A Meta-analysis of the Efficacy and Toxicity of Combining Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Rheumatoid Arthritis (RA)

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A Meta-analysis of the Efficacy and Toxicity of Combining Disease Modifying

Anti-Rheumatic Drugs (DMARDs) in Rheumatoid Arthritis (RA)

Category:  17 RA‹treatment

Ernest H S Choy, , L

GKT School of Medicine, King's College London, London, United Kingdom

Presentation Number: 368

Poster Board Number: 368

Keywords: meta-analysis, combination DMARDs therapy, randomised controlled

trial

Statement of purpose: Combination DMARDs are increasingly used to treat RA.

Initial trials suggested they were more toxic but recent studies showed

combination DMARDs have superior efficacy. This conflicting data is

difficult to interpret because the trials assessed different DMARD

combinations, investigated different patient populations (early or

established RA) and employed different trial designs (step-up, parallel or

step-down). We undertook a systematic review on combination DMARD therapy

for RA and carried out a meta-analysis to evaluate the evidence for efficacy

and toxicity.

Methods: Medline and PubMed searches with the MESH headline " arthritis,

rheumatoid " , " drug therapy, combination " and " randomised controlled trial "

(RCT) were carried out for articles published from 1975 to 2000. Articles

were also identified by hand searches. The quality of the trial was assessed

based on adequacy of allocation concealment, double-blinded and patient

attrition. Trials were excluded if the quality was poor, were not published

in English or studied DMARDs that are not current licensed treatment for RA.

Data were extracted by 2 independent assessors. Efficacy was assessed by the

number of patients withdrawn due to lack of efficacy. Toxicity was assessed

by number of patients withdrawn due to adverse events. Risk ratios with 95%

confidence intervals were calculated and meta-analysis was carried out based

on a random effect model. Sensitivity analyses were carried out based on

different treatment combinations, trial design and early/established RA.

Summary of Results

45 potentially relevant RCTs were identified and screened for retrieval. 17

were excluded were excluded. The remaining 28 studies were included in the

meta-analysis. They comprised 9 step-up, 12 parallel and 7 step-down trials.

5 studies assessed early RA and 23 established RA. 7 studies added steroids

to 1 DMARD and 1 study added steroids to 2 or more DMARDs. 4 studies

assessed methotrexate (MTX) plus TNF inhibitors compared with MTX alone.

Results are given in table.

Conclusion: DMARD combinations vary in their efficacy/toxicity ratio. MTX

plus either SASP or anti-malarial or both and MTX plus TNF inhibitors have

favourable benefit/risk ratios. Only one study assessed methotrexate plus

cyclosporin. Other DMARD combinations have poor efficacy/toxicity ratios.

Surprisingly, using corticosteroids as bridging therapy at the initiation of

DMARD therapy failed to show statistically significant benefits.

Risk ratio and 95% confidence interval

  Efficacy Toxicity

Overall 0.43[0.28, 0.65] 1.21 [1, 1.46]

MTX plus sulfasalazine or anti-malarial or both or cyclosprin 0.54 [0.34,

0.84] 0.88 [0.61, 1.26]

MTX plus TNF inhibitors 0.13 [0.02, 0.68] 0.92 [0.46, 1.82]

Steroids plus one DMARD 0.69 [0.24, 2.03] ND

Other DMARDs 0.36 [0.17, 0.77] 1.48 [1.15, 1.92]