Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919 631
Background Aiming at therapeutic targets has reduced
the risk of organ failure in many diseases such as
diabetes or hypertension. Such targets have not been
defi ned for rheumatoid arthritis (RA).
Objective To develop recommendations for achieving
optimal therapeutic outcomes in RA.
Methods A task force of rheumatologists and a patient
developed a set of recommendations on the basis of
evidence derived from a systematic literature review
and expert opinion; these were subsequently discussed,
amended and voted upon by >60 experts from various
regions of the world in a Delphi-like procedure. Levels
of evidence, strength of recommendations and levels of
agreement were derived.
Results The treat-to-target activity resulted in 10
recommendations. The treatment aim was defi ned as
remission with low disease activity being an alternative
goal in patients with long-standing disease. Regular
follow-up (every 1–3 months during active disease)
with appropriate therapeutic adaptation to reach the
desired state within 3 to a maximum of 6 months was
recommended. Follow-up examinations ought to employ
composite measures of disease activity which include
joint counts. Additional items provide further details for
particular aspects of the disease. Levels of agreement
were very high for many of these recommendations
Conclusion The 10 recommendations are supposed to
inform patients, rheumatologists and other stakeholders
about strategies to reach optimal outcomes of RA based
on evidence and expert opinion.
Over the past 15 years, rheumatologists have devel-
oped and witnessed many paradigmatic changes
in the treatment of rheumatoid arthritis (RA).
However, these insights have not yet been clearly
formulated. Consequently, many of these changes
have not been brought into effect in most countries
in Europe and other parts of the world.
In many other areas of medicine, treatment tar-
gets have been defi ned to improve outcomes, lead-
ing to a reduction in the risk of organ damage.1–7 In
the care of patients with diabetes, hyperlipidaemia
and hypertension, these aspects have been adopted
widely in practice; doctors order laboratory tests
for cholesterol and triglycerides, blood glucose
and HbA1c levels, check blood pressure and adapt
Treating rheumatoid arthritis to target:
recommendations of an international task force
Josef S Smolen,1,2 Daniel Aletaha,1 Johannes W J Bijlsma,3 Ferdinand C Breedveld,4
Dimitrios Boumpas,5 Gerd Burmester,6 Bernard Combe,7 Maurizio Cutolo,8 Maarten
de Wit,9 Maxime Dougados,10 Paul Emery,11 Alan Gibofsky,12 Juan Jesus Gomez-
Reino,13 Boulos Haraoui,14 Joachim Kalden,15 Edward C Keystone,16 Tore K Kvien,17
Iain McInnes,18 Emilio Martin-Mola,19 Carlomaurizio Montecucco,20 Monika Schoels,2
Desirée van der Heijde,4 for the T2T Expert Committee
For numbered affi liations see
end of article
Dr Josef S Smolen, Department
of Internal Medicine 3, Division
of Rheumatology, Medical
University of Vienna,Waehringer
Guertel 18-20, A-1090 Vienna,
Accepted 12 January 2010
therapy accordingly, and patients know these val-
ues and are aware of the treatment targets.
