Response to drug treatment in rheumatoid arthritis

Response to drug therapy in rheumatoid arthritis (RA) is often inconsistent and frequently disappointing. Possible reasons for the unpredictability of response, such as patient characteristics, irregular intake of drug therapy and the definition of response itself in RA, are examined in this thesis. The work covered is summarised as followed. Part I. A Community-based Study of Treatment, Response and Outcome Among Subjects with Rheumatoid Arthritis A community-based study of rheumatoid arthritis was undertaken to assess the characteristics of the subjects, patterns of drug treatment, response to treatment and factors affecting response. Subjects were accessed throughout the state of Tasmania using sampling frames other than rheumatology practice. These subjects were assessed and interviewed in their homes. Detailed medical and medication histories were obtained, the current status of the subject's RA was evaluated both clinically and serologically, the impact of the disease on his/her lifestyle was assessed and the degree of medication compliance was estimated. During the course of the study a new 1-1PLC method was developed for the estimation in plasma of seven commonly available nonsteroidal anti-inflammatory drugs (NSAIDs). A preliminary study to assess the interview technique in the evaluation of subject's compliance with prescriber's instructions was also conducted. The age distribution, the sex ratio and other characteristic of the sample studied were similar to that described for samples of rheumatoid subjects drawn from rheumatology practice. The patterns of disease severity were however significantly different, with a greater proportion of the sample having relatively benign disease. Evidence of this was provided in comparisons of the disease duration-adjusted functional capacity and treatment data, both within the sample and with similar data from clinic settings. Although patterns of drug treatment differed in the community based sample, response to drugs was similar to that seen in the clinic situation. The rationale for drug treatment was the same in both community and rheumatology practice with similar patients or disease types receiving slow acting anti-rheumatic drug (SAARD) treatment. Since this more aggressive therapy was generally reserved for those with severe disease, regardless of the treatment setting there was a spurious negative relationship between outcome and anti-rheumatic drug therapy. The merits of various disease-activity or response measures were compared in this sample. The erythrocyte sedimentation rate proved to be more suitable than the other serological measures such as C-reactive protein and beta2microglobulin in terms of cost effectiveness, ease of performing the test and the results obtained. In addition the disability score (Lee's functional index score) was found to be a useful clinical indicator of disease activity. Factors such as patient noncompliance with medication instructions and the NSAID's plasma half-life were demonstrated to have the potential to significantly influence response through their effect on plasma drug levels. Approximately 40% of the subjects were noncompliant. The major incentive for patients to take their medication as directed was disease activity, however more esoteric factors such as the subject's motivations and health beliefs were also found to have an influence especially among those with little or no active inflammation. Part 11. Chronic Administration of Aspirin in Patients with Rheumatoid Arthritis: Pharmacokinetics and Response n this study the relationship between salicylate pharmacokinetics and response to chronic aspirin therapy was investigated in patients with rheumatoid arthritis. The study design included a preliminary, single dose study with soluble aspirin to determine initial phannacokinetic parameters, followed by a chronic study in which enteric coated aspirin was ingested daily for a period of six weeks. During this period both plasma and urine drug data were collected and clinical response to therapy was monitored. The initial steady-state salicylate plasma levels obtained were extremely varied. During the six weeks there was a decline in the steady-state levels of both bound and unbound salicylate and a rise in plasma salicylurate levels. This was associated with a significant increase in both the total and unbound Vmax for salicylurate formation, though there was no apparent change in the overall elimination rate constant for salicylate. As a consequence of the high incidence of toxicity and the variability in initial response it was difficult to make any judgement about the relationship between the pharmacokinetic changes and response. Apart from the initial positive response to aspirin therapy there were no significant changes in the drug's efficacy during the study. There was however a high incidence of dose-related toxicity among the subjects which was associated with high unbound rather than total salicylate levels. Results of this study suggested that unbound salicylate levels rather than total salicylate concentration should be monitored in the assessment of therapeutic or toxic effects in patients with rheumatoid arthritis.