Rational Use of Disease-Modifying Antirheumatic Drugs

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Abstract
The currently available, most frequently used disease-modifying antirheumatic drugs (DMARDs) include auranofin, azathioprine, D-penicillamine, gold sodium thiomalate, hydroxychloroquine, methotrexate (amethopterin) and sulphasalazine. Controlled trials of these agents are reviewed to compare their relative efficacy and tolerability. Tender joint counts decreased with all drugs, as did joint swelling (measured as the percentage of patients with ≥ 50% improvement in joint swelling). Tender joint count decreased by 8 to 57% in drug-treated patients, compared with 3 to 30% (1 study exceeded this degree of placebo response) in the placebo groups. The ratio of drug to placebo improvement usually averaged greater than 2. A 50% improvement in joint swelling occurred in between 15 and 65% of drug-treated patients. Time to onset of response varied from.6 weeks (with methotrexate) to as long as 18 months (some patients on hydroxychloroquine). The remission rate was inconsistent and unusual in controlled studies (5 to 7%), but very high in some open studies (e.g. 43%). While up to 8% of patients on DMARDs stopped therapy secondary to unsatisfactory therapeutic response (with 1 exception) up to 43% of placebo patients discontinued therapy for this reason. The ratio, of dropouts for unsatisfactory therapeutic response for DMARD compared to placebo was less than 1 in 16 of 22 studies, and it was usually less than 0.5. Laboratory data examined include ESR, rheumatoid factor (RF), immunoglobulins and radiographic data. Ratios of decreases in ESR, comparing drug and placebo, were usually greater than 2. ESRs decreased from 3.6 to 27 mm/h, with gold sodium thio-malate, auranofin and methotrexate being most effective relative to placebo. RF decreased by ≥ 2 tube dilutions in 15 to 53% of the DMARD groups but also decreased in up to 26% of placebo patients, with ratios of drug: placebo usually greater than 2. Immunoglobulins tended to decrease with DMARDs but the data are fragmentary. Radiographic evidence that a drug slows the rate of bony damage is strong evidence that it is a DMARD. These data, however, are not easily available because measurement of bony damage is insensitive and difficult. The best evidence of radiographic efficacy exists for gold, although the data are not uniform even here. Studies with other DMARDs suffer from lack of convincing control populations, methodological failures or small numbers, although trends exist showing that azathioprine and D-penicillamine (and perhaps sulphasalazine and methotrexate) may also slow bony deterioration. The other side of efficacy, of course, is tolerability. By examining dropouts resulting from adverse effects, it was discovered that hydroxychloroquine, sulphasalazine and auranofin were the best tolerated DMARDs, while D-penicillamine appeared most toxic. Finally, a clinically reasonable, although not scientifically or statistically exact, method for comparing DMARDs was developed. This approach was developed a priori and resulted in the following conclusions: (a) for efficacy, gold sodium thiomalate and methotrexate were generally equivalent, D-penicillamine and azathioprine were marginally less effective, and hydroxychloroquine, sulphasalazine and auranofin were equal and less effective than the others; (b) on the other hand, hydroxychloroquine, azathioprine and methotrexate caused the least dropouts due to adverse reactions during these 6- to 12-month studies, while auranofin and sulphasalazine were equal and slightly less well tolerated; D-penicillamine and gold sodium thiomalate were most toxic.