Best Practice & Research Clinical RheumatologyVol. 21, No. 1, pp. 27e42, 2007

doi:10.1016/j.berh.2006.08.011available online at http://www.sciencedirect.com

2

Early rheumatoid arthritis: strategies

for prevention and management

Bernard Combe* MD, PhD

Professor of Rheumatology

Immuno-Rhumatologie Hopital Lapeyronie, CHU de Montpellier, University Montpellier I, 371,

Avenue du Doyen Gaston Giraud 34295 Montpellier cedex 5, France

The treatment of rheumatoid arthritis (RA) has changed considerably in the past few years sincenew tools and new concepts have been developed and validated highlighting the need for guide-lines focused on early RA. The treatment goal should now be to achieve clinical remission, inorder to prevent structural damage and long-term disability. A very early use of effectivedisease-modifying anti-rheumatic drugs (DMARDs) is a key point in patients at risk of developingpersistent and erosive arthritis. Intensive treatment such as combination DMARDs plus steroidsor biological therapies can induce a high rate of remission, control of radiological progressionand provide better outcome than DMARD monotherapy in early RA and should be consideredin at risk patients. Regarding the risk:benefit ratio and the cost-effectiveness of these strategies,a reasonable course of action in early RA should be initial DMARD monotherapy such asmethotrexate. However, a close monitoring of disease activity and radiographic progression ismandatory in order to change DMARD therapy and strategy if necessary.

Systemic glucocorticoids are effective in the short-term relief of pain and swelling and shouldbe considered, but mainly as a temporary therapy part of the DMARD strategy. Information andeducation for patients, as well as some non-pharmacological interventions, can be proposed astreatment adjuncts. Finally, the reduction or stopping of smoking, which could prevent the de-velopment and progression of early RA, is the only prevention tool currently available.

Key words: early arthritis; rheumatoid arthritis; management; recommendations; DMARD.

The definition of rheumatoid arthritis (RA) is sometimes imprecise, but this term isusually used to describe a symmetrical, persistent and destructive polyarthritis oftenassociated with rheumatoid factor and/or positive results for anti-cyclic citrullinatedpeptide (anti-CCP) antibodies. At an early stage of the disease, identification is

* Tel.: þ33 4 67 33 87 10; Fax: þ33 4 67 33 73 11.

E-mail address: b-combe@chu-montpellier.fr

1521-6942/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

28 B. Combe

somewhat difficult since no test and no diagnostic criteria are available to define earlyRA.1 In practice, early inflammatory arthritis is frequently undifferentiated.2 Early ar-thritis may develop into established RA or another definite arthropathy, but it mayalso go on to remission or stay undifferentiated. To better evaluate diagnosis and out-come in arthritis, it has been proposed to first recognise inflammatory arthritis, thento eliminate definite diagnoses of arthritis (e.g. lupus, psoriatic arthritis, seronegativespondylarthropathies, etc) and finally to estimate the risk of developing persistent and/or erosive irreversible arthritis before proposing an optimal therapeutic strategy.2e4

Although the prognosis for early arthritis is still a difficult issue to address, a combina-tion of clinical, biological and radiographical parameters may help to predict arthritisoutcome with good accuracy.5

The management of RA has changed considerably in the past few years since wehave developed new tools and validated new concepts, highlighting the need for guide-lines focussed on the management of early arthritis such as those that have been re-cently developed by the European League Against Rheumatism (EULAR: see Table 1).4

The treatments used currently are more effective and more aggressive.6 New disease-modifying anti-rheumatic drugs (DMARDs) and DMARD combinations have showntheir ability to slow disease progression.7e10 Furthermore, biological therapies havedemonstrated rapid and sustained disease control, which is associated with impressiveprevention of joint destruction.11e13 A body of evidence about early RA now exists tosupport the very early use of effective DMARDs, preferably before the first radio-graphic evidence of erosions, to prevent further joint damage and disability.14e16 Con-sequently, early referral to a specialist is key to guaranteeing the patient’s earlydiagnosis and therapeutic intervention.17 The assessment and close monitoring ofpatients with early arthritis seems crucial for better adaptation of therapeutic strate-gies and an ideal treatment proposal should be based on an appropriate prognosis forthe disease.3,10,18 In addition, management of early arthritis includes more than drugtreatment only.

