Innovative treatment approaches for rheumatoid arthritis. Combination therapy.

It is accepted that combination DMARD therapy is a useful tool in current rheumatological practice. However, well-designed, large, long-term, controlled clinical trials are needed to determine which combinations, dosage schedules, and sequences of administration are most beneficial and least toxic. Until we develop treatment regimens that reliably induce and sustain acceptable control of disease manifestations in all patients for the rest of their natural lifespan, daily oral prednisone will continue to be a troublesome component of 'bridge' therapy, as it becomes the sole surviving constant in complex regimens whose other components are eventually discontinued because of toxicity, lack of efficacy, or non-compliance. We have often seen patients in whom the replacement of a well-tolerated but presumable ineffective DMARD with another DMARD has led to worsening of disease, when the modest benefits of the discontinued DMARD were lost before the hoped for onset of benefit from its replacement became evident. Since the toxicity of combinations of DMARDs has not appeared to be excessive, one can reasonably add the second DMARD to the first, while carefully monitoring for adverse effects and planning ton continue the combination until increased benefit occurs. Subsequently, if the second DMARD is not tolerated, the partial benefit from the first has not been given up, and a longer duration of treatment with the initial DMARD is sometimes associated with satisfactory improvement. If better control of rheumatoid arthritis is evident after 3-6 months of treatment with the combination of DMARDs, one must still decide whether to stop the first DMARD, stop the second, or continue with the combination. In the absence of major toxicity, we are most likely to choose to continue the combination if the patient has had a good response, thus inadvertently embarking on prolonged combined DMARD therapy (Paulus, 1990). Of course, other drugs besides those discussed above are available to control different aspects of joint damage; they should be considered in any combination therapy. Drugs which potentially protect cartilage from damage, such as orgotein, glycosaminoglycan polysulphate (Arteparon), and Rumalon, may prove useful in rheumatoid arthritis; they have been studied in osteoarthritis, but there is evidence that they protect cartilage from breakdown by inflammation in some animal models. As one of the many goals of treatment in rheumatoid arthritis is to protect cartilage, these chondroprotective agents might also be considered as part of the combinations to be studied. The combination of modest clinical efficacy with minimal toxicity reported with minocycline treatment of rheumatoid arthritis make this another potentially interesting addition to combination therapy regimens (Tilley et al, 1995). It is also important to continue the development of so-called 'biological agents', such as interleukin-2 receptor antibodies, anti-CD4 antibodies, anti-TNF-alpha agents and anti-thymocyte globulin. Combinations which include such agents have not yet been evaluated, although is seems logical considering that these agents offer the possibility of precise intervention directed at specific steps of the immuno-inflammatory process; their combination may thus be more effective than the use of single agents alone. While we await results of well-designed studies of these newer agents in RA therapy, we should continue to consider creative ways of using drugs that are already available.