A 12-month comparative trial of auranofin and d-penicillamine in rheumatoid arthritis

Felix-Daves, Derrick D.; Stewart, Arthur D.; Wilkinson, Brian R.; Bateman, John R.; Delamere, J P

doi:10.1016/0002-9343(83)90487-4

“…The toxicity-related dropout rates for MTX reported here may have been spuriously elevated by idiosyncrasies of the clinical trials studied. While elevation of liver enzyme levels accounted for no dropouts in 5 of the 7 trials we used (16)(17)(18)(19)(20) and accounted for only 1 dropout in one other trial (21), it was an important cause of dropout in the trial conducted by the CSSRD group (22). In that trial, liver enzyme elevations that were greater than twice the normal level dictated a patient's withdrawal from the study; this occurred in 18 of the 95 patients randomized to receive MTX.…”

Section: Discussionmentioning

confidence: 99%

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

Felson¹,

Anderson²,

Meenan³

1990

Arthritis & Rheumatism

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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.

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“…A total of 29 interventions among 132 randomized clinical trials (RCTs) represented by 130 publications (mean [range], 71.0% [27.0%-100%] females in studies; mean [range] of ages in studies, 53 [36-70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The number of studies with measured outcomes was 118 studies for TJC, 116 studies…”

Section: Resultsmentioning

confidence: 99%

“…For our primary analysis of all 132 studies (represented by 130 publications) we used the most frequently reported outcome, TJC. This included imputed TJC values for studies that did not measure TJC (eMethods 5 in Supplement 1), denominated TJCi.…”

Section: Methodsmentioning

confidence: 99%

Monotreatment With Conventional Antirheumatic Drugs or Glucocorticoids in Rheumatoid Arthritis

Guski,

Jürgens,

Pedder

et al. 2023

JAMA Netw Open

2

0

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ImportanceThis is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid.ObjectiveTo analyze clinical outcomes after treatment with conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid among patients with rheumatoid arthritis.Data SourcesWith no time restraint, English language articles were searched in MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, and reference lists of relevant meta-analyses until September 15, 2022.Study SelectionFour reviewers in pairs of 2 independently included controlled studies randomizing patients with rheumatoid arthritis to mono–conventional synthetic disease-modifying antirheumatic drugs, glucocorticoid, placebo, or nonactive treatment that recorded at least 1 outcome of tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein level. Of 1098 assessed articles, 130 articles (132 interventions) were included.Data Extraction and SynthesisThe review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and data quality was assessed by the Cochrane risk of bias tool RoB 2. Data were extracted by a single author and checked independently by 2 authors. Data were analyzed using a random effect model, and data analysis was conducted from June 2021 to February 2023.Main Outcomes and MeasuresA protocol with hypothesis and study plan was registered before data recording. The most complete of recorded outcomes (tender joint count) was used as primary outcome, with imputations based on other outcomes to obtain a full analysis of all studies. Absolute change adjusted for baseline disease activity was assessed.ResultsA total of 29 interventions in 275 treatment groups among 132 randomized clinical trials (mean [range], 71.0% [27.0% to 100%] females in studies; mean [range] of ages in studies, 53 [36 to 70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The mean (range) duration of RA was 79 (2 to 243) months, and the mean (range) disease activity score was 6.3 (4.0 to 8.8). Compared with placebo, oral methotrexate was associated with a reduced tender joint count by 5.18 joints (95% credible interval [CrI], 4.07 to 6.28 joints). Compared with methotrexate, glucocorticoid (−2.54 joints; 95% CrI, −5.16 to 0.08 joints) and remaining drugs except cyclophosphamide (6.08 joints; 95% CrI, 0.44 to 11.66 joints) were associated with similar or lower tender joint counts.Conclusions and RelevanceThis study’s results support the present role of methotrexate as the primary reference conventional synthetic disease-modifying antirheumatic drug.

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“…While elevation of liver enzyme levels accounted for no dropouts in 5 of the 7 trials we used (16)(17)(18)(19)(20) and accounted for only 1 dropout in one other trial (21), it was an important cause of dropout in the trial conducted by the CSSRD group (22). In that trial, liver enzyme elevations that were greater than twice the normal level dictated a patient's withdrawal from the study; this occurred in 18 of the 95 patients randomized to receive MTX.…”

Section: Discussionmentioning

confidence: 99%

Untitled

1990

Arthritis & Rheumatism

0

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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.

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A 12-month comparative trial of auranofin and d-penicillamine in rheumatoid arthritis

Cited by 15 publications

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

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

Monotreatment With Conventional Antirheumatic Drugs or Glucocorticoids in Rheumatoid Arthritis

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