Abatacept versus other biologics in methotrexate inadequate responders with rheumatoid arthritis: you like tomato and I like tomahto... let's call the whole thing off

In the absence of head-to-head trials, analysis of available data from randomized clinical trials allows for comparison of the efficacy of biologic agents for the treatment of rheumatoid arthritis. Methotrexate (MTX) inadequate responder trials provide data suggesting no major differences among any of the biologic agents, which is also confirmed in MTX naive population trials, when available, possibly a more reliable comparison group. The decision to pick one over the other should focus on safety, long-term survival of the drug and ease of use, which is for the most part influenced by patient preferences.

In a previous issue of Arthritis Research & Th erapy, Patricia Guyot and colleagues present their elegant paper of a meta-analysis comparing abatacept to other biologics in rheumatoid arthritis (RA) patients who had an inadequate response (IR) to methotrexate (MTX) [1]. Th e authors compare MTX IR studies to see if various biologic agents diff er in achieving improvement in function as measured by the Health Assessment Questionnaire, ACR50 and DAS28 <2.6 responses, all robust measures of improvement. In their analysis, patients had similar responses with abatacept compared to other biologicsetanercept, adalimumab, infl iximab, certolizumab, rituximab and tocilizumab -at 24 and 52 weeks. As discussed in the paper, diff erences of methodology and types of patients enrolled in each individual trial may account for the few diff erences reported among the biologics. In my opinion, these are not clinically relevant and I agree with the conclusion reached by the authors that similar responses should be expected when these biologics are used for the treatment of RA patients who are MTX-IR.
Currently most of the available biologic agents have MTX-IR indications, as these are the patients where a biologic agent would be most commonly used. However, 'MTX-IR' is poorly defi ned in clinical trials, where it is up to the treating physician to decide what an 'inadequate response' is. Hence, depending on when and where the study was conducted, diff erent types of patients, with diff erent histories of MTX use, dosage and duration, all considered MTX-IR, may be included, and this makes head-to-head comparison diffi cult. Commonly the disease activity levels are similar at baseline but what really happened to them while on MTX prior to enrollment is not clear. A better comparison would probably be if patients with early RA who are MTX-naive were compared, as these patients would be more likely to be similar in their previous RA treatment and hence lead to more robust comparisons. We previously carried out such a study using number needed to treat as a com parator and got similar results, confi rming the fi ndings of the current study [2]. In addition, there are data to suggest that, in the real world routine care setting, there is no diff erence in time to response and the response achieved over one year among abatacept, adalimumab, etanercept and infl iximab treated RA patients [3].
Th is brings up the question of whether we need headto-head clinical trials, which are usually expensive and, because of the similar effi cacy demonstrated in various analyses, likely need large numbers of patients to be able to show superiority. Th is has led to several of the currently ongoing studies to use non-inferiority for effi cacy outcomes as the main study aim. I think the current report adds to the already available literature that, as far as effi cacy is concerned, there is very little

Abstract
In the absence of head-to-head trials, analysis of available data from randomized clinical trials allows for comparison of the effi cacy of biologic agents for the treatment of rheumatoid arthritis. Methotrexate (MTX) inadequate responder trials provide data suggesting no major diff erences among any of the biologic agents, which is also confi rmed in MTX naive population trials, when available, possibly a more reliable comparison group. The decision to pick one over the other should focus on safety, long-term survival of the drug and ease of use, which is for the most part infl uenced by patient preferences. diff erence among the current biologics. As most patients seen in routine care would not be able to fulfi ll criteria to be included [4,5] as they generally have milder disease, any diff erence that may exist in analyses of randomized clinical trials may not be refl ected in the real world. Most patients in the real world have less disease burden where any biologic would likely work with the same eff ectiveness. In addition, patients with comorbid condi tions are excluded from randomized clinical trials and this makes it even harder to guess at the effi cacy of any given biologic agent when used in routine care.

© 2010 BioMed Central Ltd
In summary, the available data, be it in MTX-IR or early RA, MTX-naive patients, suggests that the biologic agents currently used for the treatment of RA seem to have similar effi cacy. Th ere are currently no biomarkers, and there may never be any that would be useful and predictive in individual patients in routine clinical care, to help us distinguish among biologics. Th e decision to pick one over the other should focus on safety, long-term survival of the drug and ease of use, which is, for the most part, infl uenced by patient preferences. Th e main determinant of outcome depends not on which agent is used but when it is used and how aggressively disease activity is monitored and treated with a focus on reaching low disease activity or remission, with whichever composite index we chose to use as our target [6]. Use of outcome measures shows some regional variation among and within countries, especially if access to biologics is dependent on having a certain level of disease severity, yet overall we still have a long way to go until measurement is part of routine care. It is time to stop picking favorites among the biologic agents and focus on how we can get more physicians to monitor RA outcomes that would allow us to be as aggressive as RA demands us to be.