In RA, joint damage and physical disability are
the major adverse outcomes associated with reduc-
tion in quality of life and premature mortality.8–11
In turn, disease activity—as refl ected by swollen
joint counts, levels of acute phase reactants or by
composite indices of disease activity—is a good
predictor of damage and physical disability.12–20
The paradigmatic changes mentioned above are
related to several factors. First, less joint damage
and better physical function have been unequivo-
cally shown to be a consequence of the early insti-
tution of disease-modifying antirheumatic drugs
(DMARDs) when compared with their delayed
start.21 22 Second, the defi nition of core set vari-
ables and development of composite measures
to assess RA has allowed disease activity to be
assessed reliably.23–26 Third, newly licensed medi-
cations, especially biological agents, have enabled
the attainment of unprecedented outcomes.23 27
Fourth, structured patient management aiming
for a treatment target, usually low disease activity
(LDA), leads to better outcomes than traditional
means of follow-up.28–30
Finally, today remission is an achievable goal
in many patients in clinical trials and clinical
practice,31–34 and rapid attainment of remission
can halt joint damage irrespective of the type of
DMARD, synthetic or biological.20 Nevertheless,
patients enrolled in recent clinical trials have often
received only a very small number of DMARDs
despite long disease duration,35–37 indicating
inadequate treatment, although rheumatologists
appear to be well-informed of recent insights on
The objective of the task force was to formulate
a consensus on a set of recommendations aimed at
improving the management of RA in clinical prac-
tice, thus providing guidance for treatment to target
(‘T2T’). The consensus fi nding was based on evi-
dence obtained from a systematic literature review
which revealed improved outcomes with strategic
This activity comprised several steps. First, a
Steering Committee consisting of rheumatologists
and a patient with RA (the authors), who were
This paper is freely available
online under the BMJ Journals
unlocked scheme, see http://
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919632
identifi ed on the basis of their expertise in treating RA, partic-
ipation in clinical trials, development of consensus statements
and regional distribution across Europe and North America, was
assembled in 2008.
The Steering Committee regarded a comprehensive sys-
tematic literature review as a mandatory initial step to serve
as a basis for consensus on the defi nition of treatment targets.
After defi nition of search questions, the literature review was
performed by a fellow (MS) and is published in detail as an
accompanying paper.39 On this basis, the Steering Committee
formulated a provisional set of recommendations in line with
European League Against Rheumatism (EULAR) standardised
operating procedures40 at a second meeting.
In March 2009 these provisional recommendations were
presented for discussion, amendment and voting to more than
60 experts from Europe, North and Latin America, Japan and
Australia, including fi ve patient representatives. The level of
evidence and strength of each recommendation were deter-
mined41 42 and categorised as A (highest) to D (lowest) on the
basis of the systematic literature review39 as ratifi ed by the
Discussions took place in breakout and plenary sessions at
the expert summit and decisions were made using a modifi ed
Delphi technique.43 Each statement was then voted upon in an
anonymous fashion using a digital system. Statements supported
by ≥75% of votes were accepted while those with ≤25% were
rejected outright. Others were subjected to further discussion
and subsequent voting where ≥67% support or, in an eventual
third round, a majority of ≥50% was needed. Subsequently, the
group voted on the level of agreement with each of the derived
bullet points using a 10-point numerical rating scale (1=do not
agree at all, 10=agree completely).
The statements were then sent by email for fi nal comments.
Only suggestions for improvements of clarity of wording or
removal of redundancies were considered. Proposed changes to
the meaning were not accepted, although they will be mostly
dealt with in the comments to each bullet point.
The fi nal step of the systematic literature review included only
19 full papers and 5 recent abstracts that had targeted therapy as
a research focus. The results are published in detail in an accom-
The statements receiving a majority vote by the Expert
Committee in the fi nal 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 specifi c recommendations
can be based. These items were therefore considered to consti-
tute overarching principles, although they were discussed and
(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 benefi t 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 rheuma-
toid 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 infl ammation is the most important way
to achieve these goals. This principle relates to the fact that
the infl ammatory 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 refl ect 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 rheuma-
toid 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 state-
ment that 91.8% of the experts accepted it.
The overarching principles are followed by the fi nal set of 10
recommendations as formulated by the Expert Committee. The
sequence follows a hierarchical and a logical order; for example,
the fi rst statement was regarded as the most important one,
but other items were also deemed important. The weight of
the individual items is refl ected by the level of evidence, the
strength of recommendation and level of agreement as pre-
sented in table 1.
