RESEARCH - A meta-analysis of the efficacy and toxicity of combining DMARDs in RA based on patient withdrawal

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Rheumatology (Oxford). 2005 Nov;44(11):1414-21. Epub 2005 Jul 19.

A meta-analysis of the efficacy and toxicity of combining disease-modifying

anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal.

Choy EH, C, Dore CJ, DL.

Sir Alfred Baring Clinical Trials Unit, Academic Department of Rheumatology,

GKT School of Medicine, King's College London, UK. ernest.choy@...

INTRODUCTION: Combinations of disease-modifying anti-rheumatic drugs

(DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early

trials showed their toxicity while recent trials suggest superior efficacy.

Trials of DMARD combinations have enrolled different types of patient (early

or established RA), used different designs (step-up, parallel or step-down)

and utilized a range of outcome measures. We undertook a systematic review

of combination DMARD therapy for RA and carried out a meta-analysis to

evaluate the evidence for efficacy and toxicity. METHOD: Medline, PubMed and

EmBase were searched using MESH headlines 'arthritis, rheumatoid', 'drug

therapy, combination' and 'randomized controlled trial' (RCT) for papers

published from 1975 to April 2004. References from published articles were

also searched. Three independent assessors evaluated abstracts and selected

trials for detailed examination. Trials were excluded if their quality was

poor, were not published in English or studied DMARDs not licensed to treat

RA. Two independent assessors extracted data. Efficacy was assessed by the

numbers of patients withdrawn due to lack of efficacy.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

by the numbers of patients withdrawn due to adverse events. Risk ratios (RR)

with 95% confidence intervals (CI) were calculated and meta-analysis was

carried out based on a random effects model. Sensitivity analyses evaluated

different treatment combinations, trial designs, study populations and

outcome measures. RESULTS: Fifty-three potentially relevant RCTs were

identified. Twelve were excluded due to: using unlicensed DMARDs (n = 3);

reporting in journal supplements of RCTs already included (n = 2); follow-up

of an earlier RCT, report of biological outcomes or pharmacokinetics (n =

5); and non-English language publications (n = 2). Forty-one RCTs were

evaluated in detail and another five excluded (three open-labelled studies

and two with high patient attrition); 36 studies were included in the

meta-analysis. These comprised 13 step-up, 16 parallel and 7 step-down

trials. Nine assessed early RA and 27 established RA. Seven added steroids

to DMARD monotherapy and one study added steroids to DMARD combinations. Six

assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors.

Overall, combination DMARD therapy was more effective than monotherapy (RR

0.35; 95% CI 0.28, 0.45) although the risk of toxicity was also slightly

higher (RR 1.37; 95% CI 1.16, 1.62). Combinations of MTX with TNF inhibitors

and MTX with sulphasalazine or anti-malarials showed good efficacy/toxicity

ratios.

CONCLUSIONS: DMARD combinations vary in their efficacy/toxicity

ratio. MTX plus sulphasalazine and/or anti-malarials and MTX plus TNF

inhibitors have particularly favourable benefit/risk ratios.

PMID: 16030080

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16030080 & itool=iconabstr & query_hl=22 & itool=pubmed_DocSum

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