Immunosuppressive activity of 15-deoxyspergualin (15-DOS) on various models of rheumatoid arthritis.

Based on the promising results obtained thus far in various auto-immune disease models, the authors have further elucidated the disease-modifying potential of the new immunosuppressive drug 15-deoxyspergualin (15-DOS) in models of inflammatory and chronic degenerative joint disease of adjuvant arthritis (AA) and collagen type-II induced arthritis (CIA) in Lewis rats and spontaneously developing polyarthritis in MRL/1 mice. Treatment of AA animals with 15-DOS starting with the day of adjuvant injection prevented the disorder from spreading to the non-injected extremity. The drug also reduced the arthritis index (47% inhibition). The adjuvant disease can thus be prevented nearly totally, even after discontinuation of drug application. Even when starting the therapy during the established disease, 15-DOS still exerts a protective action on the development of the adjuvant disease. In the present model of CIA, the animals showed the same progression as reported by others. Approximately 80% of the animals had bilateral hind paw swelling. The production of autoreactive anti-type-II collagen antibodies and also high levels of circulating rheumatoid factor (RF) can be demonstrated in the serum of CIA rats. Treatment of these animals with 15-DOS was very effective in inhibiting swelling of the joints. Average antibody titres were also depressed and circulating RF was reduced. Even when treatment with 15-DOS started on day 15 after CIA induction on established lesions of polyarthritis, not only a significant suppression of the paw diameters occurred, but also the humoral response (antibody formation) could be inhibited in animals with established CIA disease. The disorder of MRL/1 mice is characterized by the development of auto-antibodies most prevalently directed against double-stranded DNA (dsDNA) and type-II collagen. These mice also have circulating rheumatoid factor (RF) and develop histological changes in their joints characterized by pannus formation, cartilage and bone erosions. Treating MRL/1 mice with 15-DOS resulted in a decrease in the amount of auto-antibodies and inhibited developing polyarthritis. Even in an established disease, 15-DOS reduced circulating RF and increase in paw volume (signs of polyarthritis) was inhibited. These results suggest that 15-DOS might be used as a therapeutic agent for human RA and that this new immunosuppressive drug could be an effective nonsteroidal antirheumatic agent.