EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Overarching principles

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.

• Rheumatologists are the specialists who should primarily care for patients with RA. This statement stems from the evidence that patients with RA followed up by rheumatologists, in comparison with other doctors, are diagnosed earlier, receive DMARD treatment more frequently and have better outcomes in all major characteristics of RA, in particular joint damage and physical function.24–28 Rheumatologists check the disease activity of their patients with RA with appropriate instruments and are well aware of the indications, contraindications and adverse effects of DMARDs; this has become of particular importance with the advent of modern treatments and strategies. Therefore, patients with inflammatory arthritis, in general, and suspected RA, in particular, should be referred to rheumatologists as early as possible, since a delay in such a referral is one of the most daunting causes of tardy institution of effective treatment.929 However, the task force intentionally added the term ‘primarily’ to this statement, since the management of patients with RA should be shared with primary care doctors and other health professionals in a multidisciplinary approach. Also, in countries lacking sufficient numbers of rheumatologists, this task may have to be taken over by other doctors with experience in caring for patients with RA.

• Treatment of patients with RA should aim at the best care and must be based on a shared decision between the patient and the rheumatologist. Two themes govern the contents of this principle—first, the term ‘best care’, which the task force felt to be conveyed by the subsequent recommendations, and second, the phrase ‘shared decision’ with the patient, which refers to the need to discuss treatment aims, management plans and reasons for the recommended approaches with the patient.

• RA is expensive in regards to medical costs and productivity costs, both of which should be considered by the treating rheumatologist. The expert committee wished to encapsulate that the direct and indirect costs of RA, especially if insufficiently treated, are very high.2830–33 Modern treatments, particularly biological agents, are expensive,303435 but may enable lowering of short- and long-term indirect costs of disease—an actuality that should be kept in mind for individual treatment approaches as well as reimbursement considerations. This underlying principle also reinforces the decision to evaluate economic aspects in relation to the individual recommendations to examine the cost effectiveness of RA treatment.

Recommendations

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.

Figure 1

Algorithm based on the European League Against Rheumatism recommendations on rheumatoid arthritis management. DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RF/ACPA, rheumatoid factor/anti-citrullinated peptide antibodies; TNF, tumour necrosis factor. *The treatment target is clinical remission or, if remission is unlikely to be achievable, at least low disease activity.

• Synthetic DMARDs early— The task force was unanimous in its view that in the vast majority of patients with RA the first treatment approach should include synthetic DMARDs, since a significant proportion of patients can attain a state of very low disease activity or remission36–39; the types of DMARD with evidence of efficacy will be discussed in items 3–6. Moreover, since any delay in the start of DMARD treatment in patients with RA may lead to a worse outcome in comparison with an early start of treatment,81040 DMARD treatment should be started as soon as a diagnosis of RA has been made. However, a diagnosis of RA in its earliest stage is not always easy and a suspected diagnosis of RA may be sufficient to initiate DMARD treatment. Importantly, American College of Rheumatology (ACR) and EULAR have collaboratively developed new criteria that are pertinent for this early phase of the disease.41

• Treatment targeting remission or low disease activity—Undoubtedly, attaining a state of remission or low disease activity leads to better structural and functional outcomes than allowing residual disease activity1142–46 and the earlier such a state is achieved the better.4347 Thus, remission is the primary therapeutic aim, especially in early RA, though low disease activity may be an appropriate alternative, especially in patients with longstanding RA, as was also concluded by an expert committee recently engaged in defining a treatment target for RA.48 Strategic trials have shown that aiming at low disease activity or remission by adjusting treatment every 1–3 months in conjunction with strict monitoring is associated with a better clinical, radiographic and functional outcome than with an unstructured follow-up.111349 Thus, the treatment target should preferably be reached, or almost reached, within 3 months and definitely attained by a maximum of 6 months; while this time frame was not directly tested in comparative trials, this expert opinion is based on the use of a 1–3 months' period for switching treatments in strategy trials11–14 and on data showing that disease activity states at 3–6 months after treatment initiation predict outcome at later time points.50 Within this time frame of 3–6 months patients should be followed up meticulously (every month if necessary) and existing treatment should be intensified or ultimately changed for another.48 In line with these recommendations, monitoring should be regularly performed. While several different measures have been employed in various strategy trials,21 expert opinion has recently suggested using composite measures of disease activity which include joint counts.48 Valid measures for this purpose have been recently reviewed and include the Disease Activity Score (DAS), 28-joint count DAS (DAS28), Simplified Disease Activity Index and Clinical Disease Activity Index.51

