Comparison of Treatments to Maintain Disease Remission in Patients With Wegener's Granulomatosis and Related Vasculitis Syndromes
Comparison of Treatments to Maintain Disease Remission in Patients With Wegener's Granulomatosis and Related Vasculitis Syndromes
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 effects.

 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.
INCLUSION CRITERIA:

 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 immune deposits.

 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.

 EXCLUSION CRITERIA:

 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
 hemolytic anemia).