General aspects

As with the 2010 recommendations, this 2013 update reflects the balance of efficacy and safety, but does not deal with the toxicity of DMARDs in detail; this can be derived from the results of the safety SLR; all three SLRs provide an important adjunct to these recommendations, since they establish the evidence base. Thus, in line with the 2010 recommendation, the 2013 update primarily considers agents with toxicity that appears to be manageable, assuming that prescribers are either aware of the respective risks or will adhere to the information provided in the package inserts. However, where toxicity appears to be a major issue, a general warning is included in the respective recommendation.

Overarching principles

In line with the 2010 recommendations, the Task Force felt again that some of the principles of treating RA are of such a generic nature that they should be separated from individual recommendations on individual therapeutic approaches or compounds. However, the sequence of these principles was changed and the wording refined (table 1).

1. Treatment of RA patients should aim at the best care and must be based on a shared decision between the patient and the rheumatologist. This principle was originally ranked as B,3 but the Task Force decided that decision-sharing by patient and rheumatologist is of such overwhelming importance that it should spearhead the recommendations. Shared decision-making includes the need to inform the patient of the risks of RA and the benefits of reaching the targeted disease activity states as well as the pros and cons of respective therapies. It also means two-way communication and joint or shared decision-making on the therapeutic target and management plan as well as support for the patient to develop personal preferences. The term ‘best care’ inherently refers to the recommendations provided here.

2. Rheumatologists are the specialists who should primarily care for RA patients. Shifting this item from rank A to B was not at all meant to diminish the role of the rheumatologist in the care of patients with RA. Indeed, the wording of this principle remained unchanged and the rheumatologist is already mentioned in item A and should constitute the main counselling anchor for patients with RA. Further, the evidence for provision of better care by rheumatologists in comparison with other physicians (see item A: ‘best care’) has been briefly reviewed in the 2010 recommendations and further corroborated since then.17 ,18 The term ‘primarily’ constitutes a short cut with several thoughts behind it that go even beyond the considerations expressed in 2010: first, it reflects the necessity to involve other physicians experienced in the care of RA patients, including experience in novel therapies and their potential complications, where there is a lack of trained rheumatologists; second, it is consistent with multiprofessional care and thus with current trends in some countries for an increasing role of non-physician health professionals who are well trained in the care of patients with RA, such as rheumatology nurses,19 as long as the responsibility in general is in the hands of the rheumatologist; and third, the term ‘primarily’ should also remind the rheumatologist that multidisciplinary care may sometimes be needed, especially when dealing with comorbidities, such as cardiovascular disease,20 or complications of applied therapies, such as serious infections.

3. RA incurs high individual, societal and medical costs, all of which should be considered in its management by the treating rheumatologist. Slightly reworded, the meaning of this principle has not changed from last time. It consists of two parts. The first part relates to the costs incurred by RA for the individual patient/family and society and mentions the costs of modern therapies. It has been well established that RA incurs a substantial socioeconomic burden,21 and this has recently been supported by the Global Burden of Disease studies.22 ,23 In this context, the cost-effectiveness of treating RA has been repeatedly addressed, and the impact of modern therapies on late, costly consequences of RA, such as joint replacement surgery, is noteworthy.24 ,25 While rheumatologists cannot generally be held responsible for costs of treatment when attempting to provide best care in line with overarching principle A, this item does reiterate the responsibility of the rheumatologist to consider economic implications when selecting between treatment strategies or modalities with similar efficacy and safety in the short or intermediate term. Comparative meta-analyses and head-to-head studies help us to judge similarities or differences between therapies,26–30 although—as will be discussed below—the qualities of the studies may differ, which should be thoroughly weighed in therapeutic decision-making. Cost considerations by rheumatologists will become more important once biosimilar biological agents become available.31 In parallel, payers (governments or social security agencies) ought to take the overall individual and societal implications of RA into account when making decisions on medical costs.

Recommendations

The discussion process of the Task Force led to 14 (rather than the previous 15) recommendations. This reduction is due to the elimination of three of the 2010 items (Nos 10, 11 and 14) and the addition of two new recommendations. The decision to delete old item 10 (mentioning the potential use of ‘azathioprine, cyclosporine A [or…cyclophosphamide]’) was taken unanimously; the decision to remove old item 11 (‘Intensive medication strategies should be considered in every patient, although patients with poor prognostic factors have more to gain’) was likewise taken unanimously because those treatment strategies are now well established, and several of the revised recommendations inherently incorporate a strategic approach to treating RA intensively. Finally, a 94% majority vote supported deleting previous recommendation 14 (‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’); for more details see explanations on new No 9. However, it was simultaneously decided to mention these therapeutic considerations in the text accompanying pertinent recommendations.