• MTX as initial choice—MTX is a highly effective drug for disease modification in RA,52 and more recent insights suggest that MTX at higher weekly doses (20–30 mg) is more effective than MTX at lower weekly doses (7.5–15 mg).253 MTX is considered the anchor drug in RA,54 both on the basis of its efficacy as monotherapy and on the basis of its ability to increase the efficacy of biological DMARDs when used in combination,55–59 as well as the beneficial long-term safety profile.60 MTX is effective in DMARD naïve patients with early RA,13495661 and its clinical efficacy has neither been surpassed by other synthetic DMARDs nor consistently by tumour necrosis factor (TNF) inhibitor monotherapy.37555662 For these reasons the task force considered that MTX should be instituted at the earliest time point in patients with RA. This statement comprises three items in addition to the recommendation for using MTX: first, it uses the wording ‘part of the first treatment strategy’, implying that MTX may have to be combined with other agents (see below); second, it refers to ‘active RA’, implying that patients with low disease activity may not necessarily need treatment with MTX; and third, the statement indicates implicitly that a strategy using MTX should be applied also to patients with active RA who have previously not received MTX, but only other synthetic DMARDs. Obviously this recommendation does not pertain to patients for whom a contraindication for MTX use is present (see below).

• Leflunomide, SSZ or injectable gold—There is currently insufficient evidence that leflunomide, SSZ or intramuscular gold salts are inferior to MTX.373862–64 Nevertheless, because of the wealth of efficacy and safety data available for MTX, the three mentioned DMARDs should be used instead of MTX as first DMARD treatments mainly if there are contraindications to (or intolerance of) MTX. In analogy with the previous paragraph, these MTX alternatives should also be considered as a part of a treatment strategy. The rather prominent place of parenteral gold salts has been the subject of intensive debate, but can be justified by the currently available high-level evidence,636566 and this decision was ultimately backed by the majority of the task force. In addition to the drugs mentioned above, antimalarial drugs (hydroxychloroquine and chloroquine) are also used in RA. They show some efficacy as monotherapy with respect to signs and symptoms67 and are frequently used as part of combination therapies.426869 It is, however, not clearly established if antimalarial drugs confer additional efficacy in combination therapy. In addition, antimalarial drugs do not inhibit structural damage sufficiently, especially in comparison with other agents such as SSZ.70 Therefore they have not been mentioned more prominently in the recommendation statement. Nevertheless, on the basis of their clinical efficacy as monotherapy they may have some value in patients with very mild disease who have contraindications to other compounds.

• Synthetic DMARD monotherapy or combination therapy—Over the past two decades, combination therapy with various synthetic DMARDs has been suggested to convey superior efficacy in comparison with monotherapy.742686971 Results of clinical trials testing the addition of synthetic DMARDs to MTX in patients with residual disease activity despite MTX treatment have often been used to support the assumption of an added benefit7273; however, in these studies an appropriate control (switch) arm was lacking and the proportion of responders receiving combination therapy did not exceed the proportion of responders receiving the monotherapy components.74 An important fact to consider to truly appreciate the content of this recommendation, however, is that in most clinical trials comparing combination therapy with monotherapy head to head, GCs were either mandatory in the combination therapy arm or GC use was different between both arms, which probably explains the superiority of combination therapy.74 Several other trials suggest that in the absence of GCs neither a start with combinations of synthetic DMARDs nor a step up combination therapy are better than monotherapies or switching DMARDs for the major outcomes.4975–77 The SLR on this allowed a firm conclusion to be drawn.18 Furthermore, in DMARD naïve patients the balance of efficacy and toxicity favours MTX monotherapy versus combination therapy, while the evidence is inconclusive in DMARD inadequate responders.78 Therefore, the task force decided to use the word ‘may’ here. It is important to keep in mind that if combination therapy with synthetic DMARDs does not allow the treatment target to be achieved, it is impossible to disentangle which of the agents was insufficiently effective, precluding better usage of synthetic DMARDs. The statement contains yet another element—namely, the segment “irrespective of the addition of GCs”. The committee was unanimous in its opinion that the addition of GCs to either monotherapy or combination therapy with DMARDs improves outcomes. However, studies allowing a direct comparison of GCs plus DMARD monotherapy versus GCs plus combination DMARDs have not been done.