(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 fre-
quencies 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 sug-
gest that the best outcomes are achieved on attaining remission,
even when compared with LDA.20 47 Moreover, remission can be
achieved in a signifi cant 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 defi ned as the absence of signs and
symptoms of signifi cant infl ammatory disease activity. This
statement is entirely expert-based (category IV). While there
are many defi nitions 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 dis-
ease activity than others.14 52 53 Furthermore, even when swell-
ing cannot be discerned clinically, it may continue to exist at a
subclinical level.54 55 The majority of the experts felt that the def-
inition of remission should not allow for residual clinical disease
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919 633
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 remis-
sion. The term remission of ‘infl ammatory disease activity’ was
therefore coined, given that joint swelling and C-reactive pro-
tein (CRP) but not isolated tenderness or pain are associated
with progression of joint damage.13 The term ‘signifi cant’ makes
clear that a higher than very small level of residual infl ammatory
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 refl ects infl ammatory
disease activity (see also statement 9). The fi nal voting achieved
approval by 76% of the experts. An ACR/EULAR initiative on
defi ning remission is currently ongoing.
(3) While remission should be a clear target, based on
available evidence low disease activity may be an accept-
able alternative therapeutic goal, particularly in established
long-standing disease. This statement confi rms 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 forc-
ing 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 alterna-
tive target, it is important to sustain it (as was stated for remis-
sion; see also point 8).
(4) Until the desired treatment target is reached, drug ther-
apy should be adjusted at least every 3 months. Clinical trials
suggest that the maximal clinical benefi t 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 base-
line has to be taken into account in individual patients, espe-
cially in those with high disease activity at the start of therapy.
Dose adaptation of existing medication may be suffi cient for
further benefi t 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 docu-
mented regularly, as frequently as monthly for patients with
high/moderate disease activity or less frequently (such as every
Box 1 Recommendations
(A) The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist.
(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.
(C) Abrogation of infl ammation is the most important way to achieve these goals.
(D) 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:
(1) The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.
(2) Clinical remission is defi ned as the absence of signs and symptoms of signifi cant infl ammatory disease activity.
(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.
(4) Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months.
(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 3–6 months) for patients in sustained low disease activity or remission.
(6) The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to
guide treatment decisions.
(7) Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing
composite measures of disease activity.
(8) The desired treatment target should be maintained throughout the remaining course of the disease.
(9) The choice of the (composite) measure of disease activity and the level of the target value may be infl uenced by consideration of
co-morbidities, patient factors and drug-related risks.
(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.
Table 1 Evidence, agreement and votes for each of the
Percentage of votes at
last ballot (number of
*For several of the items the number of votes relates to the details of the wording,
while the inclusion of the statement has been agreed upon at earlier ballots.
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919634
experienced in reading these images. In addition to joint dam-
age, continuing impairment of physical function despite achieve-
ment of the targeted disease activity level may also necessitate
a therapeutic change (category IV). However, in some patients,
functional impairment may not be suffi ciently captured by func-
tional measures, particularly in individuals with certain occu-
pations who experience reduction in functioning and personal
working capacity by involvement of a specifi c joint, necessitat-
ing a change of treatment even if otherwise in LDA. Thus, spe-
cial treatment options may be needed for optimal caretaking of
(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 (cat-
egory 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
fl are-ups and diffi culties 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 infl uenced by consider-
ation 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 invali-
date 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 fi bromyalgia; or when
erythrocyte sedimentation rate (ESR) is employed, diseases
with abnormalities of the ESR may infl uence 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 impor-
tance (category IV). Likewise, it is paramount that a rheuma-
tologist defi nes 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 benefi ts 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 edu-
cation programmes in a specifi c structured way, as well as the
design of programmes to help health professionals address the
appropriate issues with their patients.
Evidence and agreement
For all statements, the category of evidence and the strength
of recommendation have been determined in accordance with
the systematic literature review39 and are shown in table 1. In
addition, the level of agreement as determined during the fi nal
3–6 months) 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 suffi cient. The focus here is on the term ‘sustained’, indi-
cating that even if a particular desired state is reached, more fre-
quent control examinations are necessary initially to ensure that
the state does not change (ie, rebound) rapidly. The fi rst exam-
ple 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 reactiva-
tion of RA which could be detected early with 3-monthly exam-
inations. Among patients who are in sustained remission and
are adequately informed to see their rheumatologist earlier upon
status changes, annual control examinations may suffi ce.
