The role of biologic agents in damage progression in rheumatoid arthritis: indirect comparison of data coming from randomized clinical trials

Abstract

Objectives: All biologic agents approved for the treatment of rheumatoid arthritis (RA) have been tested versus methotrexate (MTX) for efficacy on damage progression in several randomized clinical trials (RCTs), but direct head-to-head comparisons have never been conducted. The purpose of this investigation is to analyse data coming from main RA RCTs and to perform an indirect comparison.

Methods: A systematic review of literature from 1988 to 2011 was conducted. Only randomized, double-blind, controlled, comparative trials, with evaluation of radiographic progression were included. The radiographic score was standardized and mean difference in the percentage of the annual radiographic progression rate was used as the effect measure. Heterogeneity between studies was estimated by I(2) test. For each trial, the effect was plotted according to its standard error in a funnel plot.

Results: Of 44 potentially relevant trials, 12 RCTs were included in the study. In order to optimize RCTs comparison, studies were stratified in early and late RA group. Main population characteristics were similar in both early and late RA groups, whereas the standardized baseline radiographic score value significantly differs among trials in both early (range 2.7-21.9) and late (range 23.46-75) RA groups. The standardized annual estimated progression is similar across the late RA group. Strong evidence of heterogeneity (I(2) = 97%, p = 0.00001) but no asymmetry of the funnel plot was observed in the early RA group. Total mean difference was -16.28 (95% confidence interval [CI] -24.42 to -8.14). For the late RA group a random model was used (I(2) = 99%, p = 0.00001) and a total mean difference of -39.25 (95% CI -53.77 to -24.73) was found.

Conclusions: All biologic agents provide a favourable effect on disease progression both in early and late RA. The significant heterogeneity among various RCTs did not allow an effective comparison of the performance of biologic agents in each study.

Keywords: Rheumatoid arthritis; biologic therapy; metaanalysis; radiographic progression.

Figure 1.

Flow chart of the study selection process.

Figure 2.

Forest plot of the findings of the meta-analysis of studies of biologic agents plus methotrexate (MTX) versus methotrexate alone in all RA main RCTs. 95% CI = 95% confidence interval.

Figure 3.

Forest plot of the findings of the meta-analysis of studies of biologic agents plus methotrexate (MTX) versus methotrexate alone in early RA main RCTs. 95% CI = 95% confidence interval.

Figure 4.

Forest plot of the findings of the meta-analysis of studies of biologic agents plus methotrexate (MTX) versus methotrexate alone in late RA main RCTs. 95% CI = 95% confidence interval.