Immunosuppressive Drugs: Mechanisms of Action, Toxicity and Clinical Effects

Abstract

SUMMARY Immunosuppressive (cytotoxic or cytostatic) drugs are at present rather widely used in the treatment of rheumatoid arthritis and other connective tissue or autoimmune diseases. Their mechanisms of action in these diseases are not fully understood. They appear to exert an immunosuppressive effect which may be of primary importance, but it is not possible to precisely correlate this action on the immune apparatus by any of the tests utilised to date. It is entirely possible that a rather nonspecific anti-inflammatory action is of importance (possibly major) in the action of these drugs. To date, only two of the agents have been utilised in trials of patients with rheumatoid arthritis. These drugs are azathioprine and cyclophosphamide. The former has been demonstrated to have some anti-inflammatory properties along with its action as a purine antagonist. Cyclophosphamide, on the other hand, an alkylating drug, has not been shown to have anti-inflammatory properties, although more definitive testing may show these effects. So far, controlled clinical trials of either cyclophosphamide or azathioprine demonstrate that in a significant proportion (more than 50 per cent) of patients with moderately advanced and active rheumatoid arthritis, either of the agents may suppress the disease activity after a period of time (three to six months). There is no evidence that either of these compounds cure rheumatoid disease. It therefore appears that the observed effects are symptomatic, but they are more effective over a period of three to six months’ administration than are the currently available anti-inflammatory drugs. Each of the compounds tested has some short-term toxicity, especially cyclophosphamide when administered at high dosage level. The long-range risk of development of malignancy or of teratogenic effects is unknown. A number of questions remain to be answered about the true role of the cytostatic drugs in rheumatology in general and specifically against rheumatoid arthritis. These consist of the following: 1. The mechanisms of action of the immunosuppressive drugs. 2. The relative efficacy of the different immunosuppressive drugs. 3. The effects of combined therapy using more than one immunosuppressive drug at low dosage in patients or utilising them with corticosteroids. 4. The risks and the nature of the side effects in relation to the benefit of the drugs. 5. The long-term effects of immunosuppressive or cytostatic drugs, including their prognostic significance. Based on this series of background observations, it may be concluded that in the immediate future the use of these drugs should be restricted primarily to controlled clinical trials. The application of such drugs in rheumatoid arthritis (and other rheumatic diseases) outside of controlled studies must be limited to patients with serious disease activity which has proved to be refractory to conventional antirheumatic therapy. Furthermore, the use of immunosuppressive drugs outside of controlled studies imposes on the physicians using such compounds an obligation to ensure a prompt and effective registration of their side effects, especially the risks of development of neoplasms and of teratogenesis. Only by the utilisation of a reliable registration at an international level will it be possible to obtain the added information that we require about these potent compounds as soon as is possible.