• Glucocorticoids—GCs have been shown to have not only anti-inflammatory but clearly also disease-modifying properties.57980 The evidence that DMARD monotherapy is as efficacious as DMARD combination therapy suggests that the significantly better outcomes of trials using combinations of synthetic DMARDs plus GCs versus DMARD monotherapy might be due to the GC component.71242 This notion finds important support in studies which show that adding GCs to DMARD monotherapy34 is beneficial. GC treatment has been added to DMARDs successfully at low doses (<10 mg/day),3442 but more rapid improvement may be achieved by addition of GCs at higher doses for the short term.749 However, the added efficacy of high-dose GCs has not yet been compared with that of low-dose GCs and, therefore, sufficient evidence for this is lacking. Importantly, long-term use of GCs can lead to adverse events,81 but there may also be safety concerns in the intermediate term, although most studies on the toxicity of GCs are of low quality and short duration. Nevertheless, their toxicity, particularly in the intermediate to long term, should in the opinion of the task force not be disregarded and thus GCs should be used with caution and preferably for only short periods of time. Consequently, GCs should be tapered as rapidly as possible in accordance with the clinical situation. The safety of GCs was also an important aspect of the EULAR recommendations on the management of GC treatment.82

• Addition of a biological DMARD or switch to another synthetic DMARD—This statement introduces the importance of prognostic markers in treatment decisions in RA. Factors believed to predict bad outcome independently are (a) the presence of autoantibodies, that is, rheumatoid factor and/or anticitrullinated peptide antibodies, particularly at high levels; (b) high disease activity as measured by composite indices (DAS, DAS28, Simplified Disease Activity Index and Clinical Disease Activity Index), swollen joint counts or acute phase reactants (C reactive protein, erythrocyte sedimentation rate); (c) early occurrence of erosions83–87; these factors have recently also been amalgamated into a risk model.88 The task force agreed that patients failing to reach the treatment target on an initial strategy with synthetic DMARDs, in whom poor prognostic markers as defined above are absent, could be switched to another synthetic DMARD strategy for 3–6 months before further decisions on the institution of a biological agent are taken; these other DMARDs have been mentioned in recommendation 4. However, patients for whom an initial DMARD failed and who have poor prognostic markers should have the opportunity to receive a biological DMARD in addition to their synthetic DMARD. Interestingly, closing a gap of information by using a control arm receiving active treatment, a recent study which was not part of the SLR reported that for patients with early RA who had failed to reach low disease activity after 3 months' MTX monotherapy, the addition of a TNF inhibitor yielded significantly better clinical outcomes than the addition of SSZ plus hydroxychloroquine.89 These data also corroborate the conclusions discussed in recommendations 5 and 6—namely, that a combination of synthetic DMARDs in the absence of added GCs (even triple treatment of MTX, SSZ and hydroxychloroquine) has limited efficacy and may not have higher efficacy than if the patients had been switched to SSZ, as was shown in the BeSt trial.12 This limited (but partly exhibited) efficacy of such a synthetic DMARD regimen also supports the expert opinion of switching patients for whom a first DMARD strategy has failed and who do not have bad prognostic markers to another DMARD (or eventually DMARD combination). In contrast, for patients for whom initial MTX or other synthetic DMARDs (ideally with GCs) has failed and who have bad prognostic indicators a biological DMARD, in general, and a TNF inhibitor, in particular, should be employed. Importantly, however, no randomised controlled or observational clinical trials to date have tested this approach of differential treatment based on prognostic factors. Therefore, this statement is at the level of an expert opinion, but is supported by various indirect evidence provided in the existing literature.

