EULAR recommendations for the management of early
arthritis: report of a task force of the European Standing
Committee for International Clinical Studies Including
B Combe, R Landewe, C Lukas, H D Bolosiu, F Breedveld, M Dougados, P Emery, G Ferraccioli,
J M W Hazes, L Klareskog, K Machold, E Martin-Mola, H Nielsen, A Silman, J Smolen, H Yazici
............................................................... ............................................................... .....
See end of article for
Professor Bernard Combe,
Lapeyronie – 34295
Montpellier cedex 5, France;
Accepted 4 January 2006
Published Online First
5 January 2006
Ann Rheum Dis 2007;66:34–45. doi: 10.1136/ard.2005.044354
Objective: To formulate EULAR recommendations for the management of early arthritis.
Methods: In accordance with EULAR’s ‘‘standardised operating procedures’’, the task force pursued an
evidence based approach and an approach based on expert opinion. A steering group comprised of 14
rheumatologists representing 10 European countries. The group defined the focus of the process, the target
population, and formulated an operational definition of ‘‘management’’. Each participant was invited to
propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen
issues for further research were selected by use of a modified Delphi technique. A systematic literature search
was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations
was proposed on the basis of the research questions and the results of the literature search.. The strength of
the recommendations was based on the category of evidence and expert opinion.
Results: 15 research questions, covering the entire spectrum of ‘‘management of early arthritis’’, were
formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for
the management of early arthritis were selected and presented with short sentences. The selected statements
included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis
(information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of
the disease process). On the basis of expert opinion, 11 items were identified as being important for future
Conclusions: 12 key recommendations for the management of early arthritis or early rheumatoid arthritis
were developed, based on evidence in the literature and expert consensus.
associated with rheumatoid factor or with positive results in
tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies.
An early diagnosis is complicated by the absence of specific
tests and diagnostic criteria.1In practice, early inflammatory
arthritis is often undifferentiated.2Early arthritis may develop
into established rheumatoid arthritis or into another definite
arthropathy, may resolve spontaneously, or may remain
undifferentiated. For an improved evaluation of the diagnosis
and outcome in arthritis, it has been proposed that the first step
should be to recognise the presence of inflammatory arthritis,
the next should be to exclude definite diagnoses of arthritis (for
example, systemic lupus erythematosus (SLE), psoriatic arthri-
tis, seronegative spondylarthropathies, and so on), and the final
step should be to estimate the risk of developing persistent or
erosive irreversible arthritis and to propose an optimal
therapeutic strategy.2 3Although the prognosis of early arthritis
is still a difficult issue to address, a combination of clinical
biological and radiographic indices may help to predict the
outcome of arthritis with acceptable accuracy.
In the past few years the development of effective new
treatments and the validation of new concepts have highlighted
the need to develop guidelines for the management of early
arthritis. New diseasemodifying
(DMARDs) and DMARD combinations have shown their ability
he definition of rheumatoid arthritis is sometimes impre-
cise, but the term is normally used to describe a
symmetrical, persistent, and destructive polyarthritis often
to slow disease progression.4–7Furthermore, biological treat-
ments have resulted in rapid and sustained disease control,
associated with an impressive prevention of joint destruction.8–
10There is now a body of evidence about early rheumatoid
arthritis to support the very early use of effective DMARDs—
preferably before the first radiographic evidence of erosions—to
prevent further joint damage and disability.11–13The assessment
and close monitoring of patients with early arthritis seem
crucial for the optimisation of therapeutic strategies.7 14In
addition, management of early arthritis includes more than
drug treatment alone, and an ideal treatment proposal should
be based on an appropriate assessment of the prognosis in the
A potential limitation is that management of early rheuma-
toid arthritis varies widely among countries, doctors (rheuma-
tologists or general practitioners), and settings (university
hospital, private practice, and so on), owing to differences in
Abbreviations: ACR, American College of Rheumatology; ASPIRE, Active
Controlled Study of Patients Receiving Infliximab for Treatment of
Rheumatoid Arthritis; DAS, disease activity score; DMARD, disease
modifying antirheumatic drug; ESCISIT, European Standing Committee for
International Clinical Studies Including Therapeutics; EULAR, European
League Against Rheumatism; RCT, randomised controlled trial; TEMPO,
Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes;
TICORA, Tight Control for Rheumatoid Arthritis study; TNF, tumour necrosis
culture, health care reimbursement policies, patients’ and
physicians’ preferences, and similar issues.
The objective of this task force was to formulate, and obtain
consensus on, a set of recommendations aiming at improving
the management of early arthritis. The European League
Against Rheumatism (EULAR) standardised operating proce-
dures for the elaboration, evaluation, dissemination, and
implementation of recommendations15has served as a frame-
work to achieve this goal.
The EULAR standardised operating procedures prescribe a
discussion among experts in the field about the focus, the target
population, and an operational definition of the term ‘‘manage-
ment’’, followed by consensus building based on currently
available literature (evidence based), as well as on expert
opinion, in order to arrive at a consensus on a set of
recommendations.15An international expert committee should
be formed as a platform for these discussions.
The expert committee
The expert committee comprised 14 rheumatologists and one
research fellow (CL) from 10 European countries. All these
experts have been involved in early arthritis clinics or early
arthritis trials, or both, for many years. After discussion, the
group voted to define the focus of the process (early undiffer-
entiated arthritis, with a certain propensity to become persistent
and erosive arthritis), and the target population (rheumatolo-
gists, GPs, medical students), and to obtain an operational
definition of the term ‘‘management’’ (‘‘All organisational,
diagnostic, medical and educational procedures related to
patients seeking help for arthritis of a peripheral joint’’).
