This study will compare the safety and effectiveness of two drugs-methotrexate and
mycophenolate mofetil (MPM)-in preventing disease recurrence in patients with Wegener's
granulomatosis and related inflammatory blood vessel disorders. The standard treatment for
these conditions is combination drug therapy with prednisone plus cyclophosphamide.
However, although most patients improve on this therapy and achieve disease remission, many
experience a relapse (return of the disease) some time after therapy is stopped. Also,
these drugs can produce serious side effects during treatment. This study will test a new
treatment regimen to try to maintain disease remission in these patients with minimal side
Patients with Wegener's granulomatosis or other related blood vessel disorders between 10
and 80 years old will be considered for this study. All participants will start therapy
with daily doses of prednisone and cyclophosphamide. Prednisone will be reduced gradually
and then stopped after symptoms improve significantly. Cyclophosphamide will continue until
the disease is in remission. Patients in remission will then be randomly assigned to
continue treatment with either MPM or methotrexate. MPM is taken twice a day by mouth.
Methotrexate is taken once a week, usually by mouth, but in some cases, by injection into a
muscle or under the skin. Patients who do well and have no side effects will continue
treatment for 2 years. Then, the drug will gradually be reduced (usually at monthly
intervals) and finally stopped. No further treatment will be given unless a relapse occurs.
At that time, the type of treatment will depend on various medical factors, including the
severity of the recurrence and the patient's history of drug side effects.
Physical examinations and various tests, including blood and urine analyses, and X-rays,
will be done periodically to evaluate the response to treatment and monitor drug side
effects. The total duration of the study-from the screening evaluation through a 2-year
follow up after all medications have been stopped-is about 5 to 6 years.
The purpose of this study is to assess the comparative efficacy of using methotrexate versus
mycophenolate mofetil for maintaining remission that has been induced by cyclophosphamide
and glucocorticoids in patients with Wegener's granulomatosis and related vasculitides. In
this study, all patients will initially receive daily cyclophosphamide and glucocorticoids
and then at disease remission, cyclophosphamide will be discontinued and patients will be
randomized to receive either methotrexate or mycophenolate mofetil for remission
maintenance. They will continue to receive the agent to which they are randomized for 2
years, after which time it will be tapered and discontinued. Patients will be prospectively
monitored for evidence of disease relapse 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 events.
1. Documentation of Wegener's granulomatosis (WG) or a related systemic vasculitis based
on clinical characteristics and histopathologic and/or angiographic evidence of
vasculitis. In the absence of histopathologic and/or angiographic evidence of
vasculitis, patients who meet one of the following criteria and in whom infectious
and autoimmune diseases that may mimic WG or a related systemic vasculitides have
been excluded will also be eligible:
A. A positive assay for anti-neutrophil cytoplasmic autoantibodies (C- or P-ANCA)
and the presence of glomerulonephritis defined by red blood cell casts and
proteinuria or renal biopsy showing necrotizing glomerulonephritis in the absence of
B. A positive assay for anti-neutrophil cytoplasmic autoantibodies (C- or P-ANCA)
and the presence of granulomatous inflammation on biopsy plus abnormal chest
radiograph (defined as the presence of nodules, fixed infiltrates, or cavities) plus
nasal/oral inflammation on clinical examination.
2. Age 10-80 years.
3. Evidence of active disease as defined by a Vasculitis Disease Activity Index of
greater than or equal to 3 or if begun on CYC 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.
1. Evidence of active infection which, in the judgment 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.
2. 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.
3. 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.
4. 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.
5. History of CYC- or methotrexate- induced pneumonitis with past treatment.
6. Hypersensitivity to CYC, MPM, or methotrexate.
7. Transitional cell carcinoma of the bladder.
8. Inability to comply with study guidelines.
9. Hemocytopenia: platelet count less than 80,000/mm(3), leukocyte count less than
3,000/mm(3), hematocrit less than 20% (in the absence of gastrointestinal bleeding or