The statements receiving a majority vote by the Expert Committee in the final voting round are shown in Box 1. These are discussed in detail below.
The Committee felt that certain aspects related to the treatment of RA form a framework on which specific recommendations can be based. These items were therefore considered to constitute overarching principles, although they were discussed and voted on.
(A) The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist. Not only must the patient be informed on the therapeutic options and the reasons for recommending a particular therapeutic approach by weighing benefit and risk, but the patient should participate in the decision as to which treatment should be applied. This item was accepted unanimously.
(B) The primary goal of treating the patient with rheumatoid arthritis is to maximise long-term health-related quality of life through control of symptoms, prevention of structural damage, normalisation of function and social participation. This general statement pertains to all aspects of the therapeutic procedures including selection of drugs, application of treatment strategies and follow-up of RA (81.6% acceptance).
(C) Abrogation of inflammation is the most important way to achieve these goals.
This principle relates to the fact that the inflammatory response underlying RA is responsible for the signs and symptoms of the disease and is associated with adverse outcomes in all areas listed in (B)12 13 19 44 45
(72.9% acceptance in the second voting round). There was discussion as to whether the term ‘abrogation’ could be easily translated into other languages; to this end, synonyms such as abolition, reversal, suppression, halt, arrest, stop or inhibition reflect the meaning, although abrogation leaves less room for residual interpretations than most other terms.
(D) Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in rheumatoid arthritis. While the endeavour was to focus on individual items related to the topic of T2T, the Expert Committee felt so convinced on the principal nature and truthfulness of this statement that 91.8% of the experts accepted it.
The overarching principles are followed by the final set of 10 recommendations as formulated by the Expert Committee. The sequence follows a hierarchical and a logical order; for example, the first statement was regarded as the most important one, but other items were also deemed important. The weight of the individual items is reflected by the level of evidence, the strength of recommendation and level of agreement as presented in .
Evidence, agreement and votes for each of the recommendations
(1) The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.
The level of evidence supporting this statement was low (category III or IV) because strategic trials have hitherto aimed at attaining LDA,28–30
while no formal study compared a strategy to treat RA with the target ‘remission’ with another strategy. Some trials evaluated the frequencies of remission by different therapies46
or had remission as the primary end point32 46
but, with one exception,46
this was investigated with static treatment and not by strategic switching. On the other hand, the functional and radiographic outcomes of these latter trials provide important supportive evidence for the statement. Also, subanalyses of various clinical trials suggest that the best outcomes are achieved on attaining remission, even when compared with LDA.20 47
Moreover, remission can be achieved in a significant proportion of patients, especially with early RA. It was therefore deemed to be a pivotal aspirational target for all
patients (83% support; average agreement 9.1/10). The importance of sustained remission is addressed later.
(2) Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity.
This statement is entirely expert-based (category IV). While there are many definitions of remission, such as that by the American College of Rheumatology (ACR) or based on composite disease activity measures14 48 49
and all of them are contained in the EULAR/ACR recommendations for clinical trial reporting,50 51
it is well established that some criteria allow for more residual disease activity than others.14 52 53
Furthermore, even when swelling cannot be discerned clinically, it may continue to exist at a subclinical level.54 55
The majority of the experts felt that the definition of remission should not allow for residual clinical disease activity. On the other hand, it was accepted that some residual joint tenderness or a single swollen joint in a patient with long-standing disease may still be compatible with a state of remission. The term remission of ‘inflammatory disease activity’ was therefore coined, given that joint swelling and C-reactive protein (CRP) but not isolated tenderness or pain are associated with progression of joint damage.13
The term ‘significant’ makes clear that a higher than very small level of residual inflammatory activity was not acceptable, in line with survey results.56
In this regard, acute phase reactants such as CRP have also to be taken into account, as their increase likewise reflects inflammatory disease activity (see also statement 9). The final voting achieved approval by 76% of the experts. An ACR/EULAR initiative on defining remission is currently ongoing.
Box 1. Recommendations
- The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist.