(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 (cate-
gory 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 mea-
sures should include joint assessments, because the joints consti-
tute the ‘organ’ involved in RA and using measures that do not
contain joint counts may lack face validity or not be accurate
(infl uenced 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 simplifi ed 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 dis-
ease 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 var-
ies 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 instru-
ments 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 suffi ciently
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919635
The overall targeted therapeutic approach is summarised in a
simplifi ed form in fi gure 1.
While several items provide additional guidance in relation
to the major statements (1) and (3), three additional recom-
mendations stick out in the context of current practice, namely
numbers (4), (5) and (6). Recommendation (6) received one of
the highest votes and levels of agreement and calls for the need
to use composite disease activity measures which include joint
counts in the follow-up of patients with RA. Indeed, 93.4% of
the experts voted to include joint assessments. Items (4) and (5)
recommend adjustment of therapy at least every 3 months if
the therapeutic target is not reached and to assess patients with
higher disease activity states within a shorter term and thus up
to monthly to allow timely adaptation of therapy.
These recommendations come at a time when both remis-
sion and LDA are achievable goals with the current therapeu-
tic armamentarium.31 32 The recommendations are primarily
meant to provide guidance on ways towards this goal, as seen
by experts. They are aimed at all stakeholders: patients who
are informed by these statements on the optimal strategies to
prevent or contain damage and disability; rheumatologists and
other health professionals who may further their drive to do the
best for the patients; and also offi cial bodies such as govern-
ments or payers which may wish to use this document as a ref-
erence for the assessment of success in treating patients with RA
in their environment.
Many sets of recommendations have been developed in the
past for treating early and established RA.66–68 However, none
of these comprised the important aspects of specifi cally defi ning
the treatment target for RA and detailing the ways to achieve
the therapeutic goal. This is now provided with the present set
of recommendations. Bringing them into practice will enable the
prevention of progression of joint damage and reversal of physi-
cal disability, a pivotal goal for the new decade.
Recommendations such as those presented here usually elicit
a number of research questions. This research agenda is implic-
itly indicated by the contents of all statements with category
IV evidence; it would be important to perform studies which
examine the evidence for these expert opinions. On the other
hand, many of these category IV recommendations are based
on a large array of indirect evidence so it would also be worth-
while to look into the possibility of improving the appraisal of
ballot at the Expert Committee meeting is provided (table 1).
For reasons of transparency, we also show the number of ballots
needed for the fi nal formulation of the statements as well as the
percentage of participants who voted for that formulation. The
level of agreement ranged from 7.8 to 9.7 on a 10-point scale.
The recommendations presented are based on a combination of
a systematic literature review and expert opinion.
The process was initiated by a Steering Committee which
adhered to the EULAR operating procedures for the develop-
ment of recommendations.40 It was fi nalised after discussions
by more than 60 experts from all over the world. Importantly,
fi ve patients were among these experts. The very high level of
agreement on most of the statements is also noteworthy and,
given that the Expert Group came from so many countries and
regions of the world, this agreement implies a broad interna-
tional recognition and consensus.
The recommendations were formulated with the optimal out-
come of RA in practice in mind. They do not account for poten-
tial fi nancial constraints or access to particular therapies, since
no one particular type of therapy was the focus of attention but
rather the therapeutic target that needs to be attained, indepen-
dent of accessibility. However, with different accessibilities, dif-
ferent proportions of patients may be able to attain the desired
target, although it has been shown that adhering to treatment
strategies may signifi cantly improve outcomes even when easily
accessible and affordable therapies are employed.28–30
As its major conclusion, the Expert Committee was almost
unanimous that remission must be the ultimate therapeutic
goal in RA. However, since no therapeutic trial has studied
this approach—for instance, by comparing it with the aim of
achieving LDA—this recommendation is actually expert-based
although it is supported by a large body of circumstantial evi-
dence. True evidence exists for the benefi cial effect of treating
RA to a target of LDA in a structured strategic way when com-
pared with non-structured therapy.28 29 However, the Expert
Committee felt that, while being an important step and a major
alternative goal, reaching LDA could only pertain to patients
with long-standing RA whose disease may have become refrac-
tory to therapeutic intervention. In contrast, in early RA, LDA
should only be an intermediate step on the way to remission.
