The comparative efficacy and toxicity of second‐line drugs in rheumatoid arthritis results of two metaanalyses

Abstract

We performed 2 metaanalyses of placebocontrolled 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 < O.OOOl), DP (P < O.OOOl), 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 Submitted for publication January 3, 1990; accepted in revised form April 11, 1990. 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 < 0.05) and higher total dropout rates (P < 0.01) than any other drug; 30% of goldtreated 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. If a curative drug is not found, large multicenter trials or data synthesis from multiple drug trials may be necessary to identify new treatment regimens that have promise.

Guidelines for the management of rheumatoid arthritis: 2002 Update

“…AZA, a purine analog myelosuppressant, has demonstrated benefits in controlling RA, but it is rarely used (98)(99)(100)(101)(102). D-Pen is effective (98,99,103,104), but its use is limited, in part, by an inconvenient dosing schedule (i.e., slow increases in the dosage) and rare, but potentially serious, complications, including autoimmune diseases, such as Goodpasture's syndrome and myasthenia gravis. Intramuscular gold treatment is effective (98,99,105), but injections are required every week for 22 weeks before less-frequent maintenance dosing is initiated.…”

“…D-Pen is effective (98,99,103,104), but its use is limited, in part, by an inconvenient dosing schedule (i.e., slow increases in the dosage) and rare, but potentially serious, complications, including autoimmune diseases, such as Goodpasture's syndrome and myasthenia gravis. Intramuscular gold treatment is effective (98,99,105), but injections are required every week for 22 weeks before less-frequent maintenance dosing is initiated. Although oral gold is more convenient than injectable gold, there is a long delay (up to 6 months) before benefits are evident, and it is less efficacious (98,99).…”

Successful Desensitization for Hydroxychloroquine Anaphylaxis

“…About 10% of patients treated with HCQ develop skin eruptions, some due to hypersensitivity. Other patterns of cutaneous hypersensitivity reactions have also been described with antimalarials 1,2 .…”

“…HCQ is a cornerstone in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis 1,2 . It has multiple beneficial effects.…”

Pharmacogenetic approaches to rheumatoid arthritis

“…The frequency of the toxicities with SSZ has been reported to be about 20-30% in patients with RA. [19][20][21] NAT2 is a key enzyme in the acetylation of SSZ. The rate of acetylation is genetically determined and follows a bimodal distribution.…”