The 14 recommendations arising from the current activity are presented in table 1 and discussed in detail below. With the exception of the first two items, which are the mainstay of the therapeutic approach to RA, they are not primarily weighted by an order of importance, but rather follow a logical sequence and procedural hierarchy. They are summarised in abbreviated form in the algorithm presented in figure 1. Table 2 displays the levels of evidence and grades of recommendation based on the Oxford Levels of Evidence assessment, as well as the primary voting results at the Task Force meeting and level of agreement/strength of recommendation voting by the Task Force.

1. Therapy with DMARDs should be started as soon as the diagnosis of RA is made. This recommendation is almost the same as in 2010; the term ‘synthetic’ before DMARDs was omitted to emphasise the generic nature of this recommendation, focusing particularly on the importance of diagnosing RA early and treating it appropriately as soon as such a diagnosis is presumed. To this end, the 2010 American College of Rheumatology (ACR)–EULAR classification criteria (which had only been in development when the 2010 EULAR RA management recommendations were discussed and are now well established)32 should be used to support diagnosis and facilitate early introduction of effective therapy in RA. Although diagnosis relies on the individual rheumatologist's judgement about the disease in a particular patient at a particular point in time, whereas classification relates to the group level and is important primarily for clinical studies, the new classification establishes general criteria for early diagnosis. In the course of its discussions, the Task Force reiterated both the importance of the presence of clinical synovitis in at least one joint (in line with the 2010 classification criteria) and the essential importance of starting DMARD therapy as soon as possible.

2. Treatment should be aimed at reaching a target of remission or low disease activity in every patient. The definition of the treatment target was deemed of such fundamental importance that the Task Force decided that aspects of patient follow-up should not dilute it. Therefore the former recommendation 2 is now split into two recommendations, items 2 and 3. When the 2010 EULAR recommendations were set forth to target remission,3 ,33 the ACR–EULAR remission definition was still in development; in the meantime, more stringent criteria have been published34 by ACR and EULAR and should be applied in the context of these recommendations for the actual definition of remission as the optimal treatment target. Remission as defined by the Disease Activity Score based on 28 joint counts (DAS28<2.6) is not regarded as sufficiently stringent to define remission.34 The proportion of patients reaching remission by the ACR–EULAR criteria in clinical trials and practice is sufficiently large to warrant their preferential and widespread use in daily care of RA patients.35–38 A large array of data has confirmed the value of reaching stringent remission not only with regard to signs and symptoms of RA, but also with regard to achieving maximal functional improvement and halting progression of structural damage39–44; thus good outcomes in terms of physical function and structural changes are implicitly included in targeting good clinical outcome. Moreover, the Task Force agreed with the 2010 recommendations and similar recommendations by another expert committee,27 namely that low disease activity defined by composite measures45 is a good alternative goal for many patients who cannot attain remission even today, especially those with long-standing disease who actually constitute the majority of patients in clinical care. Indeed, although somewhat worse than remission, low disease activity conveys much better functional and structural outcomes than moderate or high disease activity.38 ,40 ,46 Because a significant proportion of patients in clinical practice still do not attain a state of remission,37 ,47 ,48 implementation of this combined therapeutic target appears to be particularly relevant and significant. Also, once any patient has reached a low disease activity that is close to remission, the individual disease activity variables have to be considered in detail before major therapeutic changes are made.

3. Monitoring should be frequent in active disease (every 1–3 months); if there is no improvement by at most 3 months after treatment start or the target has not been reached by 6 months, therapy should be adjusted. In contrast with the second half of prior recommendation 2, which also dealt with follow-up and treatment adjustments that could be interpreted or used differently than intended, statement 3 of the updated recommendations is very specific and clarifies any potential incongruity. First, monitoring should be performed as frequently as disease activity necessitates, namely more frequently (such as every 1–3 months) with active disease and less frequently (such as every 6–12 months) once the treatment target has been stabilised. EULAR also advocates the use of composite measures of disease activity, which include formal joint counts and the application of the ACR–EULAR criteria for remission.34 ,45 Further, this item clearly specifies that the treatment target (remission or at least low disease activity, see item 2) should be attained within 6 months and not necessarily within 3 months; the 3-month time point relates solely to assessing improvement, meaning reduction of disease activity from a high to at least a moderate state by composite measures.45 If there is no improvement in disease activity (such as persistence of high disease activity as assessed by composite scores) after 3 months and provided that therapy has already been adjusted to maximise treatment effect, the ongoing therapeutic regimen is usually unlikely to lead to the treatment goal in many additional patients even by 1 year and should be modified.49 Maximisation of treatment effects includes reaching an optimal MTX dose within a few weeks and maintaining the maximal dose (25–30 mg weekly) for at least 8 weeks.50 If improvement is achieved at 3 months,51 ,52 it must be borne in mind that maximal efficacy will not be seen before 6 months in many patients with most treatment strategies. This is true for all types of therapies, including most biological agents. A similar approach should be made if the treatment target (remission or low disease activity) is not attained at 6 months. Of note, individual patients may be well on their way to reaching the targets of low disease activity or remission at 6 months and might just take slightly more time to attain this desired state. Therefore the change in disease activity from treatment start to the 6-month time point will have to be taken into account when making final treatment decisions in the individual patient.