The European Bone and Joint Health Strategies Project has recently providedrecommendations on the prevention and management of early RA (Table 2).19

SIZE OF THE PROBLEM

RA is the most common inflammatory disease of the joints. It usually presents withpain, stiffness and symmetrical swelling of the small joints of the hand and feet, butmay also involve any other synovial joint. The incidence of RA is estimated as 4e13per 100 000 for adult males and 13e36 per 100 000 for adult females. Estimates ofthe prevalence of RA range from 1e6 per 1000 for men and 3e12 per 1000 forwomen.19 The peak age of onset is between 35 and 45 years of age. However malesand females of all ages are at risk. RA has a significant impact on a patient’s physical,emotional and social functioning that often occurs very early in the disease. Thereis also a high incidence of psychological stress during the early stages of RA, which per-sists into established RA and is attributed to symptoms such as pain, fatigue and dis-ability. Even in its early stages, RA can have a significant impact on a patient’s ability tocarry out their activities of daily living, work and leisure. Health status is significantlyimpaired from the onset, as measured by generic instruments (e.g. SF36, Euroquol 5D)or by disease-specific instruments (Health Assessment Questionnaire (HAQ)). Within2 years of onset, the HAQ score was between 0.8 and 1.04 out of a maximum of3.0.20,21 RA has an early impact on a patient’s ability to work and their socio-economic

Prevention and management of early rheumatoid arthritis 29

status. Work capacity is restricted in one-third of patients within 1 year22 and within3 years about 40 % will be registered as work-disabled.

Targets that are most important in the prevention and management of earlyRA are:

e To reduce pain and inflammatione To reduce disabilitye To prevent radiological damage and progressione To reduce the development of co-morbidities

Table 1. EULAR recommendations for the management of early arthritis based on both evidence and

expert opinion.

1. 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 e and seen by e a rheuma-

tologist, ideally within 6 weeks after the onset of symptoms.

2. Clinical examination is the method of choice for detecting synovitis. In doubtful cases, ultrasound,

power doppler and magnetic resonance imaging (MRI) might be helpful in detecting synovitis.

3. The exclusion of diseases other than rheumatoid arthritis (RA) requires careful history-taking and

clinical examination and ought to include at least the following laboratory tests: complete blood

cell count, urinary analysis, transaminases, anti-nuclear antibodies.

4. 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, erythro-

cyte sedimentation rate (ESR) or C-reactive protein (CRP), levels of rheumatoid factor, anti-cyclic

citrullinated peptide (anti-CCP) antibodies and radiographic erosions.

5. Patients at risk of developing persistent and/or erosive arthritis should be started with disease-mod-

ifying anti-rheumatic drugs (DMARDs) as early as possible even if they do not fulfill established

classification criteria for inflammatory rheumatological diseases yet.

6. Patient information concerning the disease and its treatment and outcome is important. Education

programmes aiming at coping with pain disability and the maintenance of work ability may be em-

ployed as adjunct interventions.

7. Non-steroidal anti-inflammatory drugs (NSAIDS) have to be considered in symptomatic patients af-

ter evaluation of gastro-intestinal, renal and cardiovascular status.

8. Systemic glucocorticoids reduce pain and swelling and should be considered as a (mainly temporary)

adjunct therapy as part of the DMARD strategy. Intra-articular glucocorticoid injections should be

considered for the relief of local symptoms of inflammation.

9. Among the DMARDs, methotrexate is considered the anchor drug and should be used first in

patients at risk of developing persistent disease.

10. The main goal of DMARD therapy is achieving remission. Regular monitoring of disease activity

and adverse events should guide decisions on the choice of and changes in treatment strategies

(DMARDs including biological agents).

11. Non-pharmaceutical interventions such as dynamic exercises, occupational therapy and hydro-

therapy can be applied as adjunct treatments to pharmaceutical interventions in patients with

early arthritis.

12. 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 1 to 3-month

intervals, for as long as remission is not achieved. Structural damage should be assessed using

radiographs of the hands and feet every 6e12 months during the first few years. Functional

assessment (e.g. Health Assessment Questionnaire (HAQ)) can be used to complement the

disease activity and structural damage monitoring.

