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Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
The management of rheumatoid arthritis (RA) rests on several principles. Drug treatment, which comprises disease-modifying antirheumatic drugs (DMARDs), but also non-steroidal anti-inflammatory drugs and glucocorticoids (GCs), as well as non-pharmacological measures, such as physical, occupational and psychological therapeutic approaches, together may lead to therapeutic success. However, the mainstay of RA treatment is the application of DMARDs. It is DMARD treatment, especially, which has undergone dramatic changes during the past decade, providing previously unforeseen therapeutic dimensions. New and highly effective DMARDs have continued to emerge until the most recent years—in particular, biological agents which target tumour necrosis factor, the interleukin 1 (IL-1) receptor, the IL-6 receptor, B lymphocytes and T-cell costimulation.1 In addition, a chemical DMARD, leflunomide, has become available and compounds which have been in use for many decades, such as methotrexate (MTX) and sulfasalazine (SSZ), as well as GCs, have been re-examined in order to achieve better efficacy. For example, the use of high dose MTX2 and the disease-modifying effects of GCs, especially when combined with traditional DMARDs,3–7 are now well established. Furthermore, treatment strategies have changed during this period, initially by calling for early referral and early institution of DMARD treatment on the basis of respective evidence of clinical efficacy,8–10 and later by showing that tight control using composite measures of disease activity and appropriate switching of drug treatment are highly efficacious approaches.11–14
While all these data of clinical and observational trials on drugs and strategies have been highly enlightening, patients and rheumatologists are currently overwhelmed by this information which does not always allow one to decide easily and conclusively which path to follow when initiating or changing therapeutic strategies in patients with RA. Indeed, some inconsistencies in therapeutic targets and strategies among rheumatologists have been recognised in a survey performed at a recent annual European Congress of Rheumatology.15 These inconsistencies may be partly based on differences in attitudes among doctors caring for patients with RA, settings (academic centres vs private practice), patient preferences and reimbursement policies. Information on the current state of evidence for the efficacy of different agents or therapeutic strategies may also not always be regarded as sufficiently complete or available.
Along these lines, the European League Against Rheumatism (EULAR) has recently formulated major objectives, which among other aspects specify that “by 2012, EULAR will have provided standards of care and foster access to optimal care of people with musculoskeletal conditions in Europe”.16 Since disease modification constitutes the most important therapeutic intervention in RA, it was the objective of this EULAR Task Force to find a consensus on recommendations for the management of RA with synthetic and biological DMARDs.
The task force aimed at aggregating available information on disease modification in RA into practical recommendations. The basis of the activities of the task force were the EULAR standardised operating procedures for the development of recommendations,17 which suggest the institution of an expert committee in charge of consensus finding on the basis of evidence provided by a systematic literature review (SLR) and expert opinion. The task of developing management recommendations for RA was regarded as large and therefore warranted division of the topic into five main areas: (a) synthetic DMARDs as monotherapy or in combination without GCs; (b) GCs alone and in combination with synthetic DMARD(s); (c) biological DMARDs; (d) treatment strategies; (e) economic issues. The last aspect was deemed important to understand the cost implications of treating RA by retrieving the existing evidence; the fourth area was intended to look at the best approaches to attain the therapeutic goals, define the term ‘strategy’ as a long-term plan of action to achieve that goal; and, most importantly, the first three areas were related to the evidence available for the efficacy, safety and monitoring of currently employed drugs.
The recommendations will reflect the balance of efficacy and safety and will not deal in detail with the toxicity of DMARDs. The most important pieces of information in this regard are provided in separate publications on the SLRs,18–22 which indeed are part and parcel of these recommendations, since they provide their bases. Thus, the recommendations shown here will primarily deal with agents whose toxicity appears to be manageable, assuming that users are either aware of the respective risks or will adhere to the information provided in the package inserts. Also, where toxicity appears to be a major concern, a general warning will be included in the respective recommendation.
The expert committee comprised 25 rheumatologists, two patients, one infectious disease specialist, one health economist and five fellows. The members of this task force came from 12 European countries and from the USA. The expert committee was divided into five subgroups; each consisted of five to seven members including one fellow and dealt with one of the above topics. At the first meeting, these subgroups prioritised the research questions, defined the appropriate search terms and reported to the full committee, which took the final decisions by consensus.
Subsequently, the fellows, with the help of their mentors, performed the respective SLR searching PubMed, Embase, Medline and the Cochrane library and also recent abstracts, up to the middle of 2009. The SLRs included meta-analyses, systematic reviews, randomised controlled trials (RCTs), non-RCTs and observational studies, including data from registries. The individual research questions, in particular on the efficacy and toxicity of the agents under investigation, were examined by looking at the population of adult patients with RA, the type of agent, the control used for comparison and the outcome. If possible, outcome was quantified using effect sizes, which are unitless and therefore allow for the analysis of efficacy irrespective of the measures evaluated in individual clinical trials; these data will be solely discussed in the reports on the SLRs. Categorisations of evidence and strength of recommendation were determined according to the standards of the Oxford Centre for Evidence Based Medicine.23
At the second task force meeting, the fellows presented the results of the SLR in an aggregated form to the subgroups. The members of the subgroups debated and evaluated the evidence presented and formulated preliminary sets of recommendations. These proposals were reported to the entire task force, which discussed the suggestions on the recommendations in detail, amended them as deemed appropriate in the course of the consensus finding and took the final decisions. An ultimate round of refinement of the wording was done via electronic communication, by which also an anonymous voting on the level of agreement was performed. In addition, respondents were asked to indicate which of the statements were in line with their current treatment practice and, if not, whether they would change that practice. The task force started its work in December 2008 and finalised it in June 2009.