• Initiation of a TNF inhibitor—This expansion of statement No 7, which applies to patients followed according to that previous statement, emphasises that biological agents are effective if synthetic DMARDs have failed (level 1a, grade A) and that they should be combined with MTX (or other DMARDs), since this combination has greater efficacy than monotherapy with most biological agents; this is well established for TNF inhibitors on the basis of respective comparative phase III trials5556 and for rituximab and tocilizumab on the basis of comparative phase II trials5859 (level 1b, grade A). At the time of the SLR, the only biological agents licensed in Europe for treating patients with RA with active disease despite synthetic DMARD treatment were the TNF inhibitors and tocilizumab; rituximab and abatacept are currently licensed only for use after failure of TNF inhibitors. In the USA, though not currently in Europe, abatacept can also be used in these former patients; in light of more recent clinical trial data,9091 abatacept and rituximab may receive similar approval as first biological agents by the European regulatory authorities in due course. It is noteworthy that some TNF inhibitors such as adalimumab and etanercept are licensed as monotherapy on the basis of their efficacy in clinical trials, but the data on their clinical superiority compared with MTX monotherapy are partly mixed.555692 Recent data suggest that monotherapy with tocilizumab is more effective than monotherapy with DMARDs such as MTX9394; however, this RCT did not include a third arm using the combination of both so that it is not clear to date whether in patients with early RA monotherapy with tocilizumab is similarly or less effective than combination therapy with tocilizumab and MTX. Currently, the largest array of safety information is available for the TNF inhibitors owing to their use for more than one decade and the availability of large long-term registries. These compounds comprise adalimumab, etanercept and infliximab, but certolizumab and golimumab have meanwhile also been approved. However, it should be borne in mind that this represents current expert opinion and may change over time, specifically with the recent approval of other biological agents as potential first biological agent for DMARD inadequate responders—namely, tocilizumab in Europe and abatacept in the USA and other non-European countries. It should also be mentioned here that anakinra, the IL-1 receptor antagonist, while effective in individual patients with RA, did not show a high level of clinical efficacy in clinical trials9596 and therefore has not been recommended as a major biological agent for use in RA.

• Abatacept, rituximab or tocilizumab—There is high-level evidence from one RCT each that abatacept, golimumab, rituximab and tocilizumab are effective in patients for whom TNF inhibitor therapy has failed97–100 (level 1b, grade A). These data are partly supported by observational studies stemming from registries which suggest that switching from one TNF inhibitor to another, as well as switching from TNF-blocking agents to rituximab, is beneficial.101–103 To date, the committee could not identify RCTs in which switching was appropriately compared between different biological agents and therefore a preference for a particular biological agent in this situation could not be established.104

• Azathioprine, ciclosporin A or cyclophosphamide—RA can run a course that is refractory to several DMARDs and biological agents and can be severely destructive and disabling.99100105106 While in the previous recommendations four synthetic DMARDs and nine biological agents have been mentioned, allowing a variety of therapeutic options, refractoriness may and still will occur. In order to meet the needs of this group of patients, the task force has referred to agents for which the literature provides evidence on efficacy. However, one needs to bear the toxicity in mind, especially in the case of ciclosporin A and cyclophosphamide; the latter drug should only be used in exceptional situations. A number of presumed DMARDs were excluded here, because the evidence for their efficacy was deemed insufficient; these include D-penicillamine, minocycline, auranofin, tacrolimus and chlorambucil. With respect to antimalarial drugs we refer to the paragraph on recommendation 4.

