The use of the disease activity score in the analysis of clinical trials in rheumatoid arthritis.

OBJECTIVE: To ascertain how well the disease activity score discriminates drug from placebo treated patients. METHODS: Three placebo controlled trials in rheumatoid arthritis (RA) were reanalyzed using the disease activity score: DAS = 0.53938 x SQRT (Ritchie index) + 0.06465 x (# swollen joints) + 0.330 x 1n (erythrocyte sedimentation rate) + 0.224. RESULTS: Patient groups receiving methotrexate, high dose D-penicillamine and sulfasalazine had the statistically greatest improvement vs placebo treated groups; patient groups receiving gold sodium thiomalate (GSTM) and low dose D-penicillamine also showed statistically significant improvement versus placebo treated groups. Patients receiving sulfasalazine or GSTM were deemed to benefit compared to placebo treated patients in this analysis, unlike the results presented in the initial analyses of this trial. CONCLUSION: The disease activity score is a simple and effective measure of inflammation that can discriminate between active drug and placebo treated patient groups. Use of this composite measure may improve analysis of clinical trials and also be applicable to clinical care.

Long-term evaluation of penicillamine or cyclofenil in systemic sclerosis. Results from a two-year randomized study.

In a two-year prospective therapeutic trial 13 patients with systemic sclerosis (SSc) were treated with penicillamine, 9 with cyclofenil, and 7 with neither. At entry skin involvement and esophageal, lung, heart, and kidney function did not differ significantly between the groups. Reevaluation after one and two years did not show any significant changes in skin, esophageal, heart, and kidney manifestations, while lung function had slightly improved in both drug-treatment groups. This study thus shows little overall effect of penicillamine and cyclofenil, although both drugs may arrest worsening of pulmonary dysfunction.

Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomized, double blind, multicenter study.

Ninety-two patients with active rheumatoid arthritis (RA) were entered in a randomized double blind study of 24 weeks comparing cyclosporine (initial daily dose 5 mg/kg) with D-penicillamine (initial daily dose 250 mg). The groups were well balanced in baseline characteristics. In the cyclosporine group, 10 patients stopped prematurely, one because of inefficacy. In the D-penicillamine group, 9 patients stopped prematurely, 3 because of inefficacy. The 2 antirheumatic drugs were equally effective in reducing disease activity, except for a significant (p = 0.005) decrease in erythrocyte sedimentation rate with D-penicillamine treatment. We conclude that under the conditions of this trial, cyclosporine can serve as an alternative to D-penicillamine for the treatment of patients with RA.

The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses.

We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P less than 0.0001), DP (P less than 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)