Cyclophosphamide and Prednisone Followed by Methotrexate To Treat Vasculitides

Overview

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.

The purpose of this study is to assess the efficacy and safety of a staged treatment regimen in Wegener's granulomatosis and related vasculitides in which patients will receive glucocorticoid plus cyclophosphamide at disease onset; cyclophosphamide will be switched to methotrexate upon disease remission. At the current time, cyclophosphamide plus glucocorticoids are the standard of care for the treatment of these disorders. Although this regimen has brought about a marked improvement in survival rate, it has been associated with significant toxicity. Methotrexate plus glucocorticoids have recently been investigated in patients with non life-threatening disease and while this regimen appears to have less toxicity than standard therapy it may be associated with a higher rate of disease relapse. By inducing patients with cyclophosphamide and glucocorticoids then switching to methotrexate at remission, we hope to combine the efficacy of cyclophosphamide with the more favorable toxicity profile of methotrexate. If successful, this regimen could provide a safer, yet effective therapeutic option which would be applicable to all patients regardless of disease severity. In this study, patients will be initially treated with cyclophosphamide and glucocorticoids and then switched from cyclophosphamide to methotrexate upon quiescence of disease activity. If at the end of two full years of methotrexate therapy there is continued evidence of disease remission, the drug will be tapered and ultimately discontinued. Patients will be prospectively monitored for evidence of disease activity and drug toxicity. Specific parameters that will be obtained include the time to disease remission, the rate and time of disease relapse, and the incidence of drug related adverse effects. This study will be open to patients with systemically active Wegener's granulomatosis or related vasculitis regardless of their degree of disease severity.