- The primary goal of treating the patient with rheumatoid arthritis is to maximise long-term health-related quality of life through control of symptoms, prevention of structural damage, normalisation of function and social participation.
- Abrogation of inflammation is the most important way to achieve these goals.
- Treatment to target by measuring disease activity and adjusting therapy accordingly optimises outcomes in rheumatoid arthritis.
10 recommendations on treating rheumatoid arthritis to target based on both evidence and expert opinion:
- The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.
- Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity.
- While remission should be a clear target, based on available evidence low disease activity may be an acceptable alternative therapeutic goal, particularly in established long-standing disease.
- Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months.
- Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 3–6 months) for patients in sustained low disease activity or remission.
- The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions.
- Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity.
- The desired treatment target should be maintained throughout the remaining course of the disease.
- The choice of the (composite) measure of disease activity and the level of the target value may be influenced by consideration of co-morbidities, patient factors and drug-related risks.
- The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist.
(3) While remission should be a clear target, based on available evidence low disease activity may be an acceptable alternative therapeutic goal, particularly in established long-standing disease.
This statement confirms remission as the ultimate therapeutic goal. Nevertheless, since all strategic clinical trials have focused on LDA,28–30
the target with the best evidence is a state of LDA according to established cut-off points of composite measures (category Ib). In patients with long-standing disease, considerable joint damage and several prior treatment failures, remission may not be realistic and LDA may be the best achievable state. Indeed, many patients with established RA may prefer to accept an ‘LDA state’ above forcing them into remission at all costs. Importantly, however, LDA should be the minimal aspired goal (an ‘acceptable alternative to remission’), and patients clearly should not remain in moderate or high disease activity states. Finally, when LDA is an alternative target, it is important to sustain it (as was stated for remission; see also point 8).
(4) Until the desired treatment target is reached, drug therapy should be adjusted at least every 3months.
Clinical trials suggest that the maximal clinical benefit is usually not achieved before 3 months of treatment. A change of DMARD therapy has been done successfully every 1–3 months in strategic trials.28 30
Thus, if patients do not attain at least a state of LDA within 3 months from starting therapy, treatment should be amended (category Ib). This does not necessarily mean a change of drugs, since the degree of the change of disease activity from baseline has to be taken into account in individual patients, especially in those with high disease activity at the start of therapy. Dose adaptation of existing medication may be sufficient for further benefit to be judged over the subsequent 1–3 months. On the other hand, in patients in whom the disease activity did not show major improvement within 3 months, changing the drug regimen may have to be considered at that early point in time. The choice of this time point is supported by respective studies.28–30 47 57
(5) Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 3–6months) for patients in sustained low disease activity or remission.
Progression of joint damage can be recognised within a few weeks in patients with high disease activity.58
Therefore, in patients with high disease activity, there is a need for frequent assessment of the disease status (eventually even monthly) to adapt treatment accordingly (category Ib). Once patients reach remission (or the alternative goal of LDA when having long-standing RA) and sustain this state, less frequent evaluations may be sufficient. The focus here is on the term ‘sustained’, indicating that even if a particular desired state is reached, more frequent control examinations are necessary initially to ensure that the state does not change (ie, rebound) rapidly. The first example for high disease activity, ‘as frequently as monthly’, leans against available strategic trials evaluating patients every 1–3 months28 30
in high disease activity. The other example, ‘such as every 3–6 months’ has been a compromise constituting expert opinion, since some rheumatologists feared short-term reactivation of RA which could be detected early with 3-monthly examinations. Among patients who are in sustained remission and are adequately informed to see their rheumatologist earlier upon status changes, annual control examinations may suffice.
(6) The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions.