Source: Combe et al (2006).4

30 B. Combe

TREATMENT GOALS

The introduction of new drugs that can control disease progression and the demon-stration that DMARDs are more effective if used earlier rather than later in diseaseprogression, have led to crucial changes in management goals in early arthritis andearly RA.11e16, 23 The objective should now be to achieve remission, in order to pre-vent structural damage and long-term disability.4

One recent therapeutic strategy in the treatment of RA is the early use of combi-nation therapy with conventional DMARDs (‘intensive’ therapy). Some randomisedcontrolled trials (RCTs) have evaluated the combination of two DMARDs (mainlymethotrexate (MTX) esulphasalazine or MTXecyclopsorine) in early RA with con-troversial results both in clinical efficacy and radiographic evidence of progres-sion.24e27 However, a combination of MTX and sulphasalazine with high-dosesteroids in a step-down therapeutic strategy resulted in protracted effects on radio-graphic progression, compared to sulphasalazine monotherapy in 155 patients withearly RA.8 These results are consistent with those from the FIN-RACo study, in which

Table 2. Key recommendations for early rheumatoid arthritis.

Recommendation

Lifestyle To prevent rheumatoid arthritis:

No recommendation

To reduce pain:

Undertake weight bearing exercise

To prevent radiological progression:

Stop or reduce smoking

To maintain and restore function:

Undertake weight bearing exercise

Pharmacological To prevent rheumatoid arthritis:

Oestroprogestins (in child-bearing females)

To reduce pain:

NSAIDs

DMARDs

To prevent radiological progression:

DMARDs

Biological agents

Steroids

To maintain and restore function:

DMARDs

Painkillers

Rehabilitative To prevent rheumatoid arthritis:

Physical fitness

To reduce pain:

Physical modalities

Hydrotherapy

Multidisciplinary interventions

Source: The Bone and Joint Decade. European Bone and Joint Health Strategies Project.19

NSAIDs, non-steroidal anti-inflammatory drugs; DMARDs, disease-modifying anti-rheumatic drugs.

Prevention and management of early rheumatoid arthritis 31

197 patients with RA onset within the previous 2 years were randomly assigned toreceive either a four-drug therapy, with MTX, sulphasalazine, hydroxychloroquineand prednisolone (5 mg/day), or a single DMARD.9 After 18 months, a greater propor-tion of the combination-therapy group were in remission. After 5 years, the combina-tion group were less likely to have radiographic progression and the work disabilityrate was lower, compared to patients on monotherapy. However, in both studies,there was no arm with DMARD monotherapy plus steroids.

The concept that intensive interventions early in the course of persistent arthritismay profoundly affect long-term radiographic progression is also supported by fourrecent RCTs with tumour necrosis factor (TNF) blockers in early RA. In patientswith a disease duration of less than 3 years, the use of a TNF blocking drug, espe-cially in combination with MTX, revealed an increased rate of clinical remissions andslowing of radiographic change when compared with MTX monotherapy.28e30 Theeffect size of such a combination versus MTX alone on total radiographic score inpatients with early RA varied from 0.42e0.96. These data are consistent with thosefrom several RCTs in established RA, showing that intensive treatment with a com-bination of conventional DMARDs plus steroids or with biological therapy in com-bination with MTX, may provide better clinical and radiological efficacy comparedto monotherapy.6,12 In addition, a recent RCT compared four treatment strategiesin early RA, including a progressive step-up regimen, sequential monotherapy,a step-down combination strategy with MTX, sulphasalazine and high-dose predni-sone, and infliximab plus MTX.10 The two groups with initially intensive treatment(combination and infliximab group) showed a more rapid clinical response and a bet-ter radiographic outcome than the sequential monotherapy or the step-up DMARDtherapy groups.

In the TICORA study17, patients with early RA were randomly assigned to anintensive treatment in order to reach a low disease activity state (DAS44 < 2.4)that is close to remission, or to regular clinical care. The intensive treatment grouphad developed less radiographic damage than the control group after 18 months offollow-up, suggesting an association between remission (or low disease activity) andfurther joint destruction. Other data support the need to achieve clinical remissionin order to control the disease process, including the long term follow-up of twoDutch cohorts, which found a positive relationship between disease activity (DASand DAS28) and radiological progression, after adjustment for time effects andbaseline predictors of radiological destruction and their interactions with time.31

In the PREMIER30, ASPIRE29 and TEMPO (despite being performed in establishedRA)32 studies, clinical remission was achieved in some patients and higher remissionrates were associated with arrest of radiographical progression (there might evenbe some repair) and better physical function. There is now ample evidence thatwith treatment combinations with or without biological agents clinical remissionis an achievable goal.

