These studies explore the role of lymphocytes in the pathogenesis of inflammatory arthritis and attempt to identify therapeutic alternatives for treatment-resistant autoimmune rheumatic diseases. The clinical efficacy, toxicity, and immunological effects of the newer adenosine analogs, such as fludarabine are being studied in patients with autoimmune rheumatic disorders in phase I/II clinical studies. These agents primarily affect lymphoid cells because these cells have small amounts of an enzyme necessary to break down these compounds. Previous investigations employing these drugs in patients with low-grade lymphoid malignancies have shown that they selectively target immune cells by inducing a physiologic form of cell death called apoptosis. Their effects on the clinical course of immunologic diseases, as well as on the function and regeneration of immune cells have not been characterized. Twenty-six patients have completed an open two-dose study for treatment of refractory rheumatoid arthritis and seven have been enrolled into a placebo-controlled study for the treatment of psoriatic arthritis. To date, no major or unexpected toxicities have been encountered. Fludarabine treatment has resulted in sustained B and T lymphopenia (>T). Recovery of T cells has been constrained by a limited thymic regenerative capacity. We are attempting to determine whether the level of lymphopenia should be a major determinant of safe drug doses; no substantive changes in total immunoglobulin or antibody levels have been seen. In addition to depleting lymphocytes these agents also result in a prolonged and profound suppression of their function. At the low doses of fludarabine used, significant clinical effects have been observed in up to 50% of patients with rheumatoid arthritis who have completed this therapy.
