The LIR is prospectively studying one of the largest groups of patients with the vasculitic syndromes in the world. On the basic of clinical, pathophysiologic, immunopathogenic, and therapeutic results obtained over the last 24 years, we have designed a revised scheme for the vasculitides which has now achieved worldwide acceptance. On the basis of our observations, lymphomatoid granulomatosis is classified as a subset of malignant lymphoma and not as a primary vasculitis. We have described a new vasculitic syndrome termed polyangiitis overlap syndrome. We have developed and instituted aggressive chemotherapeutic regimens consisting of chronically administered cyclophosphamide together with corticosteroids. This therapy has dramatically altered the 5-year survival in patients with systematic vasculitis from 13% in untreated patients to 48% after treatment with corticosteroids to greater than 90% in our patients treated with both cyclophosphamide and corticosteroids. This therapeutic protocol has been evaluated in over 175 of our patients with Wegener's granulomatosis. It has also been successfully used in treating other vasculitides such as polyarteritis nodosa, allergic angiitis, and granulomatosis, isolated central nervous system vasculitis, Takayasu's arteritis, and the acute vasculitis of Sjogren's syndrome. Our therapeutic protocols for the vasculitic syndromes are now used worldwide. However, the longterm toxicity of daily cyclophosphamide therapy in some patients has led to studies of alternative treatment including (1) intermittent intravenous high dose cyclophosphamide, (2) weekly low dose methotrexate and (3) daily trimethoprim/sulfamethoxazole in limited Wegener's granulomatosis. Preliminary results have not revealed any of these alternatives to be superior to daily cyclophosphamide and prednisone. However, methotrexate therapy done have significant efficacy and is thus far less toxic than cyclophosphamide. Our studies of the pathophysiology of vasculitis include a prospective analysis of bronchoalveolar lavage in Wegener's granulomatosis and controls. We have demonstrated that disease exacerbations are characterized by neutrophilic alveolitis, macrophage- leukocyte phagocytosis and the production of anti-neutrophil cytoplasmic antibodies in the lung. These observations suggest that neutrophilic inflammation and abnormal immune reactivity to neutrophil antigens may play a role in the pathogenesis of this disease. The pathogenesis of the vasculitides is also being investigated in vitro with the aid of endothelial cell systems. We have found that estrogens and progesterone substantially increase binding of neutrophils to endothelial cells. No increase in neutrophil adhesion was noted int he presence of testosterone. This observation is particularly relevant to Takayasu's disease and systemic lupus erythematosus, which are autoimmune diseases effecting blood vessels and having a predilection for women of reproductive age. It appears that female sex hormones may enhance certain types of vascular injury in the setting of autoimmunity. We have also discovered that the serum from patients with different vasculitides contains substances that stimulate new blood vessel formation. The predominant serum component responsible for angiogenic activity is haptoglobin. This is a normal serum protein, present in increased amounts in vasculitis patients. Increased production of haptoglobin may be a compensatory mechanism for local ischemia. Animal studies have demonstrated that injection of haptoglobin stimulates angiogenesis in surgical wounds. This property can potentially be exploited to enhance wound healing in man. We have also established a computerized data bank to store, retrieve and analyze and extensive collect (24 years/ > 200 patients) of epidemiological, clinical and laboratory information about the systemic vasculitides. An epidemiologic analysis of patients with Wegener's granulomatosis has continued to evaluate environmental factors, such as inhalant exposures and patient clusters.