Clinical remission is usually measured according to Pinals criteria or DAS score,which is easier to perform in daily practice.33,34 The gold standard for evaluating struc-tural damage in early RA is still based on radiographs of the hands and feet. Structuraldamage should be assessed by X-ray every 6e12 months during the first few years.4

Monitoring of radiographic progression is useful in view of the objective of themanagement of early arthritis (to prevent joint destruction) and the observationthat radiographic progression is highest during the first 2 years after disease onset.The scientific evidence for the clinical value of using ultrasonography in early arthritisis limited. In one controlled study and in a few comparative studies magnetic

32 B. Combe

resonance imaging (MRI) has been shown to be more sensitive than radiography forthe detection of erosions in early RA.35 There is also evidence suggesting that MRIfindings (e.g. synovitis, bone oedema, bone erosions) may predict subsequent radio-graphic progression.36 However, the level of evidence is rather low and changes re-sembling mild synovitis or small bone erosions were occasionally found in the jointsof healthy subjects, questioning the specificity of this technique.37 Nevertheless, thesearch for persistent synovitis using ultrasonography or MRI may help in the definitionof true remission. Issues of standardisation and reliability of these techniques havebeen addressed and are ongoing.

WHAT CAN BE DONE: THE EVIDENCE FOR DIFFERENTINTERVENTIONS

The evidence for different interventions is considered in the context of the agreed tar-gets for the prevention and treatment of RA and for the populations that the evidenceapplies to.19

Lifestyle interventions

A combination of genetic and environmental factors, such as infections, reproduc-tive or hormonal factors and factors related to lifestyle, is considered to be re-sponsible for the disease. Various lifestyle factors, such as smoking or obesity,may increase the risk of developing RA. These factors, in particular smoking,also impact on the progression of the disease and can lead to an increase in theassociated pain and functional limitations of RA.38 The reduction or stopping ofsmoking could prevent the development of radiological damage and progressionof RA. Ensuring an appropriate body weight by following a healthy diet and main-taining physical activity can influence pain in RA. To prevent early, undifferentiated,symmetric arthritis progressing to RA with disability, there is evidence to recom-mend smoking cessation. The effect of smoking on the occurrence and courseof RA has been shown to remain for several years after stopping. To reduce theimpact of RA for those with the condition, there is evidence to recommend phys-ical activity.4,19 There is limited evidence that other lifestyle interventions such asvegetarian diet may have a modest effect on symptoms.4

Pharmacological interventions

It is possible to prevent or control joint damage in early RA and limit the effects of painusing pharmacological therapies, with improvement in function, activities andparticipation.

Simple analgesics are used to manage pain in all stages of the disease, often in com-bination with other therapies to control the inflammatory process.

Non Steroidal Anti-Inflammatory Drugs (NSAIDs) have an instantaneous effect onpain and stiffness without influencing the disease process. Substantial evidence,including a Cochrane review in established RA, indicates that both classical andcyclo-oxygenase 2 (COX-2) selective NSAIDs are more effective than simple anal-gesics in relieving the signs and symptoms of active disease.39 However, there areconcerns regarding the gastrointestinal (GI), renal and cardiovascular side-effects of

Prevention and management of early rheumatoid arthritis 33

NSAIDs. Replacement of conventional NSAIDS by COX-2 selective NSAIDs, or theaddition of gastroprotective drugs to classical NSAIDs can significantly reduce GIcomplications such as the incidence of GI bleeding. In addition, the long-termuse of COX-2 selective drugs has been associated with increased cardiovascularrisk. Probably, this increased cardiovascular risk is not limited to COX-2 selectivedrugs, but extends to all NSAIDs. Consequently, the US Food and Drug Adminis-tration and the European Medicines Agency have raised recommendations for theuse of these drugs. Among others, they recommend the shortest treatment dura-tion that is possible and contra-indications for at risk patients. There is no reasonto assume that these observations should not be extrapolated to early RA. Symp-tomatic patients presenting with early arthritis should, therefore, be treated withNSAIDs after careful evaluation of GI, renal and cardiovascular status.

