG) and pulmonary function tests. Other procedures, such as biopsies, will be done only as medically indicated. Participants will be treated initially with 1 milligram/kilogram body weight of prednisone once a day and 2 to 4 mg/kg cyclophosphamide once a day. If the disease improves significantly, prednisone will be gradually reduced and stopped, and if remission is achieved, cyclophosphamide will be stopped. Methotrexate will then be started at 0.3 mg/kg body weight once a week and then increased to 0.5 mg/kg after 2 to 4 weeks. Methotrexate therapy will continue for at least 2 years. If at the end of 2 years the disease remains in remission, the methotrexate will be gradually reduced and stopped. If, on the other hand, active disease recurs during methotrexate treatment, the therapy will be changed. The new choice of treatment will depend on the severity of recurrence, pre-existing medical conditions, and previous adverse reactions to prednisone, cyclophosphamide and methotrexate. Patients will be seen periodically for a physical examination and blood tests to evaluate disease activity, response to therapy and drug side effects. X-rays will be done as medically indicated. Evaluations will be scheduled once a month until the patient has been on methotrexate for 3 months and then every 3 months for the next 18 months. Patients whose disease remains in remission at that time and are off all medications will be seen every 6 months for another 4 visits.

This prospective observational study will evaluate the long-term safety of MabThera/Rituxan (rituximab) in participants with granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis. Data will be collected for a maximum of 4 years from participants initiated on MabThera/Rituxan therapy by their physician according to prescribing information.

EGPA (Eosinophilic Granulomatosis with Polyangiitis, previously Churg-Strauss syndrome) is a rare vasculitis, characterised by asthma, rhinosinusitis and eosinophilia. There has previously been confusion around diagnostic criteria, with multiple sets of classification criteria being used inappropriately for diagnosis. The ERS formed a taskforce to produce specific diagnostic criteria, and these divided the Churg-Strauss Syndrome cohort into two groups - vasculitic EGPA and tissular Hypereosinophilic Asthma with Systemic Manifestations (HASM). It is not known if the groups separated by the diagnostic criteria are also separated in clinical symptomatology, or if their disease course varies, and this could have significant impact on management and further research.

The aim of this project is to develop a disease specific patient reported outcome measure (PROM) for patients with AAV (the AAV-PRO). Investigators are developing and validating a questionnaire to assess quality of life in patients with ANCA-associated vasculitis (AAV). Patients with AAV have inflammation in the small blood vessels leading to involvement of a range of organs and can suffer from ongoing disease activity or treatment side effects. Quality of life can be measured by patient reported outcome measures (PROMs).

This study will collect fluid and tissue samples from the bronchi (air passages to the lungs) of patients with Wegener's granulomatosis for laboratory examination. Wegener's granulomatosis is a type of vasculitis (blood vessel inflammation) that can affect many parts of the body, including the brain, nerves, eyes, skin, sinuses, kidneys, intestinal tract, joints, heart, lungs and other sites. About 85 percent of patients have lung involvement. The lining of the bronchi (bronchial mucosa) is composed of cells that produce mucus, inflammatory cells, and inflammatory mediators (chemicals produced in response to inflammation). Analysis of these various substances may provide insight into what causes different types of lung problems in Wegener's granulomatosis. Patients between 18 and 75 years of age with Wegener's granulomatosis who require bronchoscopy to evaluate the cause of their lung problem may be eligible for this study. Participants will undergo a bronchoscopy in the hospital intensive care unit (ICU). For this procedure, the mouth and throat are numbed with lidocaine jelly and spray. If needed, a sedative is given for comfort. A small plastic tube (intravenous catheter) is placed in a vein to give medications. A pencil-thin tube is then placed through the nose or mouth into the lung airways to examine the airways carefully. At the time of the bronchoscopy, patients in this study will undergo the following additional procedures: Bronchoalveolar lavage - Saline (salt water) is injected through the bronchoscope into the air passage, acting as a rinse. A sample of the fluid is then withdrawn and examined for infection, inflammatory cells and inflammatory chemicals. (This may be done as part of the standard medical care procedure.) Bronchial lavage - This procedure is similar to bronchoalveolar lavage, but less fluid is used to rinse larger airways. Bronchial mucosal biopsies - A small wire is inserted through the bronchoscope next to the bronchial lining. Forceps at the end of the wire pinch off a small piece of tissue for withdrawal and examination. The patient's heart rhythm and rate and oxygen levels are monitored during the procedure. When the procedures are finished, the patient is monitored in the ICU until the numbing effect of the anesthetic has worn off and then moves to a regular hospital bed for overnight. Patients whose test results show an isolated infection or isolated Wegener's lung tissue involvement and who are being treated or are eligible for treatment under another NIH protocol will be followed by X-ray for improvement of their infection or other lung involvement with treatment. Patients whose infection or lung tissue involvement improves may be asked to undergo a second bronchoscopy as described above, but for research purposes only.

Asthma is a chronic inflammatory disease. We propose to study inflammatory changes in the lungs of subjects with atopic asthma of different severity in vivo using positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG). It has been shown that the uptake of FDG as detected by PET scanning correlates with inflammation in animal models as well as in human disease processes such as sarcoidosis, tuberculosis and abscess formation. In addition, it has been shown that the inflammation associated with allergen challenge in patients with atopic asthma can be visualized using PET scanning with FDG. We hypothesize that the degree of FDG-uptake as a measure of inflammation correlates with the severity of asthma as determined by pulmonary function tests and clinical signs and symptoms. In addition, information about the spatial distribution of the inflammatory changes will be obtained. To compare the characteristics of the inflammation in asthma with non-asthmatic inflammation of the lung, the images obtained in asthmatic subjects will be compared with images from subjects who have inflammatory changes of the lung caused by Wegener's granulomatosis. Subjects with atopic asthma and non-atopic control subjects will be selected from the community and, if eligible for the study, undergo skin testing against common allergens and pulmonary function testing. Subjects with Wegener's granulomatosis will be selected from a large group of subjects followed with this disease at NIAID. PET scanning with FDG will be used to measure inflammation in the PET scanning facility at the Clinical Center of the NIH and the results of the scanning will be correlated with the severity of the disease. We expect that for the first time this methodology will permit an objective measure of the basic pathogenic process, the allergic inflammation, in patients with atopic asthma. Using this methodology it will be possible to study the efficacy of currently available therapies for allergic inflammation. In addition, this methodology will provide an extremely useful tool for the development of new therapeutic approaches to the treatment of asthma.