The Committee was convinced that using composite measures of disease activity constitutes the best way to judge disease activity and response to therapy, although this is an expert opinion (category IV). RA is heterogeneous and composite scores capture this heterogeneity best.59 60
There exist several validated composite measures of disease activity which comprise joint assessment.61
Importantly, the vast majority of the experts felt that these measures should include joint assessments, because the joints constitute the ‘organ’ involved in RA and using measures that do not contain joint counts may lack face validity or not be accurate (influenced by factors not related to the disease). Indeed, this item as it stands achieved one of the highest levels of agreement (9.0). Recent EULAR/ACR guidelines for clinical trial reporting mention validated composite measures that include joint counts obtained by a rheumatologist or other health professional, such as the disease activity score (DAS) or the DAS employing 28 joint counts (DAS28), the simplified and the clinical disease activity index (SDAI, CDAI)50 51
; these measures are also useful in clinical practice. To leave the choice open for the clinician, the neutral term ‘composite measure of disease activity’ was used.
(7) Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity.
This item reiterates the importance of using composite measures of disease activity, but indicates that other aspects such as functional impairment and joint damage, which are governed by the degree of disease activity, also have to be considered. However, in the shorter term, the majority of patients even with high disease activity will not experience progression of joint destruction.62
Thus, the effect of active disease on radiographic damage varies between patients. The committee felt that x-rays should be obtained annually and potential progression of joint damage be estimated (not scored). If joint damage appears to progress despite achieving the desired target such as LDA, intensifying treatment may be needed (category IV). However, lag periods of x-ray progression may have to be considered.63
This bullet point does not mention x-rays, indicating that other instruments known (validated) to inform us on joint damage may also be used; this relates particularly to MRI and sonography. Importantly, judgements should be made by those sufficiently experienced in reading these images. In addition to joint damage, continuing impairment of physical function despite achievement of the targeted disease activity level may also necessitate a therapeutic change (category IV). However, in some patients, functional impairment may not be sufficiently captured by functional measures, particularly in individuals with certain occupations who experience reduction in functioning and personal working capacity by involvement of a specific joint, necessitating a change of treatment even if otherwise in LDA. Thus, special treatment options may be needed for optimal caretaking of individual patients.
(8) The desired treatment target should be maintained throughout the remaining course of the disease.
Once disease activity has been titrated to the desired therapeutic target such as remission, this state should be maintained continuously (category III). First, only sustained/persistent remission will lead to a halt in damage20 63
; second, any increase in disease activity may reignite the destructive process.64
Caution is needed to govern decisions to reduce (dose or interval of) synthetic or biological DMARD treatment, let alone stopping it. Stopping synthetic DMARD therapy in remission was followed by twice as many flare-ups and difficulties in reintroducing remission.65
Similar studies are not available for the biological agents.
(9) The choice of the (composite) measure of disease activity and the level of the target value may be influenced by consideration of co-morbidities, patient factors and drug-related risks. Measures of disease activity, such as DAS, DAS28, SDAI, CDAI, comprise several variables and some of these may be affected by comorbidities or other patient factors and thus partly invalidate the result obtained (category IV). For example, tender joints and patient's assessment of disease activity may be exaggerated in certain concomitant diseases such as fibromyalgia; or when erythrocyte sedimentation rate (ESR) is employed, diseases with abnormalities of the ESR may influence the score. It is then necessary to interpret the individual components of composite measures. Likewise, the target value may have to be eased in patients with certain comorbidities (or certain comedications); such comorbidities may be chronic infections, renal or hepatic functional impairment, congestive heart failure and others.
(10) The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist. This statement is a separate item to remind all health professionals who care for patients with RA that discussing with the patient the reasons for aiming at the selected target, the therapeutic options available and the strategies planned to reach the target is of utmost importance (category IV). Likewise, it is paramount that a rheumatologist defines the target with the patient, directs the strategy chosen and follows the patient over time, since other professions are less well informed on the disease itself, the benefits and risks of individual agents to treat RA and the risks of comorbidities. In this regard, it may constitute a challenge to inform patients with early RA on the need of intensive medication or patients with relatively mild symptoms on the necessity to adjust therapy. This item therefore also implies the importance of patient education programmes in a specific structured way, as well as the design of programmes to help health professionals address the appropriate issues with their patients.