Glucocorticoids are used either intra-articularly or systemically. Several RCTs andthree systematic reviews have demonstrated that systemic low-dose glucocorticoids,typically prednisone �10 mg/day, were effective in relieving short-term signs andsymptoms in patients with RA.40 Results of a recent open study of 100 patientswith undifferentiated arthritis suggested that a single dose of intra-muscular orintra-articular steroids may even induce remission41, although formal evidence forthis strategy is lacking. In addition, and despite controversial data, steroids are prob-ably effective in slowing radiographic progression in early and established RA. In a RCTwith patients with RA of less than 1 year’s duration, van Everdingen et al42 comparedtreatment with prednisone, 10 mg daily, versus NSAIDs. Only sulphasalazine wasallowed in this study, but only after 6 months, as a rescue medication. The prednisonegroup showed significantly less radiographic progression at 12 and 24 months. Theeffect size of low-dose steroids for Larsen score compared to symptomatic treatmentswas only 0.26 at 24 months. These data are supported by another RCT43 and by twotrials in early RA, which indicated that combination-therapy including steroids wasmore efficient in terms of radiographic progression than single DMARD therapy,but it is not possible to determine the specific benefits provided by steroid adminis-tration in these trials.8,9 The positive short-term effects of intra-articular corticoste-roid administration in relieving local symptoms of inflammation in RA patients hasbeen shown in two RCTs. Triamcinolone hexacetonide seems to have the higherefficacy.44

In summary, systemic glucocorticoids, either alone or as part of a DMARD combi-nation strategy, are effective, in the short-term, for the relief of signs and symptomsand are probably effective in retarding radiographic progression in early and estab-lished RA. The systemic use of glucocorticoids in very early arthritis has not yet been for-mally investigated. Preferably, therapy with glucocorticoids is temporary because of therisk of side-effects, including weight gain, hypertension, diabetes, cataracts andosteoporosis, which justify careful monitoring and appropriate prevention. Further-more, 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 jointsymptoms. There is still no evidence that intra-articular or intra-muscular steroidsalter the course of early arthritis.

Disease-modifying anti-rheumatic drugs (DMARDs) have an effect on the diseaseprocess within weeks or months. Among the DMARDs, MTX is considered theanchor drug and should be used first in patients at risk of developing persistentdisease.4 Underlying this statement is the observation from a meta-analysis ofpatients with established RA, showing a significantly lower discontinuation rate ofMTX compared to other DMARDs (but leflunomide and TNF-blockers were not

34 B. Combe

evaluated).45 Several RCTs have proven the clinical efficacy of MTX. These RCTswere followed by observational studies clearly establishing that MTX is effectiveover long periods of time and that MTX has a better toxicity profile than otherDMARDs.46 Importantly, MTX is one of the only conventional DMARDs withproven efficacy on radiographic progression in RA.7 In early RA, two RCTs (one12- and one 18-month study), failed to demonstrate the superiority of MTX overother DMARDs such as sulphasalazine.24,25 However, recent RCTs with TNF-blocking drugs have shown that MTX is almost as effective as TNF blocker mono-therapy in patients with early (less than 3 years’ disease duration) severe RA.28,30 Animportant argument for considering MTX as an anchor drug is that it can becombined with biological treatments if necessary. This has emerged from RCTsshowing greater efficacy for the combination of TNF-blocking drugs with MTX,compared with monotherapy.12,29,30 The combination of MTX with TNF blockersappears to convey the maximal therapeutic effect currently obtainable both in estab-lished and early RA. The combination of MTX with sulphasalazine has not beenshown to be superior to a single drug.24,25 Despite interesting reports, whetherthe combination of MTX with other DMARDs is more efficient than monotherapyneeds further investigation.

Leflunomide and, to a lesser extent, sulphasalazine, have a similar clinical efficacy asMTX in established and recent RA (category Ia).4 Leflunomide is as effective as MTX inslowing radiographic damage.7 Sulphasalazine, in contrast, may be inferior to lefluno-mide and MTX in the long term.

In summary, MTX appears to be an anchor drug in RA, both as monotherapy and incombination with conventional DMARDs and/or TNF-blocking drugs for mostpatients with early RA. Although formal evidence that prioritises MTX as the firstDMARD in early RA is lacking, starting treatment with MTX (unless contra-indicated)in patients at risk of persistent and/or erosive disease is recommended.4 This recom-mendation is based on its clinical and radiological efficacy in combination with the rel-atively beneficial safety profile and on its beneficial properties in treatmentcombinations. Leflunomide7 and, to a lesser extent, sulphasalazine are consideredthe best alternatives.