4. MTX should be part of the first treatment strategy in patients with active RA. This statement (previously No 3) remains unchanged. The Task Force felt reassured by the respective SLR13 that MTX is a highly effective agent both as monotherapy and in combination with glucocorticoids, other csDMARDs and bDMARDs, and thus continues to serve as an anchor drug in RA.53 As monotherapy with or without glucocorticoids, it is effective in DMARD-naïve patients and leads to low disease activity states or 70% improvement rates according to the criteria of the ACR (which correspond to nearly a state of low disease activity)54 in about 25–50% of patients with early RA within 6–12 months.35 ,55–60 Generally, this statement combines three aspects: first, by using the term ‘part of the first treatment strategy’, it implies that MTX, although effective as monotherapy, may be combined with other agents, such as glucocorticoids but also other csDMARDs (see above and below); second, by stating ‘active disease’ (suggested definitions: Clinical Disease Activity Index (CDAI)>10, DAS28>3.2 or Simplified Disease Activity Index (SDAI)>11),45 it implies that some patients with low disease activity (defined as CDAI≤10, DAS28<3.2, SDAI≤11) may not need MTX and can do well on alternative csDMARD therapies; the third aspect relates to patients previously treated with other csDMARDs who should receive MTX at a sufficient dose and for sufficient time before progressing to potentially more intensive therapies. Important aspects include dose optimisation,50 optimal use of folic acid,61 and recognition that the maximum effect of MTX is attained only after 4–6 months55–59; in this respect, the optimal dose (25–30 mg a week with folate substitution, or somewhat less in the case of dose-limiting side effects62), should be maintained for at least 8 weeks as an important aspect on the way to ultimate treatment success.50 For patients with contraindications to MTX, other drugs should be used (see next recommendation).

5. In cases of MTX contraindications (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy. While MTX is usually quite well tolerated, especially with folate supplementation,61 ,63 safety issues do exist62 ,64 and contraindications to MTX include hepatic or renal disease; a further safety aspect of concern may be MTX-induced lung disease. Sulfasalazine and leflunomide were also included as alternatives for MTX in 2010 in statement 4, so this item has only been shifted. Both sulfasalazine and leflunomide have shown clinical, functional and structural efficacy,65–69 and, although MTX doses in respective comparative trials may not have been optimal, both have shown efficacies similar to MTX. No new studies have disproved this conclusion, and both drugs have been used effectively in combination with biological agents.70 ,71 Optimal therapeutic dosing of sulfasalazine is 3–4 g/day as enteric coated tablets72–76; the usual leflunomide dose is 20 mg/day. As with all other agents mentioned, safety risks and contraindications should be considered, and—aside from its higher cost—some issues stated in relation to MTX above may also pertain to leflunomide. Of note, sulfasalazine is considered to be safe during pregnancy.77 Prior recommendation No 4 also mentioned injectable gold salts as an alternative to MTX. While the Task Force does not at all withdraw its evidence-based opinion on the efficacy of parenteral gold salts (which is similar to that of MTX in clinical, functional and structural terms) set forth in 2010, gold salts are used rarely and, indeed, are unavailable in many countries. Although some members of the Task Force expressed safety concerns, these were not found to be substantiated in the previous SLR4; however, no study has evaluated intramuscular gold since the last SLR was performed. Therefore it was decided to remove gold salts from its relatively prominent place in the table, while acknowledging that its efficacy remains established by high-quality evidence.78 Further, antimalarials, such as hydroxychloroquine and chloroquine, are used in RA, especially in combination therapy, but also as monotherapy in patients with very mild disease.79 Interestingly, beyond their mild DMARD activity, antimalarials exhibit a variety of positive metabolic effects and are also considered to be safe during pregnancy.80 ,81 Because they may not retard progression of joint damage to the same extent as other agents,65 ,82 they have not been mentioned more prominently in this statement, although patients with low disease activity have a low propensity for joint destruction. Finally, compared with the previous statement on these drugs, the term ‘early’ has now been added to ‘intolerance’ to indicate the Task Force's view that early intolerance to MTX (within 6 weeks) should be viewed as a contraindication and not as a failure of the first treatment strategy. Of note, the Task Force decided unanimously to delete recommendation 10, which also dealt with potential alternative therapies for desperate cases (‘In the case of refractory severe RA or contraindications to biological agents or the previously mentioned sDMARDs, the following sDMARDs might be also considered, as monotherapy or in combination with some of the above: azathioprine, cyclosporine A [or exceptionally cyclophosphamide]’) from the table of recommendations. Given the many currently available effective csDMARDs and bDMARDs and the view that the benefit/risk ratio of the mentioned drugs was not convincingly favourable, especially in relation to other therapies, their use in a first treatment strategy should be restricted to rare, exceptional situations (for details see 2010 recommendations).3