Fifteen specific issues for further research were selected by
use of a modified Delphi technique. The selected topics included
recognition of arthritis, referral, diagnosis, prognosis, classifica-
tion, information, education, non-pharmacological interven-
tions, pharmacological treatments, and monitoring of the
disease process (table 1). These research questions were
adjusted for further literature research if appropriate, and key
index terms were derived by three of us (BC, RL, CL).
Evidence based approach
A systematic search of PubMed, Medline, Embase, CINAHL,
and the Cochrane library was carried out. All publications in
English language up to January 2005 were included. A further
selection was based on reading the title or the abstract. As the
topics varied widely, no systematic scoring system was used.
Categories of evidence were applied according to Shekelle et
al.16They include a hierarchy of evidence in descending order by
study design (table 2). Questions posed were answered with the
use of the best available evidence. An estimation of treatment
effect was assessed when possible, by calculating the effect size
and 95% confidence interval (CI) for validated continuous
outcome measures of disease activity and structural damage
compared with placebo or active control. We considered an
effect size around 0.2 as small, around 0.5 as moderate, and
greater than 0.8 as large.
Expert opinion approach
The results of the literature search were summarised, aggre-
gated, and disseminated to the expert committee with the
accompanying levels of evidence. A set of 15 draft recommen-
dations was prepared by three of us (BC, RL, CL), which was a
compilation of the research questions (expert opinion) and the
results of the literature search (evidence based). This set of
draft recommendations formed the basis for discussion during
a second meeting. After discussion, voting, and adjusting the
formulation, the expert committee eventually arrived at 12 final
recommendations for the management of early arthritis.
Further, the expert committee proposed topics for a research
agenda. The recommendations are presented in brief sentences.
The strength of the recommendations, according to the category
of evidence (table 3) and the knowledge of the experts, was
proposed by two members of the committee (BC, RL), graded
from A (highest) to D (lowest),16and ratified by the expert
The relevance of the recommendations was checked accord-
ing to the AGREE instrument (www.agreecollaboration.org).
Evidence based approach
The general search identified a large number of publications
related to arthritis. After deleting publications and articles
irrelevant to the research questions, 284 manuscripts were
further evaluated. They included reports of meta-analyses,
randomised controlled trials (RCTs), controlled trials, observa-
tional studies, comparative studies, case–control studies, cross
Selected research questions for a literature search
l What is the clinical presentation of early arthritis that a GP should
recognise in order to refer to the rheumatologist?
l How early should patients with arthritis be referred to a medical
l What are the diagnostic procedures that need to be undertaken in order
to confirm early synovitis?
l What are the minimum diagnostic procedures necessary in a patient
with early arthritis in order to exclude other diseases?
l What are the prognostic procedures that need to be carried out in a
patient with confirmed early arthritis?
l Can we substitute distinct disease classifications (rheumatoid arthritis,
psoriatic arthritis) with prognostic eponyms such as ‘‘persistent’’ or
‘‘persistent and erosive’’?
l What is the efficacy of non-pharmaceutical interventions compared to
efficacy of drug treatment in early arthritis? (Note: most findings are in
established rheumatoid arthritis.)
l How should information be given (route of administration) in early
l Are NSAIDs (classical and/or coxibs) more efficacious (efficacy in
relation to toxicity) than analgesics (including opioids) in early arthritis?
(Note: there have been no trial in early arthritis.)
l Is there a place for (intra-articular and/or systemic) corticosteroids in the
treatment of early arthritis?
l Is an early treatment start with DMARDs better than a delayed treatment
start in early arthritis?
l Is aggressive treatment (for example, combination therapy with or
without corticosteroids) better than less aggressive treatment
(monotherapy) in early arthritis?
l Can an optimal starting point (for example, X weeks of arthritis) be
defined in early arthritis? (Is the starting point dependent on the
l Can consensus be obtained with regard to the choice of DMARD
strategies in early arthritis?
l Can consensus be obtained on whether or not disease activity,
radiographic progression, and function should be monitored, and if yes,
how (by what instruments) and how often?
DMARD, disease modifying antirheumatic drug; NSAID, non-steroidal anti-
Categories of evidence16
Ia Evidence from meta-analyses of randomised controlled trials
Ib Evidence from at least one randomised controlled trial
IIa Evidence from at least one controlled study without randomisation
IIb Evidence from at least one type of quasi-experimental study
III Evidence from descriptive studies, such as comparative, correlation, or
IV Evidence from expert committee reports or opinions or clinical experience
of respected authorities, or both
EULAR recommendations for early arthritis 35
sectional surveys, systematic reviews, and expert reports or
opinions. As original publications about early arthritis or early
rheumatoid arthritis were missing on some topics such as non-
pharmacological treatment or symptomatic treatments, some
publications relevant to established rheumatoid arthritis,
including 10 Cochrane reviews, were also examined.
Assessment of propositions
Table 4 summarises the final set of 12 recommendations as
proposed by the expert committee. The strength of each
recommendation is presented in table 5. The recommendations
are ordered by topic, with no weighting according to order.
Arthritis is characterised by the presence of joint swelling,
associated with pain or stiffness. Patients presenting with
arthritis of more than one joint should be referred to and
seen by a rheumatologist, ideally within six weeks after the
onset of symptoms.
Although the level of evidence supporting the content of this
recommendation is rather low (category III or IV), there was
general agreement that a recommendation regarding the
recognition of arthritis and about early referral should be
included. Joint swelling not caused by trauma or bony swelling
should suggest a diagnosis of early arthritis, preferably if it
includes involvement of at least two joints, with or without
morning stiffness of more than 30 minutes’ duration, and/or
involvement of metacarpophalangeal and/or metatarsophan-
geal joints.17–19Involvement of hand and foot joints is suggested
by a positive ‘‘squeeze test’’18 20(category III).