Rehabilitative interventions

RA is commonly associated with limited function that can be improved with a widevariety of rehabilitation interventions aimed at the whole person and not just at thepainful area. These are part of the multidisciplinary approach to the management ofa person with early RA.19 The effect of non-pharmaceutical therapy has not beeninvestigated in early RA and can only be extrapolated from the results of severalRCTs and eight Cochrane reviews in established RA.4,19 RCTs have shown thatjoint-specific dynamic exercises may improve strength and physical function in RA,but without a clear effect on pain or disease activity.47,48 However, the optimal exer-cise programme has not yet been determined. One recent RCT and a Cochranereview49 reported a positive effect of occupational therapy on functional ability andself-management, but without an effect on disease activity. Hydrotherapy in RApatients has been evaluated in two recent meta-analyses, with positive findings butinsufficient evidence to support a strong recommendation.

Nine RCTs have been undertaken to investigate the efficacy of diet.4 The resultsare controversial: the diets and the study designs varied widely. Most of the trials

Prevention and management of early rheumatoid arthritis 35

with diets have major inclusion problems and only highly selected and motivated pa-tients could be recruited. A 1 year study randomised 66 patients to receive a vege-tarian diet free of gluten or a well-balanced non-vegan diet. The vegetarian diet groupexperienced significantly better effects in most clinical variables, including the ACR20response, compared to the non-vegetarian group.50 Two other RCTs found a positiveeffect of a vegetarian diet on pain and parameters of disease activity. Numerous othernon-pharmaceutical interventions have been investigated in RA patients including acu-puncture, laser therapy, use of compression gloves, transcutaneous electrical nervestimulation (TENS), ultrasound, thermotherapy, use of splints or ortheses and home-opathy. Controversial effects have been reported and, if positive, the RCTs demon-strated a short-term relief of pain, rather than an effect on disease activity.

Psychological interventions can reduce pain in the short term but, at follow-up,no post intervention on pain was seen, however coping with the disease wasmaintained.19

Three RCTs have demonstrated that written information may increase knowledgeabout the disease. One systematic review, four RCTs and two controlled trials showedthat a self-management education programme resulted in improved clinical outcomein RA patients, producing short-term effects on disability, joint count, patientglobal assessment, anxiety and depression, but without any evidence of long-termbenefit.4,51 There was only weak evidence that group education is better than individ-ual education.

In summary, some non-pharmaceutical interventions, such as dynamic exercises,occupational therapy and hydrotherapy, have shown symptom-relieving effects inestablished RA. There is limited evidence that a vegetarian diet may have a modesteffect on symptoms. Patient information should be considered important, since thebenefits of educational interventions have been shown in clinical trials. However, itis considered difficult to prioritise a single educational intervention, because all inter-ventions have only shown short-term benefits and are subject to cross-national andcultural variation. The efficacy of non-pharmaceutical interventions in early arthritishas not been formally tested and there is no indication that such interventions wouldimprove long-term outcome such as radiographic progression. Non-pharmaceuticalinterventions should only be applied as an adjunct to pharmaceutical therapies inpatients with early arthritis.

HOW TO IDENTIFY THOSE WHO WILL BENEFITMORE FROM INTERVENTIONS?

Risk factors for RA can be divided into risk factors for susceptibility and risk factorsfor severity of the disease. It is possible to modify some of these factors.

Risk factors for susceptibility of RA

Genetic risk factors have classically been studied in twin studies and it has beenshown that the shared risk for RA development between a pair of identical twinsis 15%. This should be compared to a risk of 0.8% in the general population.19

However, there is no single gene expression that has been identified as accountingfor this risk.

36 B. Combe

The incidence is influenced by age and gender. It is a rare disease in men underthe age of 35, but females reach an incident peak approximately 10 years earlierthan men and, overall, it is more common among woman than men. There issome connection to female hormonal factors and reduced occurrence of RA in youn-ger women has been connected to the use of oral contraceptives. Infection or immu-nisation might act as a trigger for RA onset, but there is no connection to a singleinfectious agent. Smoking has been shown to increase the risk of developing RA38

and so has obesity.By contrast, regular consumption of alcohol might protect against RA development.