6. In DMARD-naïve patients, irrespective of the addition of glucocorticoids, csDMARD monotherapy or combination therapy of csDMARDs should be used. In the previous set of recommendations, item 5 read: ‘In DMARD-naïve patients, irrespective of the addition of glucocorticoids, sDMARD monotherapy rather than combination therapy of sDMARDs may be applied.’ This wording expressed a preference for monotherapy based on the respective SLRs,64 ,83 which had revealed no superiority of combination therapy using csDMARDs when excluding the concomitant use of glucocorticoids. However, by saying ‘may’, that statement did not generally oppose the use of csDMARD combination therapy; this was also reflected in the respective figure depicting the proposed algorithm. Since then, several additional studies suggest that csDMARD combination may be superior to MTX monotherapy, and some even found efficacy to be similar to that of bDMARDs.84–88 Nevertheless, although these trials yielded similar results strengthening their interpretation, controversy persists because of methodological limitations of these studies,13 which were also clearly stated in some of the reports themselves. Moreover, additional recent data suggest that sequential monotherapy is as effective as combination therapy in clinical, functional and structural outcomes89 ,90 and that stepping up from MTX monotherapy to a biological agent has significant superiority over a combination of csDMARDs.89 Nonetheless, the Task Force agreed unanimously that the use of csDMARD combination therapy should be mentioned as an appropriate alternative strategy alongside the use of csDMARD monotherapy, with or without glucocorticoids. The Committee thus felt that both monotherapy and combination therapy of csDMARDs are effective and that patient preferences and expectations of adverse events should be considered when discussing treatment options with them. In general, combination therapy with csDMARDs should include MTX, since other combinations have not been sufficiently studied. Finally, the Task Force recognised the limitations of meta-analyses in the light of new studies84 ,86 contradicting a meta-analysis that had suggested similar structural efficacy for csDMARD combinations and bDMARD treatment.91

7. Low-dose glucocorticoids should be considered as part of the initial treatment strategy (in combination with one or more csDMARDs) for up to 6 months, but should be tapered as rapidly as clinically feasible. As before, the Task Force heavily debated the role of glucocorticoids (previously recommendation 6). Indeed, this item was reworded (previously: ‘Glucocorticoids added at low to moderately high doses to sDMARD monotherapy [or combinations of sDMARDs] provide benefit as initial short term treatment, but should be tapered as rapidly as clinically feasible.’). Rather than just making the general statement that glucocorticoids may ‘provide benefit’, the Task Force now recommends that they should be considered as part of the initial therapeutic approach. This change is based on the respective SLR13 which includes additional information accrued over the last few years.85 ,92 Low dose refers primarily to a dose of 7.5 mg prednisone or equivalent per day or less.93 Mentioning glucocorticoids in a separate recommendation results from their proven capacity to increase clinical, functional and structural efficacy when combined with csDMARDs,92 ,94–96 and this combination has similar efficacy when compared with TNF inhibitors plus MTX60 ,97; thus glucocorticoids, both in initially high and rapidly tapered regimens (eg, COBRA) and at lower doses extended over a year or two, may increase DMARD activity and are even effective in this regard as monotherapy.98 ,99 However, glucocorticoid monotherapy is not specifically recommended by the Task Force and should only be used in exceptional cases when all other DMARDs have contraindications. A separate EULAR committee has concluded that the literature on safety of long-term glucocorticoid therapy at low doses still has important gaps, but in general does not support the notion of unacceptable safety issues100; subsequently, that committee formulated management guidelines that also address preventive measures against glucocorticoid-induced adverse events.101 The current SLRs13 ,15 are not in disagreement with any of the above findings. Nevertheless, the adverse event profile and comorbidity implications of glucocorticoids (and thus their benefit/risk profile) elicited a fierce debate within the Task Force. A compromise (based on expert opinion) to be more specific with respect to the time frame of their application by stating ‘up to 6 months’ rather than just ‘short term’ ultimately led to a majority vote; however, only 73% of the members approved this item (the lowest majority level of all recommendations), reflecting divergent opinions, with both proponents of a stronger and a weaker recommendation voting against. However, the level of agreement (strength of recommendation) was quite high (mean of 8.9) upon final anonymous grading. Thus, the Task Force suggests using them only as bridging therapy and limiting their use to a maximum of 6 months, ideally tapering them at earlier time points. However, neither chronic use of glucocorticoids in established RA nor intra-articular glucocorticoid applications were discussed. Of note, it was also decided to change the algorithm in figure 1 from the 2010 version by downsizing the ‘−’ compared with the ‘+’ in the ‘±’ symbol to reflect the increasing agreement of the Task Force that glucocorticoids should be combined with MTX or other csDMARD regimens.

