The task force has formulated 15 brief statements on the management of RA with synthetic and biological DMARDs. These statements were mostly based on a SLR with consensus finding on the wording of the recommendations, but partly also solely based on expert opinion. By this process and by stating the respective level of evidence and strength of recommendation for each item, the committee adhered to the EULAR standardised operating procedures for the development of recommendations.17
Moreover, where evidence was lacking and the task force had to arrive at an expert opinion, a research agenda was formulated to expedite the generation of evidence in the future.
The reasoning behind each statement and, particularly, behind the recommendations' specific wordings is explained in detail in the results section and will not be repeated here. Importantly, the overall agreement with these statements, assessed anonymously several weeks after their formulation, was very high with means of ≥8/10 for all and >9/10 for seven of the 15 items (statements Nos 1–3, 8, 9, 11 and 15). The lowest agreement (8/10) was received by the recommendation to start biological agents plus MTX as first DMARD strategy in selected patients with very high disease activity and poor prognostic markers (No 14). Indeed, it was also the only item where many rheumatologists stated that it was not their current practice and that this recommendation would change their current treatment practice (data not shown).
Dividing the task into five specific areas may have helped unambiguous conclusions to be reached. Three of these areas were related to actual pharmacological treatment. Moreover, separating the SLRs on synthetic DMARDs into those with and those without addition of GCs facilitated the derivation of recommendations on combination therapy with a clarity that had previously been unappreciated; at the same time, this clarity raised new questions which require further elucidation.
It is worth noting that the task force felt that the best evidence for efficacy was available for four synthetic DMARDs (MTX, leflunomide, SSZ and parenteral gold; statements Nos 3 and 4) and eight biological agents (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab and tocilizumab; statements Nos 7–9). These 12 agents are also clearly stated in the itemised recommendation sentences. Two additional agents are mentioned in the text only—namely, antimalarial drugs and anakinra, because while effective in RA, their efficacy is lower than that of other agents in their general class, synthetic or biological. A final group of DMARDs is referred to as a last resort for patients for whom the above drugs have failed (statement No 10). It should be mentioned here that GCs also have disease-modifying ability,80
but the task force does not suggest using them as monotherapy owing to their adverse event profile.81
Also, the readers are referred to the accompanying papers on the SLRs for full information on the efficacy of the respective agents.
The task force was convinced that modern treatment of RA should be goal oriented and governed by a strategic treatment approach. Remission or at the least low disease activity should be the therapeutic goal, in line with a recent recommendation on treatment goals in RA.48 115
On the way to attaining this target, patients should be closely monitored using composite disease activity measures116 117
and treatment adapted in accordance with the current recommendation if the treatment aim is not reached within preferably 3, but at most, 6 months.
The task force also felt strongly that, in general, DMARD treatment should be started with MTX at appropriately high doses, possibly with the addition of GCs for the short term, before other measures are taken if the therapeutic goal is not reached within a maximum of 6 months. The type of other measures should depend on prognostic factors: while biological agents may be considered in all patients after lack of achievement of remission or low disease activity on the above treatment, such treatment is of more importance in the presence of poor prognostic factors, like the presence of autoantibodies, a high disease activity state or early erosive disease; it was felt quite appropriate to consider alternative synthetic DMARDs in the absence of poor prognostic factors. However, the task force also voiced its opinion that occasional patients with a particular need for rapid, highly effective intervention, may benefit from starting a biological agent plus MTX as a viable and useful option.
Particular emphasis emerged upon analyses of combination therapies with synthetic DMARDs. The SLR did not reveal general superiority of such combinations in comparison with respective monotherapies. Only in studies where GCs were added to synthetic DMARD(s) (or were given in higher doses or more frequently than in controls) was there compelling evidence for superiority of such combinations, but notably, the superiority was present regardless of whether GCs were added to synthetic DMARD monotherapy (such as MTX) or to combinations of synthetic DMARDs (such as triple treatment with MTX, SSZ and antimalarial drugs).
GCs have a special place in the discussion (statements Nos 5, 6, 8 and12). On the one hand, with respect to all outcomes, their efficacy as monotherapy, but especially in combination with synthetic DMARDs is indisputable. On the other hand, their toxicity, particularly in the intermediate to long term, was considered to be significant,82
so they should be used with caution and for only short periods of time. Tapering of GCs, but also of biological agents and eventually synthetic DMARDs, was an area of discussion too (statement No 13), but there is currently insufficient evidence available about outcomes and potential risks and hence how to proceed in this regards. Therefore, the committee felt that tapering should only occur in cases of sustained remission and should be part of the research agenda.
summarises the recommendations and the resulting algorithm. Phase I comprises the initiation of DMARD treatment once RA has been diagnosed (statements Nos 1–6). Phase II deals with patients who did not achieve the treatment target with strategy I (statements Nos 7 and 8); here, patients are stratified according to prognostic factors and this strategy contains the all steps until the use of the first biological agent. Phase III relates to patients for whom the first biological compound failed (statement No 9).
The recommendations on the management of RA provided here by the EULAR Task Force are not the first of their kind. Indeed, EULAR has already published recommendations for early RA,115
but the present document relates to all patients with RA, rather than only those with early RA or undifferentiated arthritis and provides far more detail about pharmacological compounds. However, in line with the guidance document by Combe et al
, the first bullet point calls for a DMARD to be initiated as soon as RA is diagnosed.
Aside from the EULAR document on early RA management, the ACR has provided therapeutic recommendations for several years.118
However, its most recent 2008 recommendations are complex and may not fully cover several aspects of drug treatments and therapeutic strategies and goals.119
A comprehensive document published by the National Institute of Health and Clinical Excellence (NICE) of the UK29
at a time when our investigations were well advanced arrived at many conclusions that are supported by ours and vice versa, although the NICE publication does not consider biological treatments. Finally, many national rheumatological societies, such as the French or German societies, have published national guidance documents.
These EULAR recommendations have been developed by task force members from 12 European countries and the USA. They are meant to serve rheumatologists in Europe and elsewhere, although we are aware that not all agents mentioned here are approved everywhere and, indeed, some agents had not yet been approved in Europe when we dealt with the respective literature, in the expectation that they would be licensed by the time this manuscript was submitted for publication.
Beyond rheumatologists, the document is also provided for patients with RA to inform them about current treatment goals, strategies and opportunities, as recognised through the important participation of patients in the task force. Finally, this document is also meant for officials in governments, social security agencies and reimbursement agencies, since it provides the current state of thought in the area of RA management and is based on as much evidence as was available. In this regard, the economic valuation is also of significance; indeed, all recommendations are supported by cost-effectiveness data, with the exception of starting biological agents before synthetic DMARDs; indeed, this conclusion is further supported by a recent Cochrane meta-analyis which stated that in patients with early RA. biological agents plus MTX may not differ significantly from placebo plus MTX with risk ratios of 1.43 and 95% confidence intervals of 0.98 to 2.09.120
However, in this regard more research is needed, since the recommendation only pertains to limited exceptional patients whose treatment has not yet been studied economically. Indeed, several of the recommendations are more strongly based on expert opinion and on clinical practice that has emerged in certain institutions than on available evidence. It is here where the opportunity to garner evidence has to meet or disprove expert opinion or practice and this is in part, the driver for the research agenda. Also, as has been the case over the past decade, new data on existing or new drugs or therapeutic strategies will emerge over the next few years. Therefore, we will carefully watch developments in the field and assume that an amendment of these recommendations may be needed in 2 years. Finally, irrespective of availability or affordability of certain agents, these recommendations can also serve as a template for national societies which can adapt them to national clinical practices while remaining within their general framework.