One systematic review,21several randomised controlled
studies,22–25and a number of prospective observational stu-
dies11–13 26showed a better outcome of arthritis when treatment
is started earlier. Evaluation of the impact of a delay in the start
of treatment on the outcome of arthritis is difficult. From
evidence in published reports and the clinical experience of the
members of the committee, it was recommended that drug
treatment by a rheumatologist should start within a relatively
short period after the onset of complaints, which justifies to the
committee the wording ‘‘ideally within six weeks’’ in this
recommendation. Several comparative studies27–33have shown a
better functional status and earlier DMARD start in cases
treated by rheumatologists, which further supports the view
that patients with clinical presentations suggestive of arthritis
should be referred to a rheumatologist early.18
Clinical examination is the method of choice for detecting
arthritis. In doubtful cases, ultrasound, power Doppler, and
MRI may be helpful in detecting synovitis.
The expert committee was unanimous in their view that clinical
examination is still the gold standard in detecting synovitis. This
does not mean that imaging methods are incapable of detecting
synovitis, and may even do so with greater sensitivity.
Ultrasonography and power Doppler techniques allow the
assessment of synovitis, by detecting thickening of the synovial
membrane of inflamed joints and bursae or tendon sheaths. Two
controlled studies have suggested that ultrasonography is more
sensitive than clinical examination for detecting synovitis in
knee joints.34 35However, ultrasonography and power Doppler
have hardly been used at all for detecting synovitis of the small
joints of the hands and feet36(category III), and scientific
evidence of the clinical value of ultrasonographyin early arthritis
is limited. In one controlled study and in a few comparative
studies, MRI has been shown to be more sensitive than clinical
examination and radiography for the detection of synovitis and
erosions in early rheumatoid arthritis.37–39There is evidence that
MRI findings (for example, synovitis, bone oedema, and bone
erosions) may predict subsequent radiographic progression.40 41
However, the level of evidence is rather low, and changes
resembling mild synovitisorsmall bone erosions are occasionally
found in the joints of healthy subjects, raising questions about
the specificity of this technique.42Issues of standardisation and
reliability of MRI have been addressed and are ongoing.
Altogether, the expert committee thought that MRI and
ultrasonography are promising techniques that may become
valuable in the diagnosis, prognosis, and therapeutic monitor-
ing of early arthritis. However, their use is still experimental
and sometimes controversial, and their merits in routine
clinical practice have yet to be defined.
Exclusion of other diseases than rheumatoid arthritis requires
careful history taking and clinical examination, and ought to
include at least the following laboratory tests: complete blood
cell count, urinary analysis, transaminases, and antinuclear
This recommendation is entirely expert based. As experimental
evidence from appropriately designed clinical trials was
unavailable, the group considered that ‘‘good clinical practice’’
and a ‘‘high level of training’’ sufficed to address this topic, so
no literature search was carried out. In order to exclude patients
in whom the arthritis has differentiated into diseases other
than rheumatoid arthritis which may have a different prognosis
and treatment (such as connective tissue diseases, reactive
arthritis, infectious arthritis, and others), the group proposed
that the minimum diagnostic procedures should include a
careful history and clinical examination, a complete blood cell
count, transaminase analysis, urinary analysis, and anti-
nuclear antibody testing.
The diagnostic procedure may also include tests for uric acid
and Lyme disease, parvovirus infection, urethral or cervical
swab cultures, anti-bacterial serology, tests for hepatitis B or C,
or chest x ray, according to the context and the country. Tests
for erythrocyte sedimentation rate (ESR), C reactive protein
(CRP), rheumatoid factor, and anti-cyclic citrullinated peptide
(anti-CCP) antibodies were excluded here, as these tests are
related to the extent of the inflammation and the (prognostic)
severity of the arthritis rather than to other diagnoses.
In every patient presenting with early arthritis to the
rheumatologist, the following factors predicting persistent
Strength of recommendations16
A Directly based on category I evidence
B Directly based on category II evidence or extrapolated recommendations
from category I evidence
C Directly based on category III evidence or extrapolated recommendation
from category I or II evidence
D Directly based on category IV evidence or extrapolated recommendation
from category II or III evidence
36 Combe, Landewe, Lukas, et al
and erosive disease should be measured: number of swollen
and tender joints, ESR or CRP, level of rheumatoid factor and
anti-CCP antibodies, and radiographic erosions.
After exclusion of diseases other than rheumatoid arthritis, the
third step in the diagnostic procedure should be to try to
determine the patients at risk of developing persistent or
erosive arthritis. This prognostic typing was considered crucial
to guide the optimal therapeutic strategy. Forty five studies that
evaluated the prognostic factors in early arthritis (n=5) or
early rheumatoid arthritis (n=40) were examined. They are all
observational or case–control studies (category III). Most
prognostic factors were analysed in a multivariate manner in
these studies, so that their independent contribution could be
tested. In many of the studies, the variable to predict
(dependent variable) was radiographic progression. The pre-
sence of IgM or IgA rheumatoid factor,20 43–59high ESR or CRP
level,41 43 44 47 49 50 53 55 57 59and early radiographic evidence of
erosions,20 43 44 49 52 54 56 58 61according to most of the reports,
independently predict long term radiographic progression. The
number of swollen joints probably correlates better with
joints.20 44 46–49
Recently, several studies have shown that
presence of anti-CCP antibodies is also an independent
prognostic factor for radiographic progression in early arthritis
and early rheumatoid arthritis.20 54 60–64The presence of HLA-
DRB1*0401 and DRB1*0404 is also consistently associated with
joint damage in different ethnic groups.43 49 61This association
appears to be dose dependent, as patients with two rheumatoid
arthritis associated genes show more radiographic evidence of
destruction than those with non-associated alleles.43 61HLA-
DRB1*01 genes alone are not associated with the severity of
rheumatoid arthritis. However, when DRB1*04 genes are
included in logistic regression analyses, they do not often
the number oftender
evidence and expert opinion
Final set of 12 recommendations on the management of early arthritis based on both
l Arthritis is characterised by the presence of joint swelling, associated with pain or stiffness. Patients presenting with
arthritis of more than one joint should be referred to, and seen by, a rheumatologist, ideally within six weeks after the
onset of symptoms.