Dietary factors are discussed, but the findings are not consistent. Patients often relatethe onset of RA to some traumatic event, physical or psychological, but there is noclear evidence to support this hypothesis.

Risk factors for severity of RA

After exclusion of diseases other than RA, the third step in the diagnostic proce-dure of early arthritis should be to try to determine which patients are at risk ofdeveloping persistent and/or erosive arthritis. This prognostic typing is consideredcrucial for guiding the optimal therapeutic strategy. At least 45 studies have evalu-ated the prognostic factors in early arthritis (n¼ 5) or early RA (n¼ 40).4,5 Theywere all observational or caseecontrol studies. Most prognostic factors wereanalysed in a multivariate manner in these studies, so that their independent con-tribution could be tested. In most of these studies, the variable to predict wasradiographic progression. The presence of IgM or IgA rheumatoid factor, higherythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level and earlyradiographic evidence of erosions, according to most of the reports, independentlypredicted long-term radiographic progression.52e54 The number of swollen jointsprobably correlates better with radiographic progression than the number of ten-der joints. Recently, several studies have demonstrated that presence of anti-CCPantibodies is also an independent prognostic factor for radiographic progression inearly arthritis and early RA.55 The presence of HLA-DRB1*0401 and DRB1*0404 isalso consistently associated with joint damage in different ethnic groups.53 Thisassociation appears to be dose-dependent, since patients with two RA-associatedgenes show more radiographic evidence of destruction than patients with non-associated alleles. HLA-DRB1*01 genes alone are not associated with RA severity.However, when DRB1*04 genes are included in logistic regression analyses, theydo not frequently contribute to explaining variation in the model, which makesDRB1 genotyping a less suitable tool for prognostic purposes.52,54 Duration of cig-arette smoking has also been shown to be an interesting susceptibility factor andaccelerator of disease progression in RA, but this variable has been infrequentlyinvestigated and selected as an independent parameter in multivariate studies.Smoking is also associated with a higher risk for the development of extra-articulardisease. It has also been shown that the prognosis may be worse in sociallydeprived areas. Abnormalities seen on MRI may be of prognostic interest.36 In gen-eral, single variables have shown limited prognostic value and several reports havetried to develop prediction models with a combination of the most reliablemarkers.5,52,53 Although some of these models seem promising, the developmentand (cross)-validation of a robust model, easy to use in all settings in clinical prac-tice, is still pending.

Prevention and management of early rheumatoid arthritis 37

WHAT STRATEGIES SHOULD BE USED FOR PREVENTIONAND TREATMENT IN EARLY RA?

To prevent the impact of RA on quality of life, individuals at greatest risk must beselected and encouraged to take measures to reduce their risk.19 Patients with earlyinflammatory arthritis should be identified and assessed as soon as possible, as manywill progress to develop persistent and erosive arthritis such as RA.4,19 There shouldbe education programmes to encourage self management. These should include infor-mation on the conditions, lifestyle and treatment.

Patients presenting with arthritis of more than one joint should be referred to andseen by a rheumatologist, ideally within 6 weeks of the onset of symptoms4, althoughthe level of evidence supporting the content of this recommendation is rather low.Joint swelling, not due to trauma, or bony swelling should suggest a diagnosis of earlyarthritis, especially if it includes involvement of at least two joints and/or morningstiffness >30 mins duration and/or involvement of metacarpophalangeal and/or meta-tarsophangeal joints.18 Involvement of hand and foot joints can be identified by apositive ‘squeeze test’.

The evaluation of the impact of a delay in the start of treatment on the outcome ofarthritis is difficult. Using the evidence in the literature and clinical experience, it isusually recommended that drug treatment should start within a relatively short periodafter the onset of complaints, ‘ideally within 6 weeks’.4,19 Several comparative stud-ies27e33 have shown a better functional status and earlier DMARD start by rheuma-tologists, which further supports the idea that patients with clinical presentationssuggesting arthritis should be referred early to a rheumatologist.4,18,56,57 The choiceof treatment should take into account the presence of prognostic indicators support-ing the use of more intensive therapy. Patients at risk of developing persistent and/orerosive arthritis should be started with DMARDs (in addition to symptomatic therapyand rehabilitative interventions) as early as possible even if they do not yet fulfill estab-lished classification criteria for inflammatory rheumatological diseases.4 Early arthritisis frequently undifferentiated at presentation and six studies have shown that classifi-cation criteria for established disease have little discriminant value during the earlymonths of the disease. Recent studies have shown that joint erosion occurs early inRA and that more than 80% of patients with a disease duration of less that 2 yearsmay already have radiographic evidence of joint damage. The concept of a ‘windowof opportunity’ for effective treatment of recent-onset RA has been supported byone meta-analysis23, six RCTs and several comparative or observational studies.14e16

