Steroids and Methotrexate to Treat Systemic Vasculitis

• Status: Completed
• Trial end date: 2004-02-01
• Target enrollment: 0
• Participant gender: All

Summary

This study will evaluate the safety and effectiveness of prednisone and methotrexate in treating severe Wegener's granulomatosis and other systemic vasculitides. These diseases involve inflammation of blood vessels (vasculitis) that may affect the brain, nerves, eyes, sinuses, lungs, kidneys, intestinal tract, skin, joints, heart and other sites. Current treatment with prednisone and the anti-cancer drug cyclophosphamide is effective, but has significant side effects and a high rate of disease recurrence. In a small number of patients with vasculitis, prednisone and methotrexate, another anti-cancer drug, have led to marked improvement, with fewer side effects than are seen with cyclophosphamide. This study will evaluate this drug combination in a larger patient population.

Patients 10 to 80 years of age with active Wegener's granulomatosis, polyarteritis nodosa, Churg-Strauss vasculitis, or microscopic polyangiitis overlap may be eligible for this 2 1/2 to 3-year study. In addition, patients with glomerulonephritis (a type of kidney disease) and a positive blood test for C-ANCA (antibodies found in certain vasculitic kidney diseases) or inflammatory sinusitis or lung nodule or infiltrates in the absence of infection may also be enrolled.

Participants will take prednisone daily, by mouth, and low-dose methotrexate weekly, by mouth or by injection either under the skin, into a muscle or into a vein. Patients who significantly improve with treatment will gradually reduce, and eventually stop, the prednisone. If the remission lasts, methotrexate will also be reduced and stopped after 2 1/2 years. If active disease recurs, the original treatment program may be started again. Patients who never achieve complete remission with treatment but whose symptoms are well controlled and experience no serious side effects may choose to either continue low-dose methotrexate or stop therapy.

Patients will be hospitalized 4 to 6 times a year, about 2 to 8 days each time, depending on their disease severity and response to illness. In addition, they will have the following tests and procedures:

• Medical history and physical examination (upon admission to the study and then every 1 to 3 months).

• Blood tests for blood cell counts and for levels of enzymes that indicate liver damage (upon admission, then weekly, and finally, no less than monthly).

• Additional blood tests to measure blood chemistries and evaluate kidney function (upon admission and again when clinically indicated).

• Chest X-rays (upon admission and when clinically indicated).

• Computerized tomography (CT) and magnetic resonance imaging (as needed).

• Electrocardiogram (upon admission and then as clinically indicated).

• Lung function studies (upon admission and at least every 6 months or as clinically indicated).

• Ear, nose and throat evaluations (as clinically indicated).

• Liver biopsy, if blood tests to monitor liver function are persistently abnormal. This procedure is done in the hospital under sedation to induce relaxation and drowsiness. The skin over the liver (upper right abdomen) is numbed with a local anesthetic and a needle is passed rapidly in and out of the liver to collect a small tissue sample for microscopic examination.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Methotrexate; Prednisone

Criteria

INCLUSION CRITERIA:

Diagnosis: Wegener's granulomatosis.

Age: 10-80 years.

Qualifications to eligibility:

Prior documentation of vasculitis based on clinical characteristics and histopathological and/or angiographic evidence of vasculitis. Patients will be eligible for this study regardless of whether they are currently receiving immunosuppressive therapies. Failure to respond to prior therapy with other cytotoxic agents or toxicity from such agents, in the setting of persistent disease, will constitute one reason for eligibility for this study.

In the absence of histopathological and/or angiographic evidence of vasculitis, patients with the following criteria will also be eligible:

A. Positive C-ANCA (done at the NIH), and

B. Glomerulonephritis as evidenced 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, and

C. One or more of the following:

Inflammatory sinusitis with histopathological evidence of granulomatous inflammation and negative special stains for mycobacteria and fungi. Sinusitis must be present for at least 3 months and have failed to respond to at least 2 weeks of antibiotic therapy directed against likely pathogens (H. influenza, S. pneumonia, and upper respiratory tract anaerobic bacteria);

Pulmonary nodule or infiltrates in a patient in the absence of infection.

Evidence of active disease as defined by a Vasculitis Disease Activity Index of greater than or equal to 3 (Appendix I) or if begun on immunosuppressive therapy at an outside institution, a history of a Vasculitis Disease Activity Index greater than or equal to 3 during the past 6 months.

EXCLUSION CRITERIA:

Evidence of infection by gram stain and/or culture specimens. 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.

Recent (within four weeks) increase in GC or cytotoxic drug therapy.

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

Processes that would predispose to enhanced risk of MTX toxicity: acute or chronic liver disease, alcohol abuse (greater than 14 oz of 100 proof liquor or equivalent per week), active peptic ulcer disease, and inability to comply with study guidelines.

Serological evidence of infection with human immunodeficiency virus (a serological determination will be performed within two weeks of study entry).