8. If the treatment target is not achieved with the first DMARD strategy, in the absence of poor prognostic factors, change to another csDMARD strategy should be considered; when poor prognostic factors are present, addition of a bDMARD should be considered. Slightly reworded compared with 2010, this statement reiterates the unanimous view of the Task Force that risk stratification is an important aspect in the therapeutic approach to RA. These risks have been well defined over the years and include a high disease activity state, autoantibody positivity (rheumatoid factor and/or antibodies to citrullinated proteins) and the early presence of joint damage.102 ,103 In patients with a low risk of poor RA outcome, another csDMARD strategy (plus glucocorticoids) would be preferred, while in patients with a high risk, the addition of a bDMARD would be preferred. It should be noted that the Task Force changed the sequence compared with the 2010 recommendation, since it assumed that many patients may not be at high risk after a first DMARD strategy, especially in terms of a reduced disease activity and maybe even lower autoantibody levels, and that a rapid change of the csDMARD regimen within 6 months, in line with recommendation 3, may convey further efficacy for a significant proportion of patients. ‘Change’ rather than the previously used ‘switch’ is semantically more in line with potentially adding drugs, especially in patients initially treated with MTX monotherapy, and inherently also comprises switching. ‘Another conventional DMARD strategy’ has to be seen in relation to the first DMARD strategy; if the first DMARD was MTX monotherapy, then a switch to, or the addition of, other csDMARDs would be the appropriate choice; if the first DMARD strategy was combination therapy of MTX, sulfasalazine and hydroxychloroquine, then the next csDMARD strategy to choose in patients at low risk of poor outcome may be leflunomide, all of this under the proviso that optimal doses of the csDMARDs have already been used before (see above). The term ‘considered’ was used in both instances to reflect the Committee's preferences, but inherently acknowledges and implies that treatment decisions have to be made individually and that using a bDMARD after a first csDMARD also in a patient with lower risk of a poor outcome may be appropriate, just as using another csDMARD strategy in a patient at high risk of a poor outcome may be appropriate, as long as the target-oriented strategy to attain remission or low disease activity within 6 months remains paramount; the latter approach, indeed, may be a common or enforced approach in many healthcare systems. Studies suggesting that step-up csDMARD combination therapy was as effective as a step-up combination of a biological agent with MTX87 ,88 ,104 were seen to be in conflict with results from other studies showing better efficacy of addition of a bDMARD.89 Obviously, and for reasons of clarity, when speaking of csDMARDs, the Task Force had only the hitherto employed csDMARDs in mind and not any potential new targeted synthetic (ts) DMARD, such as a kinase inhibitor.

