Cyclophosphamide without corticosteroids for treatment of severe systemic necrotizing vasculitis.

Systemic necrotizing vasculitides are a group of rare inflammatory conditions that cause inflammation and necrosis of arterial blood vessels. The ongoing damage to blood vessel walls can be followed by thrombosis and narrowing of their lumens, resulting in a profound visceral ischemia. Two of these conditions are polyarteritis nodosa and antineutrophil cytoplasmic antibody (ANCA)Yassociated vasculitis with granulomatosis (the latter formerly known as Wegener granulomatosis). In severe life-threatening cases, the use of corticosteroids alone in any dosage form is associated with a mortality rate of 80% at 1 year. The addition of cyclophosphamide to glucocorticoids has dramatically improved survival in these illnesses. This fact raises the following question: If steroids alone in severe cases are not remitting (and convey numerous life-threatening adverse effects of their own), why is it not appropriate to recommend treatment solely with cyclophosphamide? Stated another way, during the past 3 decades, why do the standard treatment recommendations continue to encompass the initiation of both medications together? From an era before the availability of ANCA testing, we present 1 case of severe polyarteritis nodosa and 1 case of severe Wegener granulomatosis that both completely remitted with the use of oral cyclophosphamide alone. Prolonged follow-up (27 and 13 y, respectively) reinforces the efficacy and rationale for our treatment decisions. Patient 1 was a 30-year-old white man who presented with 3 months of malaise, anorexia, weight loss, abdominal discomfort, and intermittent fevers, accompanied by abnormal results in liver function tests, a persistent leukocytosis, and a positive hepatitis B surface antigen. Four days before hospitalization, he developed numbness and weakness in his right foot. Physical examination revealed generalized muscle wasting, temperature of 101-F, and blood pressure of 170/100 mm Hg. Serial laboratory tests are shown in Table 1. Urinalysis showed microscopic hematuria and 1+ protein. Results of antinuclear antibody, cryoglobulin screen, rheumatoid factor, and Venereal Diseases Research Laboratory test were all negative. Results of chest radiography and abdominal ultrasound were normal. Biopsies of the right sural nerve and the gastrocnemius muscle both revealed a necrotizing vasculitis in smalland medium-sized arteries, consistent with polyarteritis nodosa. On the 11th hospital day, oral cyclophosphamide 175mg/dwas started (weight, 60 kg). No corticosteroids were given. Adequate hydration and urine output were maintained, along with adequate control of his hypertension. Clinical remission was achieved within 5 months. All lost weight was regained, all neurologic symptoms and findings resolved, and no relapses have occurred. Total cyclophosphamide use spanned 14months.Metoprolol 50mg twice daily was needed to control residual hypertension. He remains in good health 27 years after his initial presentation. No follow-up of hepatitis B serology was obtained. Patient 2 was a 54-year-old white man who presented with an 8-month history of decreased hearing in his right ear and calf myalgias. Five months after the onset of these symptoms (and 3 months before admission), he developed arthralgias in his hands, wrists, shoulders, and feet. Three weeks before admission, results of laboratory tests were normal (Table 2). Ten days before admission, he developed night sweats, chills, cyanosis of his fingers, small purplish nodules on his right leg, fatigue, exertional dyspnea, intermittent fevers, and a dry nonproductive cough. Physical examination revealed subungual infarcts of the left second and fifth fingernails, intact peripheral pulses, blood pressure of 160/95 mm Hg, variable cyanosis of the tips of several fingers on both hands, 6 cutaneous nodules overlying the right tibia, and scattered rales at the base of the left lung. Chest radiograph showed two 3-cm nodules in the right upper lobe and scattered smaller nodules in the left lower lobe. Open lung biopsy performed on the night of admission showed marked granulomatous inflammation, neutrophilic microabscesses, scattered multinucleated giant cells, and long-term vascular inflammation. Findings were consistent with Wegener granulomatosis. All biopsy cultures (including fungi and mycobacteria) were negative. On the second hospital day, oral cyclophosphamide was initiated at a dosage of 200 mg/d. No corticosteroids were given. Three months later, clinical and radiographic remission was achieved, thereby allowing for gradual tapering of cyclophosphamide (which was discontinued after 1 y) and eventual introduction of maintenance methotrexate at 7 months (Table 2). Five and a half years after initial hospitalization, while still taking continuous maintenance methotrexate, he developed fever, chills, lower extremity myalgias, diffuse arthralgias, fatigue, hemoptysis, and night sweats. Chest radiograph revealed recurrent multiple scattered lung nodules. Cyclophosphamide was resumed at a dosage of 150 mg/d, yielding clinical and radiologic remission after 3 months. Cyclophosphamide was discontinued after 13 months, and he remains in good health 6 years later on small doses of enalapril and metoprolol for residual hypertension. Maintenance methotrexate has never been interrupted.