Figure 1 Algorithm for treating rheumatoid arthritis (RA) to target based on the recommendations provided in box 1 and discussed in more detail
in the explanatory notes. Indicated as separate threads are the main target (remission and sustained remission) and the alternative target (low
disease activity in patients with long-term disease), but the approaches to attain the targets and sustain them are essentially identical. Adaptation of
therapy should usually be done by performing control examinations with appropriate frequency and using composite disease activity measures which
comprise joint counts.
of disease activity
every 1–3 months
disease activity about
every 3–6 months
if state is lost
if state is lost
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919636
6. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in
men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207.
7. Mora S, Musunuru K, Blumenthal RS. The clinical utility of high-sensitivity C-reactive
protein in cardiovascular disease and the potential implication of JUPITER on current
practice guidelines. Clin Chem 2009;55:219–28.
8. Mitchell DM, Spitz PW, Young DY, et al. Survival, prognosis, and causes of death in
rheumatoid arthritis. Arthritis Rheum 1986;29:706–14.
9. Pincus T, Callahan LF, Sale WG, et al. Severe functional declines, work disability, and
increased mortality in seventy-fi ve rheumatoid arthritis patients studied over nine
years. Arthritis Rheum 1984;27:864–72.
10. Wolfe F, Michaud K, Gefeller O, et al. Predicting mortality in patients with rheumatoid
arthritis. Arthritis Rheum 2003;48:1530–42.
11. Yelin E, Trupin L, Wong B, et al. The impact of functional status and change in
functional status on mortality over 18 years among persons with rheumatoid arthritis.
J Rheumatol 2002;29:1851–7.
12. Dawes PT, Fowler PD, Clarke S, et al. Rheumatoid arthritis: treatment which controls
the C-reactive protein and erythrocyte sedimentation rate reduces radiological
progression. Br J Rheumatol 1986;25:44–9.
13. van Leeuwen MA, van der Heijde DM, van Rijswijk MH, et al. Interrelationship of
outcome measures and process variables in early rheumatoid arthritis. A comparison
of radiologic damage, physical disability, joint counts, and acute phase reactants. J
14. Aletaha D, Ward MM, Machold KP, et al. Remission and active disease in
rheumatoid arthritis: defi ning criteria for disease activity states. Arthritis Rheum
15. Smolen JS, Van Der Heijde DM, St Clair EW, et al. Predictors of joint damage in
patients with early rheumatoid arthritis treated with high-dose methotrexate with
or without concomitant infl iximab: results from the ASPIRE trial. Arthritis Rheum
16. van der Heijde DM, van Riel PL, van Leeuwen MA, et al. Prognostic factors for
radiographic damage and physical disability in early rheumatoid arthritis. A prospective
follow-up study of 147 patients. Br J Rheumatol 1992;31:519–25.
17. Combe B, Cantagrel A, Goupille P, et al. Predictive factors of 5-year health
assessment questionnaire disability in early rheumatoid arthritis. J Rheumatol
18. Welsing PM, Landewé RB, van Riel PL, et al. The relationship between disease
activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal
analysis. Arthritis Rheum 2004;50:2082–93.
19. Drossaers-Bakker KW, de Buck M, van Zeben D, et al. Long-term course and
outcome of functional capacity in rheumatoid arthritis: the effect of disease activity
and radiologic damage over time. Arthritis Rheum 1999;42:1854–60.
20. Smolen JS, Han C, van der Heijde DM, et al. Radiographic changes in rheumatoid
arthritis patients attaining different disease activity states with methotrexate
monotherapy and infl iximab plus methotrexate: the impacts of remission and tumour
necrosis factor blockade. Ann Rheum Dis 2009;68:823–7.
21. Lard LR, Visser H, Speyer I, et al. Early versus delayed treatment in patients with
recent-onset rheumatoid arthritis: comparison of two cohorts who received different
treatment strategies. Am J Med 2001;111:446–51.