Among patients with recent-onset polyarthritis, those who received DMARD therapyearly had a better outcome with regard to radiographic progression, function andability to work than those in whom DMARD therapy was delayed by a few months.Results of a meta-analysis of 1435 patients also support this concept: disease durationat the time of DMARD initiation was shown to be the main predictor of the responseto DMARD therapy.23

Treatment of early RA should be closely monitored to ensure ideal disease control17

and to adapt, as soon as possible, the therapeutic strategy.6 Monitoring of disease activityshould include tender and swollen joint count, patient’s and physician’s global assess-ments, ESR and CRP. Arthritis activity should be assessed at 1e3-month intervals, foras long as remission is not achieved. Structural damage should be assessed by X-ray every6e12 months during the first few years. Functional assessment (e.g. HAQ) can be used tocomplement the disease activity and structural damage monitoring.4

38 B. Combe

SUMMARY

Reduction or cessation of smoking is the only known preventive factor for RA.However, it is often possible to prevent damage of the joints with appropriate earlytreatment. Recent studies have shown that early, intensive treatment for RA candelay the onset of joint destruction. For the at risk population, that is thosewith early inflammatory arthritis, there is evidence that early diagnosis and treat-ment (early start with DMARDs, systemic or intra-articular corticosteroids) pre-vents the full occurrence of RA. The early use of DMARD treatment canreduce pain and stiffness and prevent joint erosions, as defined by radiologicalchanges. This improves the long-term outcome of the disease, as assessed by jointdamage, pain and disability. Initial intensive treatment provides a better outcomethan DMARD monotherapy including MTX in patients with recent-onset chronicarthritis, but mainly in a subset of patients with severe disease. Consequently, re-garding the risk:benefit ratio and the cost-effectiveness of these strategies, a reason-able course of action should be initial DMARD monotherapy with MTX (orleflunomide or sulphasalazine). There is also indirect evidence from various RCTsand observational studies that remission is associated with better radiographic out-come and better preservation of physical function. Since there is emerging evidencethat maintaining remission is as important as achieving remission, it is obvious thatdisease activity should be closely monitored, in order to change DMARD therapyand strategy if necessary.

Practice points

� Reduction or cessation of smoking could prevent the development andprogression of early rheumatoid arthritis (RA)� Early referral to a specialist is key to guaranteeing the patient’s early and appro-

priate diagnosis and therapeutic intervention� The objective of early RA management should be to achieve remission and to

prevent further joint damage and disability� A very early use of effective disease-modifying anti-rheumatic drugs (DMARDs)

is mandatory in order to prevent further joint damage and disability� To prevent the impact of RA on quality of life, patients at risk of developing

joint damage must be selected on the basis of prognostic factors and encour-aged to take measures to reduce their risk� A reasonable course of action based on the risk:benefit ratio and the cost-

effectiveness of the available medications should be initial DMARD monother-apy in most of the cases� Among the DMARDs, methotrexate should be used first in patients at risk of

developing erosive arthritis. Leflunomide seems to be the best alternative� A close monitoring of disease activity and radiographic damage is mandatory in

early RA in order to guide decisions and changes in treatment strategies,including intensive therapies such as biological agents� Systemic glucocorticoids induce a fast improvement of pain and swelling and

could be used as adjunct and temporary therapy as part of the traditionalDMARD strategy

Prevention and management of early rheumatoid arthritis 39

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Research agenda

� Ultrasonography and power Doppler should be validated for the diagnosis ofearly synovitis� Magnetic resonance imaging (MRI) should be validated for the diagnosis of

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tion models� Studies with an appropriate design to determine the comparative effectiveness

and cost-effectiveness of different therapeutic strategies are required

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