Early treatment trials with interferon beta in multiple sclerosis.

Recent reports of the successful treatment of relapsing-remitting MS with interferon beta-1b (IFN-beta) have ushered in a new era of immunotherapy. In a sense, this was the result of a remarkable conjunction of molecular biotechnology, immunology and clinical research, resulting in the first therapeutic agent to alter the course of this previously untreatable disease. In more concrete terms, the use of IFN-beta in MS was the logical outcome of a series of clinical trials of natural and recombinant IFNs carried out over the past decade, and of concurrent laboratory research suggesting that the effects of the IFNs in MS are mediated by immunoregulatory rather than antiviral or antiproliferative mechanisms. It is now known that the proinflammatory cytokines IFN-gamma and tumor necrosis factor alpha (TNF-alpha) are probably involved in the pathogenesis of MS lesions. In contrast, type I IFNs (alpha and beta) tend to inhibit the activity of IFN-gamma and to prevent disease activity. The earliest controlled studies of natural IFN-alpha and IFN-beta, carried out in the early 1980s, led to the phase III clinical trial of systemic recombinant IFN-beta (Betaseron), recently completed in the United States and Canada. In patients treated with high-dose IFN-beta there were significant reductions in relapse rate and in the appearance of new lesions on magnetic resonance imaging (MRI). The US Food and Drug Administration approved Betaseron for treatment of relapsing-remitting MS in 1993, and it is now in widespread clinical use. A trial of another recombinant IFN-beta, given by intramuscular injection once a week, was also recently completed. The results of this study are awaited with great interest because the primary end point was progression of disability rather than relapse rate. Meanwhile, recombinant IFN-alpha was reported to prevent relapses and MRI changes in a small but well-designed trial. In this paper, the early clinical studies and some of the immunological developments leading to the use of IFN-beta in MS are reviewed.