22. Nell VP, Machold KP, Eberl G, et al. Benefi t of very early referral and very early
therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid
arthritis. Rheumatology (Oxford) 2004;43:906–14.
23. Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid
arthritis. Lancet 2007;370:1861–74.
24. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology
preliminary core set of disease activity measures for rheumatoid arthritis clinical trials.
The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis
25. van der Heijde DM, van ‘t Hof M, van Riel PL, et al. Development of a disease
activity score based on judgment in clinical practice by rheumatologists. J Rheumatol
26. Smolen JS, Breedveld FC, Schiff MH, et al. A simplifi ed disease activity index
for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford)
27. Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defi ned as a
therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med
28. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for
rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial.
29. Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with
methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted
Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial).
Ann Rheum Dis 2007;66:1443–9.
30. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of
treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med
31. Mierau M, Schoels M, Gonda G, et al. Assessing remission in clinical practice.
Rheumatology (Oxford) 2007;46:975–9.
evidence under such terms and circumstances by assigning spe-
Author affi liations 1 Department of Internal Medicine 3, Division of Rheumatology,
Medical University of Vienna, Vienna, Austria
2 2nd Department of Medicine, Center for Rheumatic Diseases, Hietzing Hospital,
3 University Medical Center Utrecht, Department of Rheumatology and Clinical
Immunology, Utrecht, The Netherlands
4 Leiden University Medical Center, Department of Rheumatology, Leiden, The
5 Department of Medicine, Faculty of Medicine, University of Crete, Crete, Greece
6 Humboldt University, Department of Rheumatology and Clinical Immunology,
Charite Hospital, Berlin, Germany
7 Service d’Immuno-Rhumatologie, Montpellier University, Lapeyronie Hospital,
8 Research Laboratory and Academic Clinical Unit of Rheumatology, Department of
Internal Medicine, University of Genova, Genova, Italy
9 EULAR Standing Committee of People with Arthritis/Rheumatism in Europe, Zurich,
10 René Descartes University, Cochin Hospital, Department of Rheumatology B, Paris,
11 Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK
12 Weill Medical College, Cornell University Hospital for Special Surgery, New York, USA
13 Santiago University Clinical Hospital, NEIRID Laboratory, Santiago de Compostela,
14 Institut de rhumatologie de Montréal, Montréal, QC, Canada
15 Fiebiger Center, Friedrich-Alexander University, Erlangen, Germany
16 University of Toronto, Toronto, Canada
17 Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway;
18 University of Glasgow, Glasgow, UK
19 La Paz Hospital, Madrid, Spain
20 Department of Rheumatology, University of Pavia, IRCCS Policlinico S Matteo,
Additional members of the T2T Expert Committee Jose Louis Andreu (Spain),
Martin Bergman (USA), Harald Burkhardt (Germany), Vivian Bykerk (Canada), Mario
Cardiel (Mexico), Filip Codruta (Romania), Hector Corominas (Spain), Alexandros
Drosos (Greece), Patrick Durez (Belgium), Hani ElGabalawy (Canada), Cristina Estrach
(UK), Bruno Fautrel (France), Gianfranco Ferracioli (Italy), Roy Fleischman (USA), Joao
Eurico Fonseca (Portugal), Cem Gabay (Switzerland), Clara Gjesdal (Norway), Laure
Gossec (France), Winfried Graninger (Austria), Espen Haavardsholm (Norway), Sesilie
Halland (Norway), Pekka Hannonen (Finland), Jamie Henderson (Canada), Jonathan
Kay (USA), Wenche Koldingsnes (Norway), Marios Kouloumas (Cyprus), Ieda Maria
Laurindo (Brazil), Marjatta Leirisalo-Repo (Finland), Carlomaurizio Montecucco (Italy),
Peter Nash (Australia), Mikkel Ostergaard (Denmark), Andrew Ostor (UK), Karel
Pavelka (Czech Republic), José Peirera da Silva (Portugal), Kim Horslev Peterson
(Denmark), Duncan Porter (UK), Enid Quest (UK), Evangelos Romas (Australia),
Marieke Scholte (The Netherlands), Luigi Sinigaglia (Italy), Tuulikki Sokka (Finland),
Ewa Stanislawska (Poland), Tsutomu Takeuchi (Japan), Guillermo Tate (Argentina),
Athanasios Tzioufas (Greece), Peter Villiger (Switzerland).
