Cyclophosphamide and Prednisone Followed by Methotrexate To Treat Vasculitides
Cyclophosphamide and Prednisone Followed by Methotrexate To Treat Vasculitides
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.
INCLUSION CRITERIA:

 Documentation of WG based on clinical characteristics and histopathological evidence of
 vasculitis. Patients with a positive C- or P-ANCA and glomerulonephritis as evidence by the
 presence of red blood cell casts and proteinuria or renal biopsy showing necrotizing
 glomerulonephritis in the absence of positive immunofluorescence for immunoglobulin and
 complement will also be eligible.

 Age 10-80 years.

 Evidence of active disease as defined by a Vasculitis Disease Activity Index of greater
 than or equal to 3 or if begun on CTX and glucocorticoid at an outside institution, a
 history of a Vasculitis Disease Activity Index greater than or equal to 3 at the time of
 therapy initiation.

 EXCLUSION CRITERIA:

 Evidence of active systemic infection which, in the judgement of the investigator, is of
 greater danger to the patient than the underlying vasculitis. In those instances in which
 infection cannot be ruled out by gram stain and culture of secretions or collections of
 fluid in involved organs, it may be necessary to obtain a biopsy of the affected tissue for
 microbiological and histopathological studies.

 Patients who are pregnant or who are nursing infants will not be eligible. Fertile women
 must have a negative pregnancy test within one week prior to study entry and must be using
 an effective means of birth control.

 Processes associated with an increased risk of MTX toxicity: acute or chronic liver
 disease, past history of alcohol abuse (greater than 14 oz. of 100 proof liquor or
 equivalent per week), ongoing alcohol use of any volume that cannot be discontinued upon
 entry into the study.

 Serological evidence of infection with human immunodeficiency virus, hepatitis C, or a
 positive hepatitis B surface antigen. A serological determination will be performed within
 two weeks of beginning study participation.

 Inability to comply with study guidelines.