9. In patients responding insufficiently to MTX and/or other csDMARD strategies, with or without glucocorticoids, bDMARDs (TNF inhibitors, abatacept or tocilizumab, and, under certain circumstances, rituximab) should be commenced with MTX. This point was approved as worded by 90% of the participants. First, the Task Force reiterated here that bDMARDs should primarily be started when patients did not achieve the therapeutic target after treatment with csDMARDs for 6 months (or had no improvement at 3 months). Second, it explicitly defined the agents it meant when mentioning ‘biological DMARDs’. In the 2010 recommendations, the Committee had added ‘current practice would be to start a TNF inhibitor’, and explained this expert opinion with the long-term use of TNF blockers and the availability of registry data when compared with abatacept and tocilizumab; this was simply an expression of a preference based on their larger and longer evidence base and was not intended to preclude use of other biological agents after csDMARD failures. Also, at that time, their application in patients with an inadequate response to csDMARDs was not yet approved for tocilizumab in the USA and for abatacept in Europe. Meanwhile, the approval status has changed for both drugs, the clinical experience with these agents has now grown for several years, and initial registry data do not seem to reveal differences in their safety profiles from the clinical trial data or when compared with TNF inhibitors.105–109 Moreover, a direct comparison of abatacept and adalimumab in patients with active disease despite MTX revealed very similar efficacy and overall safety.110 Therefore the Task Force decided by a 90% majority vote that no preference of one over another biological agent should be expressed in the 2013 update of the recommendations. However, the Task Force recognised that there was still more experience with TNF inhibitors than with other bDMARDs, and that more safety data from registries would be desirable for the newer bDMARDs. Notably, IL-1 inhibitors have not shown strong efficacy when compared with other bDMARDs in meta-analyses, so anakinra is not specifically mentioned in the abbreviated recommendation; nevertheless, some patients may respond to this bDMARD. Thirdly, the Task Force intentionally added ‘under certain circumstances rituximab’; while rituximab is approved for use after patients have responded insufficiently to TNF blockers, the Committee acknowledged that trial data in patients who were naïve for csDMARDs and those who had an inadequate response to csDMARDs have been published111 ,112 (level 1 evidence) and that, in the presence of certain contraindications for other agents—such as a recent history of lymphoma, latent tuberculosis (TB) with contraindications to the use of chemoprophylaxis, living in a TB-endemic region, or a previous history of demyelinating disease—rituximab may be considered as a first-line biological agent. Some rheumatologists also prioritise this drug in patients with a recent history of any malignancy, because there are no indications that rituximab use is associated with the occurrence of cancers113 ,114; furthermore, rituximab is the least expensive biological agent at present. Fourth, when speaking of TNF inhibitors, the Task Force listed the presently approved agents, adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, but also decided to mention biosimilars under the proviso that they become approved in the USA and/or Europe; current data suggest that at least one biosimilar, CT-P13, has a similar efficacy and safety profile to the original antibody, infliximab, in RA and axial spondyloarthritis.115 ,116 Fifth, the Task Force felt that all bDMARDs should be used preferentially in combination with MTX or other csDMARDs. For neither TNF inhibitors nor rituximab or abatacept has monotherapy been consistently found to be superior to MTX alone, whereas combination therapy has; a dose of 10 mg MTX or more a week appears to be effective and appropriate for use with adalimumab and infliximab63 ,117 and, until proven otherwise, also with all other TNF inhibitors. Only tocilizumab has been repeatedly demonstrated to be superior as a monotherapy over MTX or other csDMARDs, although the Japanese study had an oplen label design and the MTX dose was low.118 ,119 In 2010, the Committee explicitly mentioned that a three-arm trial in early RA is needed to gain full insight, and, most recently, these data became available, albeit only in abstract form,120 revealing that only in combination with MTX tocilizumab (8 mg/kg) showed consistent significant superiority over MTX with regard to clinical, functional and structural outcomes. The other arms, tocilizumab monotherapy (8 mg/kg) and tocilizumab (4 mg/kg) in combination with MTX, showed superiority mainly in reaching the primary clinical end point (DAS28–erythrocyte sedimentation rate <2.6, a measure confounded by placing a high weight on acute phase reactant levels121), with only numeric differences in most of the clinical and functional secondary end points, most of which did not reach statistical significance. On the other hand, a head-to-head trial in patients with established RA who stopped MTX therapy revealed tocilizumab monotherapy to be superior to adalimumab monotherapy in most (though not all) endpoints.36 Thus, if biological monotherapy must be initiated, tocilizumab has some supportive evidence, but taken together, the data strongly support the use of all biological agents in combination with MTX. While clinical response is usually maintained even on withdrawal of MTX in patients receiving established therapy with MTX plus tocilizumab or a TNF inhibitor (and therefore presumably also other bDMARDs),122–124 there is rarely a reason to withdraw MTX, since, with established therapy, it is usually well tolerated. Also monotherapy is not a major recommendation by the Task Force, which clearly preferred maintenance of combination therapy. Finally, it is important to note that the Task Force agreed to abandon former recommendation No 14: ‘DMARD-naïve patients with poor prognostic markers might be considered for combination therapy of MTX plus a biological’. In 2010 it was already stated that early use of a biological agent should only be considered in exceptional patients; however, as it stood, this statement could have been misinterpreted as advocating use of biological agents even before an initial csDMARD strategy had failed. With the current decision, the use of bDMARDs before trying a csDMARD approach is even more strongly discouraged than signified by the 2010 recommendation. The majority of the current Committee members felt that using a treat-to-target strategy that gave patients the initial opportunity to respond to treatment in line with items 4, 5 and 7 still provides the option of adding a biological agent within 6 months—and thus quite early in the disease course or therapeutic chronology—if the treatment target was not reached. This approach was supported by several recent clinical trials.29 ,88 ,125 ,126 Although bDMARDs in comparison with csDMARDs in early disease confer a significant structural benefit, this benefit was deemed to be neither sufficiently large nor sufficiently frequent, provided that a treat-to-target strategy with treatment adaptations within 6 months was adhered to.125–127 This decision was probably the most heavily debated one: an initial ballot revealed a 94% majority for deleting the old recommendation No 14; subsequently, after thorough discussions, a re-voting process was solicited, but only 33% of the members voted for re-inclusion of old recommendation No 14. In this context it should be clarified that the Task Force was fully aware of the data in patients with early RA who have significantly higher response rates with bDMARDs combined with MTX than MTX alone; however, embedded within this responder population are good responders to MTX monotherapy who experience about 25% (or more) ACR70 improvement (corresponding to a low disease activity state including remission) across studies without any additional treatment adaptations being allowed over a 1-year trial period; in clinical practice, many of these patients would have been overtreated if they had received biological agents instead, placing them at a potentially increased risk of serious adverse events and incurring high costs. Also, it must be borne in mind that the BeSt study showed that csDMARDs plus glucocorticoids led to very similar initial clinical, functional and structural results as with bDMARDs,97 and the IMPROVED trial showed a very high rate of good outcomes using MTX plus low-dose glucocorticoids within a few months.60 Nevertheless, there may still be an exceptional patient in whom the use of a bDMARD in combination with MTX as the first DMARD strategy is considered appropriate. One can imagine patients whose professional or family life entirely depends on a rapid complete resolution of the joint symptoms and where glucocorticoids as adjunctive therapy with csDMARDs have failed or cannot be used because of contraindications. In such cases, the exceptional use of a biological agent is not precluded now that we have dismissed this recommendation from its former place in the table, but the prominence that could be misinterpreted has now been removed. Importantly, however, there are studies suggesting that early induction therapy with anti-TNF plus MTX may result in good outcomes even after withdrawal of the biological agent.128 ,129 Nevertheless, another study, although partly confirming these results, resulted in a relatively high relapse rate on withdrawal of the TNF inhibitor.130 Thus, more data are needed to support induction therapy, but further evidence confirming the maintenance of remission after withdrawal of the biological agent may lead to a paradigm change in our approach to treating RA (see item 12).

