The comparison of effects of biologic agents on rheumatoid arthritis damage progression is biased by period of enrolment: Data from a systematic review and meta-analysis

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Abstract

Objectives

To indirectly compare the 12-month effects of available biologic agents in slowing RA radiographic progression.

Methods

A systematic review of literature of randomised, double-blind, controlled trials (RCTs) evaluating RA radiographic progression as end point was conducted using a PubMed searching of MEDLINE from January 1995 to May 2012. For each trial, the mean change from baseline of the standardised annual radiographic progression score (weighted for estimated annual progression rate) was estimated, and the effect size was calculated as the difference between biologic and non-biologic-treated groups. In order to optimise data homogeneity and improve RCTs comparison, a mixed-effect model was applied including previous responsiveness to methotrexate (MTX-experienced or MTX-naïve populations) and period of study enrolment as moderators.

Results

The PubMed search resulted in 183 references, and 14 were eligible for the meta-analysis. The analysis of study distribution in forest plots showed a high correlation between the study period of enrolment and the impact of biological therapy in both MTX-naïve and MTX-experienced subgroups. In particular, effect size was the highest for older trials and progressively decreased in the most recent ones, suggesting a highest propensity to radiographic progression in populations enroled in older trials. Some statistically significant differences among RCTs were found in both subgroups but were significantly biased by the different propensity to radiographic progression due to period of enrolment.

Conclusions

Our meta-analysis demonstrated that period of enrolment deeply influence study population propensity to radiographic progression in each trial. This finding does not allow the indirect comparison of various biologic agents, despite our mixed-model significantly reducing heterogeneity among RCTs.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy whose progression is heterogeneous, and the outcome is difficult to predict. Some RA patients do not develop any erosion even after long-term disease, but the vast majority display bone erosions and cartilage breakdown, resulting in joint destruction, functional impairment, and increased mortality [1], [2].

The outcome of the disease improved considerably in recent years with the availability of new effective therapies. In particular, biological agents displayed a rapid and sustained disease control, associated with impressive prevention of joint destruction [3]. Biological agents target several immune effectors that play a key role in local and systemic inflammation, including TNF, IL-6 receptor and IL-1 β, while rituximab is a MoAb against CD20 positive B-cells and abatacept is a fusion protein against CTLA-4, inhibiting T-cell co-stimulation.

The large number of currently available biologic drugs provides a rationale for comparing the efficacy of these agents on damage progression in order to make a reasonable therapeutic choice. To date, all these agents have been tested versus methotrexate (MTX) for efficacy on disease progression prevention in several randomised clinical trials (RCTs), whereas only few direct head-to-head comparisons have been conducted.

The purpose of this investigation is to indirectly compare the 12-month effects of all available biologic drugs in slowing radiographic progression in RCTs. In particular, we thought that RCTs inclusion criteria have been subjected to gradual changes over the years making the reported radiographic damage progression much more related to the patients’ characteristics than to the efficacy of the tested biologic agent.

Section snippets

Literature search and study selection

A systematic review of literature was conducted using a PubMed searching of MEDLINE from Jan 1995 to May 2012, according to standard reporting guidelines [4]. PubMed was searched using the medical subject heading (MeSH) terms (‘arthritis, rheumatoid/radiography’ OR ‘disease progression’) combined with ‘arthritis, rheumatoid/drug therapy’, and limited to ‘randomised control trial’ as article type, ‘humans’ as species, ‘English’ as language, ‘adult’ as age and a period between 1 January 1995 and

Results

The PubMed search (Fig. 1) resulted in 183 references. Ninety-nine were excluded because they did not include any of the biologic agents under evaluation. Out of 84 remaining potentially relevant trials, 27 were excluded as not especially designed to evaluate radiographic progression in biologic versus non-biologic-treated patients, four because of the assessment of damage progression by MRI or ultrasound only, five because of the insufficient sample number and/or follow-up period, two because

Discussion

Our meta-analysis shows statistically significant differences regarding efficacy in slowing/stopping radiographic disease progression among the available biologic agents for RA. However, data analysis reveals how such differences are deeply influenced by the heterogeneity in baseline population characteristics. In fact, the main finding of current analysis is the demonstration that both the clinical response to MTX before trial beginning and the period of study enrolment play a crucial role on

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