l Clinical examination is the method of choice for detecting synovitis. In doubtful cases, ultrasound, power Doppler,
and MRI might be helpful to detect synovitis.
l Exclusion of diseases other than rheumatoid arthritis requires careful history taking and clinical examination, and
ought to include at least the following laboratory tests: complete blood cell count, urinary analysis, transaminases,
l In every patient presenting with early arthritis to the rheumatologist, the following factors predicting persistent and
erosive disease should be measured: number of swollen and tender joints, ESR or CRP, levels of rheumatoid factor
and anti-CCP antibodies, and radiographic erosions.
l Patients at risk of developing persistent or erosive arthritis should be started with DMARDs as early as possible, even
if they do not yet fulfil established classification criteria for inflammatory rheumatological diseases.
l Patient information concerning the disease and its treatment and outcome is important. Education programmes
aimed at coping with pain, disability, and maintenance of work ability may be employed as adjunct interventions.
l NSAIDs have to be considered in symptomatic patients after evaluation of gastrointestinal, renal, and cardiovascular
l Systemic glucocorticoids reduce pain and swelling and should be considered as adjunctive treatment (mainly
temporary), as part of the DMARD strategy. Intra-articular glucocorticoid injections should be considered for the
relief of local symptoms of inflammation.
l Among the DMARDS, methotrexate is considered to be the anchor drug, and should be used first in patients at risk of
developing persistent disease.
l The main goal of DMARD treatment is to achieve remission. Regular monitoring of disease activity and adverse
events should guide decisions on choice and changes in treatment strategies (DMARDs including biological agents).
l Non-pharmaceutical interventions such as dynamic exercises, occupational therapy, and hydrotherapy can be
applied as adjuncts to pharmaceutical interventions in patients with early arthritis.
l Monitoring of disease activity should include tender and swollen joint count, patient’s and physician’s global
assessments, ESR, and CRP. Arthritis activity should be assessed at one to three month intervals, for as long as
remission is not achieved. Structural damage should be assessed by radiographs of hands and feet every 6 to 12
months during the first few years. Functional assessment (for example, HAQ) can be used to complement the disease
activity and structural damage monitoring.
CRP, C reactive protein; DMARD, disease modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ,
Health Assessment Questionnaire; MRI, magnetic resonance imaging.
Strength of the recommendations
No of studies
1 Early referral
2 Diagnosis of early synovitis
3 Minimum diagnostic procedure
4 Prediction of persistent and erosive arthritis
5 Early treatment start
6 Patient information
8 Systemic and intra-articular glucocorticoids
9 Methotrexate is the anchor drug
10 Treatment strategies
11 Non-pharmaceutical interventions
12 Regular monitoring
NSAID, non-steroidal anti-inflammatory drug.
EULAR recommendations for early arthritis37
contribute to explaining variation in the model, which makes
DRB1 genotyping a less suitable tool for prognostic purposes.
The duration of cigarette smoking has also been shown to be an
interesting susceptibility factor and a determinant of disease
progression in rheumatoid arthritis, but this variable was not
often investigated or selected as an independent variable in
Abnormalities seen on MRI may be of prognostic interest.40 41
In general, single variables have shown limited prognostic
value, and several reports have tried to develop prediction
models with a combination of the most reliable mar-
kers.20 43 48 53Though some of these models seem promising,
the development and (cross)validation of a robust model, easy
to use in all settings in clinical practice, is still pending.
Patients at risk of developing persistent and/or erosive
arthritis should be started with DMARDs as early as possible
even if they do not yet fulfil established classification criteria
for inflammatory rheumatological diseases.
Four studies (category III) have shown that early arthritis is
frequently undifferentiated at presentation,65–68and six studies
(category III) have shown that classification criteria for
established diseases have little discriminant value during the
early months of the disease.50 69–73Recent studies have demon-
strated that joint erosion occurs early in rheumatoid arthritis,
and that more than 80% of patients with a disease duration of
less than two years may already have radiographic evidence of
joint damage. The concept of a ‘‘window of opportunity’’ for
effective treatment of recent onset rheumatoid arthritis has
been supported by one meta-analysis,21six RCTs,22–25 74 75and
several comparative or observational studies.11–13 26 76 77Among
patients with recent onset polyarthritis, those who received
DMARD treatment early had a better outcome with regard to
radiographic progression, function, and ability to work than
those in whom DMARD treatment was delayed by a few
months.11–13 23 26 74Results of a meta-analysis of 1435 patients
also support this concept: disease duration at the time of
DMARD initiation was shown to be the main predictor of the
response to DMARD treatment.21
Patient information concerning the disease and its treatment
and outcome is important. Education programmes aimed at
coping with pain disability and the maintenance of work
ability may be employed as adjunct interventions.
Provision of information should be an integral part of the
management of any chronic disease. The expert committee
considered that patient information concerning arthritis, its
treatment, and its outcome was important. Three RCTs
demonstrated that written information may increase knowl-
edge about the disease.78–80One systematic review,81four
RCTs,82–85and two controlled trials86 87showed that a self
management education programme resulted in improved
clinical outcome in rheumatoid arthritis, producing short term
effects on disability, joint count, and patient global assessment,
anxiety, and depression, but without any evidence of long term
benefit.81There is only weak evidence that group education is
better than individual education (category IV).87 88
In summary, patient information was considered important,
and the benefits of educational interventions have been shown
in clinical trials. In the opinion of the expert committee,
however, it is difficult to prioritise a single educational
intervention, because all interventions have only shown short
term benefits, and are subjected to cross national and cultural
variation. It is important to bear in mind that specific objectives
in early arthritis have not been achieved, and that further
evaluation is needed.