Competing interests This work was supported by an unrestricted educational grant
from Abbott Immunology. Abbott affi liates were not involved in the programme or any
voting. At the end of the voting process, the Expert Committee was asked to vote
in an anonymous fashion if they felt they had been infl uenced by the sponsoring of
the event by Abbott. This ballot resulted in an agreement of 8.7/10 that they did not
consider that the fact that Abbott was sponsoring this programme created a bias. The
handling editor was F Berenbaum.
Provenance and peer review Not commissioned; externally peer reviewed.
1. Rachmani R, Slavacheski I, Berla M, et al. Treatment of high-risk patients with
diabetes: motivation and teaching intervention: a randomized, prospective 8-year
follow-up study. J Am Soc Nephrol 2005;16(Suppl 1):S22–6.
2. Eeg-Olofsson K, Cederholm J, Nilsson PM, et al. Glycemic and risk factor control in
type 1 diabetes: results from 13,612 patients in a national diabetes register. Diabetes
3. Patel A, MacMahon S, Chalmers J, et al. Effects of a fi xed combination of perindopril
and indapamide on macrovascular and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet
4. Egan BM, Lackland DT, Cutler NE. Awareness, knowledge, and attitudes of older
americans about high blood pressure: implications for health care policy, education,
and research. Arch Intern Med 2003;163:681–7.
5. Pearson TA. The epidemiologic basis for population-wide cholesterol reduction in the
primary prevention of coronary artery disease. Am J Cardiol 2004;94:4F–8F.
Recommendations Download full-text
Ann Rheum Dis 2010;69:631–637. doi:10.1136/ard.2009.123919637
51. Aletaha D, Landewe R, Karonitsch T, et al. Reporting disease activity in clinical trials
of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.
Arthritis Rheum 2008;59:1371–7.
52. van der Heijde D, Klareskog L, Boers M, et al. Comparison of different defi nitions
to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis
53. Mäkinen H, Kautiainen H, Hannonen P, et al. Is DAS28 an appropriate tool to assess
remission in rheumatoid arthritis? Ann Rheum Dis 2005;64:1410–13.
54. Brown AK, Conaghan PG, Karim Z, et al. An explanation for the apparent dissociation
between clinical remission and continued structural deterioration in rheumatoid
arthritis. Arthritis Rheum 2008;58:2958–67.
55. Brown AK, Quinn MA, Karim Z, et al. Presence of signifi cant synovitis in rheumatoid
arthritis patients with disease-modifying antirheumatic drug-induced clinical
remission: evidence from an imaging study may explain structural progression.
Arthritis Rheum 2006;54:3761–73.
56. Aletaha D, Machold KP, Nell VP, et al. The perception of rheumatoid arthritis core
set measures by rheumatologists. Results of a survey. Rheumatology (Oxford)
57. Soubrier M, Puéchal X, Sibilia J, et al. Evaluation of two strategies (initial
methotrexate monotherapy vs its combination with adalimumab) in management of
early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford)
58. Bruynesteyn K, Landewé R, van der Linden S, et al. Radiography as primary outcome
in rheumatoid arthritis: acceptable sample sizes for trials with 3 months’ follow up.
Ann Rheum Dis 2004;63:1413–8.
59. Goldsmith CH, Smythe HA, Helewa A. Interpretation and power of a pooled index.
J Rheumatol 1993;20:575–8.
60. van der Heijde DM, van’t Hof MA, van Riel PL, et al. Validity of single variables and
composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum
61. Aletaha D, Smolen JS. The defi nition and measurement of disease modifi cation in
infl ammatory rheumatic diseases. Rheum Dis Clin North Am 2006;32:9–44, vii.
