Efficacy And Toxicity Of Antirheumatic Therapies

There is evidence to support the efficacy of DMARDs in RA. These drugs are superior to placebo in reducing signs of inflammation and improving function (7). There is, however, variability in the response to these agents, and different drugs display different levels of efficacy. In general, drugs such as sulfasalazine and methotrexate (MTX) have been found to be more efficacious than such agents as auranofin and hydroxychloroquine (7). Recently, studies have employed more standardized measures of response. One such measure is the American College of Rheumatology 20% response criteria (ACR 20). This level of "response" is generally accepted as the minimum difference that is clinically noticeable by a patient (8). In randomized trials, an ACR 20 response is achieved by 45% to 65% of patients treated with sulfasalazine, MTX, and leflunomide (9-11). There are, therefore, a considerable number of patients who will fail to respond in a clinically important manner to any single agent. As a result of the limited efficacy of monotherapy, combinations of traditional DMARDs are increasingly being employed in the management of RA. Such combinations appear to have superior efficacy to individual monotherapy (3,12,13). The other approach to improving therapeutic responses has been to introduce biologic agents. Although these agents have a more specific mode of action, they are nevertheless not universally effective. Several trials of antitumor necrosis factor-alpha (TNF-a) agents have shown that 50% to 60% of the patients will achieve an ACR 20 response (4,5). Similarly 43% of the patients treated with anakinra, an interleukin-1 receptor antagonist (IL-1ra), achieved an ACR 20 response (14).

In addition to issues of limited efficacy, disease-modifying drugs are also associated with a significant range of adverse events, which again limit their use. In general, certain drugs have poor long-term tolerability, for example, the use of intramuscular gold salts and D-penicillamine (D-Pa) is often limited by the occurrence of rash and proteinuria. In long-term follow-up, "survival" on a particular drug is therefore limited by either lack of efficacy and/or adverse events. Pincus et al. found in a five-year follow-up study that 60% of the patients will remain on MTX over this time period. In contrast, <30% remained on DPa or oral gold, both being frequently stopped due to inefficacy and/or toxicity (15). Morgan et al. (16) have also noted similar trends. This study found that antimalarials were frequently stopped due to inefficacy, whereas 54% of the patients stopped IM gold salts due to toxicity. There were significant differences between different DMARDs in the proportion of courses ending in inefficacy. Interestingly, it was also noted that there were significant differences between subjects for the probability of failure on a particular drug. Overall, 35% of the variance of the probability of failure was due to these between subject differences. Although compliance and differences in inflammatory mechanisms between individual patients are likely to be important, individual variability in the metabolic pathways associated with each drug are also hypothesized to be important. Genetic variability in the absorption and handling of these agents is one aspect that might significantly influence the likelihood of response or toxicity. We will now consider several individual drugs and evidence for the influence of such genetic variability on the efficacy and safety of antirheumatic therapies.

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