NSAIDs have to be considered in symptomatic patients after
evaluation of gastrointestinal, renal, and cardiovascular
Substantial evidence, including a Cochrane review in estab-
lished rheumatoid arthritis but not in early (rheumatoid)
arthritis, indicates that both classical and COX-2 selective, non-
steroidal anti-inflammatory drugs (NSAIDs) are more effective
than simple analgesics in relieving the signs and symptoms of
active disease (category Ia).89 90Some data were missing to
calculate the effect size of NSAIDs versus analgesics in
However, there are concerns over the gastrointestinal, renal,
and cardiovascular side effects of NSAIDs. Replacement of
conventional NSAIDS by COX-2 selective drugs, or the addition
of gastroprotective agents (misoprostol, double doses of H2
blockers, and proton pump inhibitors) to classical NSAIDs can
significantly reduce gastrointestinal complications such as the
incidence of gastrointestinal bleeding (category Ia).91However,
the long term use of COX-2 selective drugs has been associated
with increased cardiovascular risk.92 93Probably, this increased
cardiovascular risk is not limited to COX-2 selective drugs, but
extends to all NSAIDs. Consequently, the US Food and Drug
Administration and the European Medicines Agency have
published recommendations for the use of these drugs.
Among others, they recommend the shortest treatment dura-
tion possible and contraindications for at-risk patients. The
expert committee felt there is no reason to assume that these
observations should not be extrapolated to early arthritis.
Symptomatic patients presenting with early arthritis should
therefore be treated with NSAIDs after careful evaluation of
gastrointestinal, renal, and cardiovascular status.
Systemic glucocorticoids reduce pain and swelling and
should be considered as a (mainly temporary) adjunct to
the DMARD strategy. Intra-articular glucocorticoid injections
should be considered for the relief of local symptoms of
Several RCTs and three systematic reviews have shown that
(10 mg/day, were effective in relieving short term signs and
symptoms in patients with rheumatoid arthritis.94–99Results of a
recent open study of 100 patients with undifferentiated arthritis
suggested that a single dose of intramuscular or intra-articular
steroids may even induce remission,100
evidence for this strategy is lacking.
In addition, and despite controversial data, steroids are
probably effective in slowing radiographic progression in early
and established rheumatoid arthritis. In an RCT involving
rheumatoid arthritis patients with a disease duration of less
than two years, Kirwan101reported the superior efficacy of two
years of continuous treatment with prednisolone, 7.5 mg daily,
with respect to radiographic progression compared with
standard care without prednisolone. In an RCT involving
38 Combe, Landewe, Lukas, et al
patients with rheumatoid arthritis of less than one year
duration, van Everdingen et al102compared treatment with
prednisone 10 mg daily and NSAIDs. Only sulfasalazine was
allowed in this study, but only after six months, and only as a
rescue drug. The prednisone group showed significantly less
radiographic progression at 12 and 24 months. The effect size of
low dose steroids on the Larsen score compared with sympto-
matic treatments in these two studies was only 0.28 and 0.26,
respectively, at 24 months. These data are supported by data
from another RCT103and from two trials in early rheumatoid
arthritis, which indicated that combination therapy including
steroids was more effective in terms of radiographic progression
than single DMARD therapy, but it is not possible to determine
the specific benefits provided by steroid administration in these
trials.5 6 104The published data have not all been positive. Paulus
et al105were unable to show an effect of prednisone, ( 5 mg/
day, in radiographic progression in a subgroup analysis of a
three year RCT comparing etodolac and ibuprofen in 824
patients. A recent RCT by Capell et al106failed to demonstrate
any significant difference in two year radiographic progression
between prednisone, 7 mg/day, and placebo. In addition,
subanalysis of two recent trials with new DMARDs did not
show any added benefit of low dose prednisone with respect to
radiographic progression.4 107
The positive short term effects of intra-articular corticosteroid
administration in relieving local symptoms of inflammation in
rheumatoid arthritis were shown in two RCTs.108 109Among the
intra-articular corticosteroids, there is some indication that
triamcinolone hexacetonide is the most effective.110
In summary, systemic glucocorticoids—either alone or as
part of a DMARD combination strategy—are effective in the
short term relief of signs and symptoms, and are probably
effective in retarding radiographic progression in early and
established rheumatoid arthritis. The systemic use of glucocor-
ticoids in early arthritis has not yet been formally investigated.
Preferably, treatment with glucocorticoids is temporary because
of the risk of side effects—including weight gain, hypertension,
diabetes, cataracts, and osteoporosis—which justify careful
monitoring and appropriate prevention. Furthermore, the long
term safety of low dose glucocorticoids is largely unknown.
Intra-articular steroids may be effective as an adjunct to
DMARDs in relieving local joint symptoms. There is still no
evidence that intra-articular or intramuscular steroids alter the
course of early arthritis.
Among the DMARDs, methotrexate is considered the anchor
drug and should be used first in patients at risk of developing
At the root of this statement is the observation of a meta-
analysis of patients with established rheumatoid arthritis,
showing a significantly lower discontinuation rate of metho-
trexate as compared to other DMARDs (but leflunomide and
tumour necrosis factor (TNF) blockers were not evaluated).111
Several RCTs have proven the clinical efficacy of methotrexate.