Before dealing with the actual treatment recommendations, the task force discussed several principles that were deemed important to be conveyed to those with RA or involved with the management of RA. These principles for the care of patients with RA are of such generic nature that they were felt to be ‘overarching’ (table 1). The task force decided unanimously on these three principles.
In each subgroup, the members discussed the evidence provided by the fellows in their SLRs in detail and agreed on five to eight recommendations for the respective topic. These preliminary statements on the management of RA with synthetic DMARDs, GCs and biological agents, as well as on treatment strategies and economic aspects, were subsequently reviewed intensively by the whole task force, synthesised and voted upon. This process led to 15 recommendations on drug management and treatment strategies. Each of these 15 recommendations was then subjected to an economic valuation in accordance with the results obtained by the economics subgroup of the task force.
The 15 recommendations (detailed in table 1) are presented in the text below in an abbreviated version. The levels of evidence and strengths of recommendation for each recommendation are then shown in table 2 and the economic valuation in table 3. The 15 recommendations are ordered by a logical sequence or procedural and chronological hierarchy rather than by any major weight of importance, with the exception of the first two points which constitute the foundation of all subsequent items. They also serve as basis for the algorithm provided in figure 1.
The cost effectiveness of the therapeutic measures recommended above has been assessed in detail by a dedicated SLR, which is also published separately.22 In sum, the available data suggest that all recommendations are known to be cost effective with the exception of statement No 14 (table 3). However, an economic analysis considering only the exceptional patients considered in recommendation No 14 has not been performed. The committee does not preclude the possibility that in this particular category of patients, the approach of starting biological agents as first-line DMARD treatment may be cost effective.
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.
Figure 1 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.
Competing interests: The following authors declare that they have no potential conflict of interest: CG-V, SG, RK, MK, JN, MS, JW. The following authors declare a potential conflict of interest having received grant support and/or honoraria for consultations and/or for presentations as indicated; JSS: Abbott, Amgen, BMS, Centocor, Pfizer, Roche, Schering-Plough,UCB, Sanofi-Aventis, Wyeth; RL: Abbott, Amgen, BMS, Centocor, Merck, Pfizer, Schering-Plough, UCB, Wyeth; FCB: Abbott, Schering-Plough, Wyeth; MD: Pfizer, Wyeth, Abbott, Roche, Novartis, Nordic Pharma, BMS, UCB; PE: Abbot, BMS, Centocor, Pfizer, Roche, Schering-Plough,UCB, Sanofi-Aventis, Wyeth; MS: Abbott; DA: Abbott, Roche, Schering-Plough, BMS, UCB, Sanofi-Aventis; MB: Roche, Abbott, BMS, Wyeth; LG: Abbott, Schering-Plough, Roche, UCB, BMS, Wyeth; TH: Schering Plough, BMS, Biotest, Wyeth, Novartis, Roche, Sanofi-Aventis, Abbott, Axis-Shield; JWJWB: Abbott, Roche, Wyeth, Schering Plough, Merck, Pfizer, UCB, BMS; GB: Abbott, Wyeth, Schering-Plough, Roche and UCB; BC: Abbott,BMS, Roche, Schering, UCB,Wyeth; MC: Sanofi-Aventis, BMS, Pfizer, Abbott; CG: Roche, BMS, Abbott, Essex, Wyeth, UCB; JG-R: Abbott, BMS, Pfizer, Roche, Schering-Plough,Wyeth and UCB; TKK: Abbott, BMS, Roche, Schering-Plough,Wyeth, Pfizer, MSD and UCB; EMM: Wyeth/Pfizer, Roche, Abbott Schering Plough/MSD; IM: Schering Plough, Pfizer, Roche and BMS; KP: Roche, Abbott, BMS, Pfizer, MSD; PvR: Abbott, BMS, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth; DLS: MSD, Pfizer, Novartis, Roche, Wyeth, Novartis, Schering Plough; TS: Abbott, Pfizer, Sanofi-Aventis, Roche, UCB; GV: Abbott, BMS, Roche, Sanofi-Aventis, Schering-Plugh, UCB, Wyeth; RvV: Abbott, Pfizer/Wyeth, Roche, Schering-Plough, BMS, UCB; KLW: Amgen, Wyeth, UCB, Genentech; AZ: Abbott, Amgen, BMS, Essex/Schering-Plough, Merck, Pfizer, Roche, Sanofi, UCB, Wyeth; DvdH: Abbott, Amgen, BMS, Centocor, Chugai, Merck, Pfizer, Roche, Schering-Plough,UCB, Wyeth. Francis Berenbaum was the Handling Editor.
Provenance and peer review: Not commissioned; externally peer reviewed.