• Intensive medication strategies—This statement supplements several of the previous recommendations on drug treatment. Advocating intensive medication strategies refers to content of the strategy, such as MTX plus GCs or MTX plus biological agents, as well as tight monitoring and rapid switching of treatments if treatment goals are not attained (benchmarking).12107 The statement that patients with poor prognostic factors have more to gain finds its basis in the appreciation that patients with a favourable prognosis very often respond similarly to low-intensity monotherapy or intensive medication strategies,8788 but that patients with a severe and aggressive disease course often do not respond sufficiently well to DMARD monotherapy or combination therapy without addition of GCs or biological agents.

• Tapering biological DMARDs—It is currently unclear how to continue or discontinue treatment in patients who have achieved remission. A thoroughly performed RCT on stopping synthetic DMARDs in patients in remission has shown that only about one-third of the patients who maintained their DMARDs flared as opposed to about two-thirds of those who stopped them108; moreover, remission was much harder to re-achieve after stopping DMARDs.109 This was also concluded in a recent meta-analysis devoted to this issue.110 The first aspect embedded in this statement relates to the duration of remission: it should be persistent—that is, having lasted for several months, before tapering of synthetic and/or biological DMARDs should be considered. However, before tapering DMARDs, GCs must have been tapered in line with statement No 6 and remission have persisted. The task force felt (by expert opinion) that biological agents could then be slowly tapered by expanding the interval between doses or reducing the dose, while synthetic DMARDs should be continued. No particular time frame was given here, since there are no data available; from an expert opinion's view remission for at least 12 months might be regarded as ‘persistent’.110

• Tapering of synthetic DMARDs—This statement follows the preceding one, suggesting that tapering synthetic DMARD treatment in cases of longstanding remission could be considered after GCs and biological agents have been discontinued. Evidence supporting such an approach does not exist—neither details of a time frame nor dosing or interval duration during the tapering process. Thus, the means of tapering is left to the discretion of patient and doctor. However, in light of the available data showing that stopping DMARDs is associated with an increased flare frequency,108110 the committee felt that tapering should be performed cautiously and assessed rigorously.

• Biological treatment in DMARD naïve patients While biological DMARDs, in line with statements Nos 7 and 8, should, in general, be applied to patients for whom synthetic DMARD(s) have failed, the committee strongly felt that there are some patients for whom first-line biological treatment combined with MTX has to be considered. Such patients will usually have unfavourable prognostic signs, including very active disease or early structural damage. Currently, only TNF inhibitors are licensed for such patients, but other biological agents may receive similar approval with more trial data in the future. When evaluating results of trials using TNF inhibitors plus MTX in MTX naïve individuals and studies of the same compounds in patients with active disease despite MTX treatment,1555661111–113 patients naïve to MTX had higher response rates than MTX insufficient responders, but many of the MTX-naïve patients in the combination therapy arms would have responded to MTX monotherapy anyway. Thus, while, there is also additional evidence from strategic trials that employing TNF inhibitors plus MTX early is an effective treatment,3649 more recent data suggest that this approach may not be more effective in patients with early RA than starting synthetic DMARDs first and adding a biological agent to the DMARD rapidly (in that study after 3 months) if active disease prevails.114 However, hitherto no clinical trial has examined the actual expert-based recommendations to use such a strategy in few, selected patients as described above. Indeed, this statement received the lowest level of agreement (8.0/10) and it was the only item for which a large number of rheumatologists stated that it was not their current practice and that this recommendation would change their practice.

• Adjustment of treatment—Prudence and knowledge will guide one to bear toxicity of agents and comorbidities in mind when prescribing drugs for RA. However, the rapidity of progression of joint damage, in addition to disease activity and other prognostic factors, may support decision-making in relation to statements Nos 7 and 14, especially if joint damage appears to progress considerably despite the achievement of the desired treatment target; however, lag periods47 have to be taken into consideration before making such decision.

Economic aspects

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.

Research agenda

Research questions have been formulated in all subgroups. These questions were assessed by the task force and the result of this discussion is summarised in table 4.