10. If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor or a biological agent with another mode of action. A consequence of item 9, recommendation 10 simply states that once the treatment target has not been reached with an initial biological therapy, other bDMARDs should be used; no preference is stated. The second part of this recommendation focusing on patients who have initially received a TNF inhibitor may seem somewhat redundant. However, it has two purposes: (i) to express the conclusion of the Task Force that current evidence does not suggest any one agent to be better than another TNF inhibitor when active disease prevails despite initial treatment with a TNF blocker; (ii) over the next few years, new biological agents targeting the IL-6 receptor (sarilumab) or IL-6 (clazakizumab, sirukumab) may become available131–133; without specific note on the options after failure of an initial TNF inhibitor therapy, one could infer that potentially approved new IL-6 inhibitors might be used after failure of tocilizumab, but in contrast with TNF inhibition, the efficacy of such an approach is currently unknown for IL-6 inhibition (or costimulation blockers or rituximab). Of note, with biosimilars approaching, it is self-evident that an infliximab biosimilar cannot be regarded as ‘another TNF inhibitor’ in patients with an insufficient response to infliximab. This recommendation was voted for by 97% of the members.

11. Tofacitinib may be considered after biological treatment has failed. Tofacitinib, a JAK inhibitor, was approved for the treatment of RA in the USA, Japan and Russia at the time of the Task Force's meeting on 9 April 2013. For reasons stated above, an a priori decision had been made to address tofacitinib in the recommendations based on evidence of efficacy and safety available from the literature and accrued in the course of the respective SLR.13 Tofacitinib is not a bDMARD, but a synthetic chemical compound. It is a targeted molecule interfering with specific signal-transduction pathways and thus could not be subsumed within the term ‘conventional synthetic DMARDs’. Therefore the Task Force decided to address its use in a separate recommendation as a tsDMARD, rather than as part of csDMARDs or bDMARDs.2 The evidence from published papers and abstracts has convinced the Committee that tofacitinib is sufficiently efficacious in improving clinical, functional and structural outcomes to be considered a DMARD.134–136 The fact that the 5 mg dose approved in the USA and Japan just misses statistical significance for inhibition of joint damage progression compared with placebo at 12 months (p=0.06)137 did not preclude the Task Force from recognising its structural efficacy, given significant radiological differences at this dose in another trial.138 However, little is currently known about its long-term safety. Data from clinical trials reveal a numerical increase in serious infection rates compared with controls; herpes zoster infections in particular appear to be more common than seen with TNF inhibitors;134 ,139 several cases of TB and non-TB opportunistic infections have been reported; lymphocytopenia and anaemia also occur, and haemoglobin levels appear to increase less upon clinical improvement than seen with csDMARDs and bDMARDs. In light of the many available csDMARDs and bDMARDs that have long-standing clinical experience data, the Task Force felt that tofacitinib should primarily be used when bDMARDs have been insufficiently effective, even though it is already approved in the USA, Japan, Russia and meanwhile Switzerland for use after failure of csDMARDs. Indeed, the discussion initially focused on whether tofacitinib should only be recommended for use only after failure with two bDMARDs with different modes of action, but ultimately it was decided to just reflect this discussion item in the accompanying text and not in the recommendation. More clinical experience and safety data from registries, with a particular focus on serious infections, herpes zoster and malignancies, will be needed before the actual place of tofacitinib in the treatment sequence can be clarified, and at present the Committee did not feel that tofacitinib was safer or more efficacious than rituximab, which, according to currently existing labelling, should be used after TNF inhibitor failure. While the Task Force mainly focused on efficacy and safety, it also considered economic aspects, as supported by GRADE140 and as occurred in the 2010 recommendations when all recommendations were supported by cost-effectiveness data, with the exception of starting biological agents before sDMARDs.8 Given constrained healthcare budgets, the inefficient use of healthcare resources (ie, funding those interventions that are not cost-effective) often results in either a lost opportunity to improve the health of other individuals with cost-effective interventions or increased costs through taxes or insurance premiums. Hence the Committee noticed that the annual cost of tofacitinib in the USA and Switzerland is currently about US$25 000 and CHF25 000, respectively, placing it at a similar level to biological agents.141 ,142 Notably, the first biosimilar has been approved in Europe in the meantime143 ,144 and is expected to be priced at lower levels than the currently available bDMARDs.31 Therefore, although the Task Force appreciates that tofacitinib is an oral first-in-class drug with a different mechanism of action and is aware of the approval situation in the USA, Japan and other countries, it did not believe it was yet possible to conclude that tofacitinib has a similar safety profile to tocilizumab or other biological agents for which far more person-years of exposure have been accumulated and reported to date. Thus, additional long-term safety data and clinical experience will be needed to determine an overall benefit/harm ratio. Also, a proper cost-effectiveness analysis would be desirable. Accordingly, the Committee preferred not to recommend tofacitinib after MTX failure as it did for other biological agents. Among the Task Force members, 90% voted in favour of this recommendation as phrased here. Of particular importance, at the time of the Task Force's meeting on 9 April 2013, it was unknown when the EMA would release its decision on the approval of tofacitinib. Thus, the discussions, formulation of recommendation, explanatory stipulations and on-site voting of the Committee occurred before EMA published its first and second negative decision on tofacitinib (with resubmission being planned by the company).145–147 Anonymous voting on the level of agreement (strength of recommendation), however, occurred electronically after the first EMA decision became known and was the lowest of all items (7.6 on a scale of 0–10), which may have been influenced by this information.