These RCTs were followed by observational studies clearly
establishing that methotrexate is effective over long periods,
and that it has a better toxicity profile than other DMARDs.112–
115Importantly , methotrexate is one of the first conventional
DMARDs with proven efficacy on radiographic progression in
rheumatoid arthritis.4In early rheumatoid arthritis, two RCTs
(of 12 and 18 months’ duration) failed to demonstrate the
superiority of methotrexate over other DMARDs such as
sulfasalazine.116 117. However, recent RCTs with TNF blocking
drugs have shown that methotrexate is almost as effective as
TNF blocker monotherapy in patients with early (less than
three years’ duration) severe rheumatoid arthritis.107 118
An important argument for considering methotrexate as an
anchor drug is that it can be combined with biological
treatments if necessary. This has emerged from RCTs showing
greater efficacy for the combination of TNF blocking drugs with
methotrexate than for monotherapy.9 118–120The combination of
methotrexate with TNF blockers appears to convey the
maximum therapeutic effect currently obtainable, both in
established and early rheumatoid arthritis. The combination
of methotrexate with sulfasalazine has not been shown to be
superior to single drug treatment.116–117Despite interesting
reports,5 7 104 121–128whether the combination of methotrexate
with other DMARDs is more efficient than monotherapy needs
Leflunomide, and to a lesser extent sulfasalazine, have a
similar clinical efficacy to methotrexate in established and
recent rheumatoid arthritis (category Ia).124Leflunomide is as
effective as methotrexate in slowing radiographic damage.4
Sulfasalazine, in contrast, may be inferior to leflunomide and
methotrexate in the long term.
In summary, methotrexate appears to be an anchor drug in
rheumatoid arthritis, both as monotherapy and in combination
with conventional DMARDs or TNF blocking drugs for most
patients with rheumatoid arthritis.
Although formal evidence that prioritises methotrexate as
the first DMARD in early arthritis or early rheumatoid arthritis
is lacking, the expert committee recommends that treatment
should be started with methotrexate (unless contraindicated)
in patients at risk of persistent or erosive disease. This
recommendation is based on its clinical and radiological
efficacy in combination with the relatively beneficial safety
profile, and on its beneficial properties in treatment combina-
tions. Leflunomide, and to a lesser extent, sulfasalazine are
considered the best alternatives.
The main goal of DMARD treatment is to achieve remission.
Regular monitoring of disease activity and adverse events
should guide decisions on choice and changes in treatment
strategies (DMARDs including biological agents)
The introduction of new drugs that can control disease
progression, and the demonstration that DMARDs are more
effective if used early rather than later in disease progression,
have led to crucial changes in management goals in early
arthritis and early rheumatoid arthritis. The objective should
now be to achieve remission in order to prevent structural
damage and long term disability.
One recent therapeutic strategy in the treatment of rheuma-
toid arthritis is the early use of combination therapy with
conventional DMARDs (‘‘intensive’’ therapy). Some RCTs have
evaluated the combination of two DMARDs (mainly metho-
trexate-sulfasalazine or methotrexate-ciclosporine) in early
rheumatoid arthritis, with controversial results both for clinical
sion.116 117 121 123 125 126However, a combination of methotrexate
and sulfasalazine with high dose steroids in a step-down
therapeutic strategy (COBRA) resulted in protracted effects on
radiographic progression, compared with sulfasalazine mono-
therapy in 155 patients with early rheumatoid arthritis
(category 1b).5 104These results are consistent with those from
the FIN-RACo study, in which 197 patients with onset of
rheumatoid arthritis within the previous two years were
randomly assigned to receive either a four-drug regimen,
with methotrexate, sulfasalazine, hydroxychloroquine, and
EULAR recommendations for early arthritis39
prednisolone (5 mg/d), or a single DMARD.6 127 128
18 months, a greater proportion of the combination therapy
group were in remission. After five years, the combination
group were less likely to have radiographic progression, and the
work disability rate was lower compared with the patients on
monotherapy. However, in neither study was there an arm with
DMARD monotherapy plus steroids.
The concept that intensive interventions early in the course of
persistent arthritis may profoundly affect long term radio-
graphic progression is also supported by four recent RCTs with
TNF blockers in early rheumatoid arthritis. In patients with a
disease duration of less than three years, the use of a TNF
blocking drug (adalimumab, etanercept, or infliximab)—
especially in combination with methotrexate—revealed an
increased rate of clinical remission and slowing of radiographic
progression compared with methotrexate monotherapy.118–120 129
The effect size of such a combination versus methotrexate alone
on total radiographic score in patients with early rheumatoid
arthritis varied from 0.42 to 0.96. These data are consistent with
those from several RCTs in established rheumatoid arthritis,
showing that intensive treatment with a combination of
conventional DMARDs plus steroids or with biological therapy
in combination with methotrexate may provide superior clinical
and radiological efficacy than monotherapy.8–10
In addition, a recent RCT compared four treatment strategies
in early rheumatoid arthritis, including a progressive step-up
regimen, sequential monotherapy, a triple step-down strategy
with methotrexate, sulfasalazine, and high dose prednisone,
and infliximab plus methotrexate.7The two groups with initial
intensive treatment (combination and infliximab group)
showed a more rapid clinical response and a better radiographic
outcome than the sequential monotherapy or the step-up
DMARD therapy groups.
In the TICORA study,14patients with early rheumatoid
arthritis were randomly assigned to an intensive treatment in
order to reach a low disease activity state (DAS44 ,2.4) close to
remission, or to regular clinical care The intensive treatment
group developed less radiographic damage than the control
group after 18 months of follow up, suggesting an association
between remission (or low disease activity) and further joint
destruction (category Ib). Other data support the need to
achieve clinical remission in order to control the disease
process, including the long term follow up of two Dutch
cohorts which found a positive relation between disease activity
score (DAS) and 28 joint disease activity score (DAS28) and
radiological progression, after adjustment for time effects and
baseline predictors of radiological destruction and their inter-
actions with time130(category III). In the PREMIER study,118the
ASPIRE study,119and the TEMPO study (despite the fact that it
was done in established rheumatoid arthritis),9 131clinical
remission was achieved in some patients and higher remission
rates were associated with arrest of radiographic progression
(maybe even repair) and better physical function.
