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.
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
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.