12. If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, especially if this treatment is combined with a csDMARD. In contrast with 2010—when a similar recommendation was stated—more evidence is now available and there was unanimous approval within the Task Force. In established RA, the available data suggest that most patients flare upon withdrawal of a TNF inhibitor,148–151 and more profound and persistent responses increase the likelihood of maintenance of a good outcome with csDMARDs even after withdrawal of the bDMARD.150 In the PRESERVE trial, the time frame was at least 4 months.152 However, for early RA, the data are somewhat contradictory. While the primary target in early RA clearly should be stringent remission,33 ,34 most data on withdrawal of bDMARDs come from patients who are in sustained low disease activity. The OPTIMA trial showed that a 6-month induction regimen with adalimumab plus MTX soon after diagnosis may be sufficient to allow most patients to maintain low disease activity or remission after open label and even after double-blind withdrawal of the TNF inhibitor128 ,153 ,154; however, while similar findings on withdrawal of a TNF blocker were obtained in an open label fashion in the HIT HARD study,129 somewhat contradicting data were seen in the PRIZE trial, where dose reduction but not withdrawal of the biological agent was accompanied by maintenance of good outcome.130 Thus, only if further and more broadly confirmed can short-term inclusion of a biological agent in a first DMARD strategy become a true option (see discussion to recommendation No 9). On the other hand, reduction of the TNF inhibitor dose after attainment of DAS28<2.6 in early RA allows excellent outcomes to be maintained,130 as also seen in established RA.152 ,155 While most studies on dose reduction or withdrawal have been performed with TNF blockers, some data on other bDMARDs are emerging with similar overall results,156–158 but clearly more information is needed in this regard. Importantly, before bDMARDs are tapered, glucocorticoids should have been withdrawn in line with point 7. Also of note, reinstitution of bDMARDs appears to allow the good outcome to be recaptured.150 ,156 ,159

13. In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician. Except for minimal rewording (the term ‘titration’ is replaced by ‘reduction’), this item is identical with point 13 of the 2010 recommendations; it refers solely to those patients in whom glucocorticoids, if used, have already been stopped and/or who have attained and maintained the targeted therapeutic state on csDMARDs or those in whom bDMARDs have been successfully withdrawn (see above). This recommendation received 100% of the votes. As stated then, it must be borne in mind that stopping csDMARDs in patients with established RA in remission is followed by flares in about 70% of patients, twice as frequently as maintaining therapy irrespective of regimen.160 ,161 Therefore the focus of this item is on csDMARD reduction rather than cessation. On the other hand, drug-free remission may be an option in patients in whom therapy was initiated very early and who therefore also had achieved remission early in their disease course.162 Of note, in light of the availability of the ACR–EULAR remission definitions, the term ‘persistent remission’ in this recommendation primarily pertains to these definitions; however, formal DMARD withdrawal studies using them have not yet been performed.

14. When therapy needs to be adjuusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account. Again, this point is essentially identical with the last recommendation of 2010 and was unanimously approved at the Task Force meeting. It is intended to raise awareness that reaching the outcome of low disease activity or remission is not an absolute prerequisite and that it is equally important to account for comorbidities and other contraindications when targeting a good outcome. Conversely, high disease activity is typically associated with comorbidities,163 ,164 so effective therapeutic intervention may also prevent comorbidity.165–167 Finally, some patients with low disease activity may still develop seriously progressive radiographic joint damage, so after potential lag periods have been accounted for to recognise progression,168 such patients may then need intensification of therapy.

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Figure 1

Algorithm based on the 2013 European League Against Rheumatism recommendations on rheumatoid arthritis management. ACPA, anti-citrullinated protein antibody; DMARD, disease-modifying antirheumatic drug; RF, rheumatoid factor; TNF, tumour necrosis factor.