In summary, initial intensive treatment provides a better
outcome than DMARD monotherapy including methotrexate in
patients with recent onset chronic arthritis, but mainly in a
subset of patients with severe disease.119Consequently, regard-
ing the benefit to risk ratio and the cost-effectiveness of these
strategies, a reasonable course of action should be initial
DMARD monotherapy with methotrexate (or leflunomide or
sulfasalazine). However, the expert committee felt that there is
ample evidence that with modern treatment combinations with
or without biological agents clinical remission is an achievable
goal. There is also indirect evidence from various RCTs and
observational studies that remission is associated with better
radiographic outcome and better preservation of physical
function. As there is emerging evidence that maintaining
remission is as important as achieving remission, it is obvious
that disease activity should be closely monitored in order to
change DMARD therapy and strategy if necessary (‘‘bench-
marking’’). The first studies supporting this view have just been
Non-pharmaceutical interventions such as dynamic exer-
cises, occupational therapy, and hydrotherapy can be
applied as treatment adjunct to pharmaceutical interventions
in patients with early arthritis.
The effect of non-pharmaceutical treatments has not been
investigated in early arthritis and can only be extrapolated from
the results of several RCTs and eight Cochrane reviews in
established rheumatoid arthritis. RCTs have shown that joint
specific dynamic exercises may improve strength and physical
function in rheumatoid arthritis, but without a clear effect on
pain or disease activity.132 133However, the optimal exercise
programme has not yet been determined. One recent RCT and a
Cochrane review reported a positive effect of occupational
therapy on functional ability and self management, but without
an effect on disease activity.134 135Hydrotherapy in rheumatoid
arthritis has been evaluated in two recent meta-analyses,136 137
with positive findings but insufficient evidence to support a
Nine RCTs have been undertaken to investigate the efficacy
of diets. The results are controversial—the diets and the study
designs varied widely, and most of the trials with diets only
included highly selected and motivated patients. A one year
study randomised 66 patients to receive a vegetarian diet free of
gluten or a well balanced non-vegan diet. The vegetarian diet
group experienced significantly better effects in most of clinical
variables, including the ACR 20 response, as compared with the
non-vegetarian group.138Two other RCTs found a positive effect
of a vegetarian diet on pain and indices of disease activity.139 140
Numerous other non-pharmaceutical interventions have been
Acupuncture, laser therapy, use of compression gloves, trans-
cutaneous electrical nerve stimulation (TENS), ultrasound,
thermotherapy, use of splints or ortheses, and homoeopathy are
examples of non-pharmaceutical interventions with which
controversial effects have been reported in RCTs.141–144When
positive, the RCTs showed short term relief of pain only, rather
than an effect on disease activity.
In summary, some non-pharmaceutical interventions—such
as dynamic exercises, occupational therapy and hydrotherapy—
have shown indisputable, often symptom relieving effects in
established rheumatoid arthritis. There is limited evidence that
a vegetarian diet may have a modest effect on symptoms. The
efficacy of non-pharmaceutical interventions in early arthritis
has not been formally tested, and there is no indication that
they improve long term outcomes such as radiographic
progression. The expert committee therefore felt that non-
pharmaceutical interventions should only be applied as an
adjunct to pharmaceutical treatment in patients with early
Monitoring of disease activity should include tender and
swollen joint count, patient’s and physician’s global assess-
ments, ESR, and CRP. Arthritis activity should be assessed at
one to three month intervals, for as long as remission is not
achieved. Structural damage should be assessed by x rays
40 Combe, Landewe, Lukas, et al
every 6 to 12 months during the first few years. Functional
assessment (for example, HAQ) can be used to complement
the disease activity and structural damage monitoring.
This statement is supported by at least three RCTs.7 14 145In the
TICORA study, patients with recent onset rheumatoid arthritis
were randomly assigned to receive routine DMARD treatment
at the discretion of the treating rheumatologist, or intensive
treatment with monthly assessment of clinical disease activ-
ity.14In this latter group, the treatment was intensified or drug
combinations were used if the effect on disease activity was
insufficient, as defined by a DAS44 ,2.4. This intensive
strategy appeared to be significantly more effective at all follow
up visits throughout the first 18 months, in terms of both
clinical symptoms and radiographic progression.
Intensive care based on regular monitoring of DAS28 or
DAS44 was associated with better outcome in two recent
trials,7 145and other validated composite indices can be used to
monitor disease activity equally reliably.146No evidence from an
appropriately designed clinical trial exists to support monitor-
ing of radiographic progression. The expert committee con-
sidered monitoring of radiographic progression useful in view
of the objective of the management of early arthritis (to prevent
joint destruction), the observation that radiographic progres-
sion is greatest during the first two years after disease onset,
and the appreciation that radiographic progression is clinically
meaningful in case of a change of 4 Sharp units (during six
months follow up) and can be reliably established at the group
level after a three to six months interval147(category III). In
order to facilitate radiographic monitoring, it could be desirable
to use the simple erosion and narrowing score (SENS), a
scoring method based on the van der Heijde modified Sharp
score and validated for use in clinical practice.148
These 12 recommendations, presented in short sentences, are
based on recent research evidence up to January 2005 and on
expert opinion. The task force has followed the EULAR
standardised operating procedures for formulating recommen-
dations.15Similar methods have been also used to develop the
EULAR recommendations for the management of knee and hip
osteoarthritis.149 150Early arthritis is frequently undifferentiated,
and the major issues of interest are diagnosis, prognosis, and
treatment. As these issues cannot be considered independently,
the expert committee has decided to focus its work on ‘‘early
undifferentiated arthritis with a certain propensity to become
persistent and erosive’’, and to use an operational definition for
‘‘management’’ that covers the entire process, including
referral, diagnosis, prognosis, and treatment. As a result, these
recommendations are not aimed only at rheumatologists but
also at GPs and potentially at medical students. Types of
arthritis that do not fit the framework outlined above were
excluded in this exercise.
