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While it is interesting and sometimes instructive to see what academic rheumatologists are writing about the treatment of rheumatic diseases, it is sometimes more interesting to pull back the curtains and see what the wizards are actually doing when they care for their own patients. Galindo-Rodriguez and colleagues have done just that for us by surveying the initial prescriptions for what they refer to as "second-line therapy" and in which they include the antirheumatic drugs: chloroquine and hydroxychloroquine (antimalarials), injectable and oral gold compounds, penicillamine, azathioprine, methotrexate, sulfasalazine, and cyclophosphamide. A total of 1427 adult rheumatoid arthritis (RA) patients of seven rheumatologists practicing in one geographic area in Canada had their medical records reviewed to determine which agent was initially prescribed in the years 1985-1994. Not all patients with a diagnosis of RA had "second-line" drug prescribed, and the authors present the results of the 1244 patients who did receive one of the drugs of interest. The patients were a predominantly female group, with a mean age of roughly 52 at the onset of RA and a mean duration of disease of 2.4 years. The rheumatologists’ practices were either in an academic referral hospital or in a community referral clinic. The most dramatic changes in prescribing were the increases in the percentage of prescriptions for antimalarials, which almost quadrupled from about 13% to 50% from the initial three year period 1985-1987 to the final 3.5-year period of 1990 through June 1994. During the same time periods, initial choice of intramuscular gold (IM gold) fell from about 55% to just under 20%, while penicillamine fell from roughly 5% to 1%. Fewer than 10% of patients received methotrexate as the initial "second-line" drug. The prescribing of auranofin was about 10% in the initial period, peaked at near 20% in the middle period, and ended at less than 5%. Sulfasalazine use increased from less than 10% to a peak of near 30% before ending at almost 20%. There were large differences in prescribing behavior when individual rheumatologists were compared with one another. There was more than a five-fold difference in antimalarial prescribing (5% vs 55%) and more than 26-fold difference in sulfasalazine prescribing (2% vs 53%); two rheumatologists never prescribed auranofin, while two others used it initially in about 30% of cases. None of the rheumatologists prescribed azathioprine or cyclophosphamide initially for any patient.
Multiple logistic regression models that incorporated patient and physician variables showed statistically significant odds ratios for patient’s residence, with those living in an urban setting more likely to receive an antimalarial (odds ratio 1.8) than those patients living in a rural setting. The opposite was true of IM gold, with urban dwellers having an odds ratio of 0.67 relative to their counterparts in the country. The younger rheumatologists changed their prescribing patterns more over the course of the nearly 10 years than their older colleagues did, though the number of physicians studied was too small to make this a statistically significant difference.
There are several striking things in this retrospective study. First, the dramatic increase in the use of antimalarial drugs as the first of the "second-line" agents. Two trends could help to explain this change: 1) an increasing reluctance to use drugs with unpredictable and potentially fatal adverse effects (especially injected gold and penicillamine, the initial prescribing of which fell precipitously from the start to the end of the study period); 2) an increasing cost-consciousness that recognizes not only the cost of the drug used but also the costs of monitoring for toxicity.
Secondly, I was surprised to see that initial prescription of methotrexate changed little from the initial to the final period in the study. However, between 1985 and 1994, many rheumatologists who were using methotrexate were performing surveillance liver biopsies, which meant a major commitment from the patient. Methotrexate was likely to have been held in reserve for patients who did not respond to other therapy. With careful monitoring of transaminase enzyme and albumin levels, it is now recommended that patients with persistently normal levels not have routine liver biopsies.1 Thus, the bar is now lower, and more patients and their physicians may choose methotrexate, especially for moderate or severe disease.
Finally, it is astounding that such wide variation in prescribing practice is seen in a relatively small geographic area. However, there is no clear consensus on which of these "second-line" drugs should be used first. There is some compelling evidence that combinations of "second-line" drugs are useful in initial treatment of RA.2 Perhaps we should celebrate the diversity of practice and admit that with our limited knowledge of RA and of the drugs used to treat patients, this may be the only way to assure that at least some of them get the best drug(s) first.
1. American College of Rheumatology Ad Hoc Committee Guidelines for Monitoring Drug Therapy in Rheumatoid Arthritis. Arthritis Rheum 1996;39:723-731.
2. O’Dell JR, et al. N Engl J Med 1996;334:1287-1291.