62. van der Heijde D, Landewé R, Klareskog L, et al. Presentation and analysis of data
on radiographic outcome in clinical trials: experience from the TEMPO study. Arthritis
63. Aletaha D, Funovits J, Breedveld FC, et al. Rheumatoid arthritis joint progression in
sustained remission is determined by disease activity levels preceding the period of
radiographic assessment. Arthritis Rheum 2009;60:1242–9.
64. Molenaar ET, Voskuyl AE, Dinant HJ, et al. Progression of radiologic damage
in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum
65. ten Wolde S, Breedveld FC, Hermans J, et al. Randomised placebo-
controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet
66. Combe B, Landewe R, Lukas C, et al. Eular recommendations for the management
of early arthritis: Report of a task force of the European Standing Committee for
International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
67. Saag KG, Teng GG, Patkar NM, et al.American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic disease-modifying
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84.
68. National Collaborating Centre for Chronic Conditions. Rheumatoid arthritis:
national clinical guideline for management and treatment in adults. London: Royal
College of Physicians, February 2009.
32. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with
a combination of methotrexate and etanercept in active, early, moderate to severe
rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.
33. Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann
Rheum Dis 1995;54:944–7.
34. Sokka T, Hetland ML, Mäkinen H, et al. Remission and rheumatoid arthritis:
Data on patients receiving usual care in twenty-four countries. Arthritis Rheum
35. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves
treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour
necrosis factor biologicals: results from a 24-week multicentre randomised placebo-
controlled trial. Ann Rheum Dis 2008;67:1516–23.
36. Smolen JS, Landewé RB, Mease P, et al. Effi cacy and safety of certolizumab pegol
plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. Ann Rheum Dis
37. Sokka T, Kautiainen H, Pincus T, et al. Disparities in rheumatoid arthritis disease
activity according to gross domestic product in 25 countries in the QUEST-RA
database. Ann Rheum Dis 2009;68:1666–72.
38. Schoels M, Aletaha D, Smolen JS, et al. Follow-up standards and treatment targets
in Rheumatoid Arthritis (RA): results of a questionnaire at the EULAR 2008. Ann
Rheum Dis 2010;69:575–8.
39. Schoels M, Wong J, Scott DL, et al. Evidence for treating rheumatoid arthritis to
target: results of a systematic literature search. Ann Rheum Dis 2010;in press.
40. Dougados M, Betteridge N, Burmester GR, et al. EULAR standardised operating
procedures for the elaboration, evaluation, dissemination, and implementation of
recommendations endorsed by the EULAR standing committees. Ann Rheum Dis
41. Shekelle PG, Woolf SH, Eccles M, et al. Clinical guidelines: developing guidelines.
42. The AGREE Collaboration. Development and validation of an international appraisal
instrument for assessing the quality of clinical practice guidelines: the AGREE project.
Qual Safe Health Care 2003;12:18–23.
43. Visser K, van der Heijde D. Optimal dosage and route of administration of
methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum
44. Welsing PM, van Gestel AM, Swinkels HL, et al. The relationship between disease
activity, joint destruction, and functional capacity over the course of rheumatoid
arthritis. Arthritis Rheum 2001;44:2009–17.
45. Aletaha D, Smolen J, Ward MM. Measuring function in rheumatoid arthritis:
Identifying reversible and irreversible components. Arthritis Rheum 2006;54:2784–92.
46. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy
with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo
trial group. Lancet 1999;353:1568–73.
47. Aletaha D, Funovits J, Smolen JS. The importance of reporting disease activity states
in rheumatoid arthritis clinical trials. Arthritis Rheum 2008;58:2622–31.
48. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid
arthritis. Arthritis Rheum 1981;24:1308–15.
49. Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: agreement
of the disease activity score (DAS28) with the ARA preliminary remission criteria.
Rheumatology (Oxford) 2004;43:1252–5.
50. Aletaha D, Landewe R, Karonitsch T, et al. Reporting disease activity in clinical trials
of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Ann
Rheum Dis 2008;67:1360–4.