As mentioned already by others,149the expert committee did
not find it helpful to score the quality of the studies, both
because the topics that were examined varied widely and
because of the heterogeneity of the studies that were found The
committee chose to grade the level of evidence provided by
every study, which was based on the methodology of the study,
and took this grading into consideration when discussing the
content and the strength of the recommendations. An
important consideration in the discussions always was whether
the type of study fitted the content of the research question that
was at the basis of the literature search. Besides evidence
obtained from published reports, expert opinion and the clinical
experience of the expert committee turned out to be very
important for reaching consensus, and for formulating and
weighing the strength of the recommendations. The expert
committee had to face an important limitation in that most of
the published data from which the recommendations were
derived were based on studies in patients with early rheuma-
toid arthritis or established rheumatoid arthritis, rather than on
studies in early arthritis. Nevertheless, the expert committee
considered the data in early rheumatoid arthritis robust enough
and relevant enough to be extrapolated to ‘‘early arthritis with a
certain propensity to become persistent and/or erosive’’. By
doing so, the expert committee has implicitly subordinated the
classification of rheumatoid arthritis to a clinical diagnosis of
potentially persistent erosive arthritis, which can be interpreted
as a novelty. This new line of thinking enabled the task force to
highlight key points in the management of early arthritis,
including the need for early referral to a rheumatologist; the
prediction of persistent and erosive disease; the requirement for
an early start of efficient DMARD treatment in all patients at
risk of developing persistent or erosive arthritis; the key role of
methotrexate as the first and anchor drug; the objective of the
therapeutic strategy in inducing remission and preventing joint
destruction; and the need for regular monitoring to adapt the
strategy as necessary and detect adverse events.
Reviewing the literature, the committee felt that there was a
need to develop new tools for early and accurate diagnosis and
prognosis. These include new imaging and serological measures
Research agenda based on expert opinion
l Ultrasonography and power Doppler should be validated for the diagnosis of early synovitis
l MRI should be validated for the diagnosis of synovitis, for showing early erosions and for the prognosis of further
l Accurate classification and diagnostic criteria for early (rheumatoid) arthritis are still lacking and need to be
l Available prediction algorithms for persistent and/or erosive arthritis, and for long term disability should be further
l Randomised controlled trials of non-pharmacological interventions in early arthritis are needed.
l The most efficient and effective information/education interventions and exercise programmes for early arthritis need
to be determined.
l The role of glucocorticoids in very early arthritis should be evaluated.
l Whether the temporary use of glucocorticoids can prevent the progression of joint destruction if started in early
arthritis should be further investigated.
l Effects of temporary use of intensive treatments, such as biologic agents in early arthritis, should be investigated to test
if prevention of erosions and cure (a long term remission) of the disease is possible.
l Therapeutic strategies in early arthritis should be tested on the basis of prediction models.
l Studies with an appropriate design to determine the comparative effectiveness and cost-effectiveness of different
therapeutic strategies are required.
EULAR recommendations for early arthritis41
and also prediction algorithms for long term outcome. Also
lacking is information about the effectiveness of non-pharma-
cological interventions, the role of glucocorticoids, and the
comparative effectiveness and cost-effectiveness of different
strategic modes in early arthritis. The task force proposed 11
items considered the most important for future research
according to current available evidence (table 6).
New effective treatments for rheumatoid arthritis and new
strategic concepts in the treatment of the disease have
definitely changed thinking about the management of early
The current EULAR recommendations on the management of
early arthritis value the recent therapeutic developments, but
they also point to the variety of available treatment, and the
heterogeneity of patients in whom these treatment should be
applied. Management according to protocols will become
increasingly difficult, and every health professional should
choose the most appropriate management strategy for every
individual patient. The recommendations should be considered
a reflection of current thinking in the field of early arthritis,
supported by firm evidence if possible, and dressed up by expert
opinion if necessary, in order to serve as an aid for health
professionals and patients who have to make decisions about
the most appropriate individual management strategy. To that
end, it is hoped that the recommendations will be widely
disseminated and discussed within the rheumatological com-
munity and other physicians taking care of patients with early
arthritis, and that they will help improve the standard of care
for patients with arthritis across different health care systems.
Obviously these recommendations will need an update after
few years, in order to incorporate new scientific evidence.
B Combe, C Lukas, Immuno-Rhumatologie, Lapeyronie Hosp, Montpellier,
R Landewe, Rheumatic diseases, University Hosp, Maastricht, Netherlands
H D Bolosiu, Rheumatology and Research Centre, University of Medicine,
F Breedveld, Rheumatology, Leiden University Medical Centre, Leiden,
M Dougados, Rheumatology B, Cochin Hospital, Paris, France
P Emery, Rheumatology, Academic Unit of Musculoskeletal diseases,
Leeds, United Kingdom
G Ferraccioli, Division of Rheumatology, Catholic University of the Sacred
Heart, Rome, Italy
J M W Hazes, Rheumatology, Erasmus Medical Centre, Rotterdam,
L Klareskog, Rheumatology, Karolinska Hospital, Stockholm, Sweden
K Machold, J Smolen, Internal Medicine III, Medical University, Vienna,
E Martin-Mola, Rheumatology, Hospital La Paz, Madrid, Spain
H Nielsen, Rheumatology Q, University Hospital, Herlev, Denmark
A Silman, ARC Unit, Manchester University, Manchester, United Kingdom
H Yazici, Rheumatology, Cerrahpasa Medical Faculty, Istanbul, Turkey
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BNF for Children 2006, second annual edition
In a single resource:
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EULAR recommendations for early arthritis45