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We read with great interest the paper by O’Dell.1We would like to offer some comments on it. Although we strongly believe in the rationale of the author, we feel that as clinicians our options should be based on clear cut data when treating patients with erosive progressive rheumatoid disease. In our clinical practice, in active and severe diseases, we try to optimise any treatment by using the highest doses of both non-steroidal anti-inflammatory drugs and disease modifying antirheumatic drugs (DMARDs), compatible with an acceptable risk of toxicity. According to the medical literature, in rheumatoid arthritis (RA) the highest doses of OH-chloroquine (OH-C) are 6 mg/kg/day, of methotrexate (MTX) 17.5-20 mg/week, and of sulphasalazine 3 g/day.2-4 Poor or inadequate responses can be assessed only when these amounts are reached. In the study by O’Dell,5 three groups of patients were studied, one receiving full doses of MTX, one a combination of full doses of OH-C and 1 g/day sulphasalazine, and the third a combination of the three. To our knowledge no data exist suggesting that the combination of full doses of OH-C plus 1 g day of sulphasalazine is any better than OH-C alone. It might well be that an additive effect is reached by such a combination, but this has never been proved. In addition no proof exists that 1 g/day sulphasalazine from the beginning, is clinically of any value in the long term treatment of RA.
When examining the combination studies that have been published on MTX and OH-C, we found no evidence of a statistically significant clinical or biological additive or synergistic effect of the two drugs. Therefore either the addition of low doses sulphasalazine to the two drugs exerts some peculiar, beneficial synergistic effect, still to be unequivocally proved, or the study lacks the data of a fourth group combining MTX plus 1 g/day sulphasalazine. Possible support for the additive effect, comes from a previously published open study using a combination of lower doses of MTX (mean dose throughout the study: 8.3 mg/week) plus full doses of sulphasalazine (2-3 g/day). The study showed that the association was more beneficial than the monotherapy with MTX alone.6 In fact while mean values of disease activity score (DAS) decreased by 26% in monotherapy, a mean decrease of 49% was seen in combination therapy. As the initial values of DAS were 5 or more, the results at the sixth month were certainly statistically significant, although of uncertain clinical importance. In contrast, in the O’Dell study5 the difference between groups, arose only after the 8-10th month of treatment with the multiple combination.
Therefore the real part in clinical practice, played by several combinations with low or full doses of each molecule, needs to be unequivocally confirmed.
Few studies have used full doses of single drugs or of various drugs in combination for long periods of time. Some negative results, at least, could have resulted from low doses or the results with single drug therapy could have been improved by using full doses of the drug.
As clearly hypothesised by O’Dell, by using full doses of the available drugs, the results should be even better either in terms of time lapse before the appearance of the response or of the degree of the response. We also need a clear distinction among the patients, between those who improve in a clinically meaningful manner (50% or more) and those who survive while receiving treatment without such a significant clinical benefit. For example, in our own experience with MTX, only 37% of 159 patients with active, erosive RA, followed up for three years, had a clinically important response,7 even though 83% were still receiving the drug (Ferraccioli G F and colleagues, submitted data). As far as the per cent of patients obtaining a clear improvement is concerned, our results with MTX fully agree with those by O’Dell in his two year study.
In conclusion, in our view, when establishing a combination therapy to improve the clinical results in severe, active RA, full doses of each drug should be tried, and only clinically meaningful outcomes should be taken into consideration.
I would like to thank Dr Ferraccioli and colleagues for their thoughtful letter on my leader.1-1 I certainly agree with their main points: in combination studies (and other studies as well) full dose DMARDs should be used and success should be based on a meaningful degree of response (we chose 50% improvement of composite criteria). Clearly we believe that one of the main reasons that some combination DMARD studies have not shown differences has been that the DMARD dose in the combination arms have been low.
In our study we used what we considered at the time to be full dose methotrexate (17.5 mg/wk) and full dose hydroxychloroquine (400 mg/day).1-2 We did, however, use low dose sulphasalazine (1 g/day) because of the concern about possible toxicity with the methotrexate-sulphasalazine combination. In our study the combination of methotrexate-sulphasalazine-hydroxychloroquine was clearly superior to methotrexate alone (p<0.001); as pointed out by Dr Ferraccioli and colleagues it is unclear whether this increased efficacy resulted from the hydroxychloroquine, the sulphasalazine, or a combination of the two. We have a study in progress that we hope will answer this question and in our current study the dose of sulphasalazine is increased to 2 g/day.