[Effect of cyclophosphamide (Endoxan) on experimental arthritis in rabbits]

The experimental investigation is divided into 3 parts: Firstly, it was assessed that cyclophosphamide (Cp) in different dosages was well tolerated locally when injected into the knee joint of normal rabbits as compared to saline controls on the basis of histology and cell count determination of the injected joints. In a second series of experiments a hyperimmune arthritis (HIA) was produced in rabbits by systemic administration of albumin, complete Freund's adjuvant and intraarticular stimulus by ovalbumin. Histological examination of synovial membranes reveal alterations similar to those of human rheumatoid arthritis on the 7th day after stimulus. Further experiments were aimed at assessing if Cp exerted an inhibitory effect on the 7 day old HIA. Cp in a dosage of 10 mg has been applied intraarticularly in various intervals prior, simultaneously and after the elicitation of HIA. It could be demonstrated that Cp led to a reduction of the number of lymphocytes, plasma cells and fibroblasts in the synovial membrane, the inhibitory effect on fibroblasts was bound to its administration around the point of HIA elicitation, an even stronger inhibition of lymphocytes and plasma-cells was only to be expected when Cp was applied 48 hours after ovalbumin challenge. Unwanted reactions in the course of Cp administration such as superficial and deep necrosis as well as damage of blood vessels in the synovial membrane combined with minor inhibition of lymphocytes and plasma cells were encountered when Cp was injected 120 hours after HIA elicitation. These new experimental results lead to the conclusion that efficacy and unwanted reactions during Cp administration are related to a local activation of the substance in the inflammatory milieu of HIA. Furthermore we were able to demonstrate that even the sole application of Cp if injected shortly before immigration of lymphocytes into the synovial tissue led to a marked suppression of almost all histological parameters of HIA. Our experimental findings strongly support the importance of lymphocytes and plasma cells being inactivated for the successful treatment of adult rheumatoid arthritis. They grow to consider the formation of necrosis and damage of blood vessels as sequelae of too fast a local activation of Cp in the inflammatory tissue.