Early rheumatoid arthritis: strategies for prevention and management

Best Practice & Research Clinical Rheumatology Vol. 21, No. 1, pp. 27e42, 2007 doi:10.1016/j.berh.2006.08.011 available online at http://www.sciencedirect.com

2 Early rheumatoid arthritis: strategies for prevention and management Bernard Combe*

MD, PhD

Professor of Rheumatology Immuno-Rhumatologie Hoˆpital 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 since new tools and new concepts have been developed and validated highlighting the need for guidelines focused on early RA. The treatment goal should now be to achieve clinical remission, in order to prevent structural damage and long-term disability. A very early use of effective disease-modifying anti-rheumatic drugs (DMARDs) is a key point in patients at risk of developing persistent and erosive arthritis. Intensive treatment such as combination DMARDs plus steroids or biological therapies can induce a high rate of remission, control of radiological progression and provide better outcome than DMARD monotherapy in early RA and should be considered in 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 as methotrexate. However, a close monitoring of disease activity and radiographic progression is mandatory in order to change DMARD therapy and strategy if necessary. Systemic glucocorticoids are effective in the short-term relief of pain and swelling and should be considered, but mainly as a temporary therapy part of the DMARD strategy. Information and education for patients, as well as some non-pharmacological interventions, can be proposed as treatment adjuncts. Finally, the reduction or stopping of smoking, which could prevent the development 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 is usually used to describe a symmetrical, persistent and destructive polyarthritis often associated with rheumatoid factor and/or positive results for anti-cyclic citrullinated peptide (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: [email protected] 1521-6942/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

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somewhat difficult since no test and no diagnostic criteria are available to define early RA.1 In practice, early inflammatory arthritis is frequently undifferentiated.2 Early arthritis may develop into established RA or another definite arthropathy, but it may also go on to remission or stay undifferentiated. To better evaluate diagnosis and outcome in arthritis, it has been proposed to first recognise inflammatory arthritis, then to eliminate definite diagnoses of arthritis (e.g. lupus, psoriatic arthritis, seronegative spondylarthropathies, 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 combination of clinical, biological and radiographical parameters may help to predict arthritis outcome with good accuracy.5 The management of RA has changed considerably in the past few years since we have developed new tools and validated new concepts, highlighting the need for guidelines focussed on the management of early arthritis such as those that have been recently developed by the European League Against Rheumatism (EULAR: see Table 1).4 The treatments used currently are more effective and more aggressive.6 New diseasemodifying anti-rheumatic drugs (DMARDs) and DMARD combinations have shown their ability to slow disease progression.7e10 Furthermore, biological therapies have demonstrated rapid and sustained disease control, which is associated with impressive prevention of joint destruction.11e13 A body of evidence about early RA now exists to support the very early use of effective DMARDs, preferably before the first radiographic evidence of erosions, to prevent further joint damage and disability.14e16 Consequently, early referral to a specialist is key to guaranteeing the patient’s early diagnosis and therapeutic intervention.17 The assessment and close monitoring of patients with early arthritis seems crucial for better adaptation of therapeutic strategies and an ideal treatment proposal should be based on an appropriate prognosis for the disease.3,10,18 In addition, management of early arthritis includes more than drug treatment only. The European Bone and Joint Health Strategies Project has recently provided recommendations 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 with pain, stiffness and symmetrical swelling of the small joints of the hand and feet, but may also involve any other synovial joint. The incidence of RA is estimated as 4e13 per 100 000 for adult males and 13e36 per 100 000 for adult females. Estimates of the prevalence of RA range from 1e6 per 1000 for men and 3e12 per 1000 for women.19 The peak age of onset is between 35 and 45 years of age. However males and 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. There is also a high incidence of psychological stress during the early stages of RA, which persists into established RA and is attributed to symptoms such as pain, fatigue and disability. Even in its early stages, RA can have a significant impact on a patient’s ability to carry out their activities of daily living, work and leisure. Health status is significantly impaired from the onset, as measured by generic instruments (e.g. SF36, Euroquol 5D) or by disease-specific instruments (Health Assessment Questionnaire (HAQ)). Within 2 years of onset, the HAQ score was between 0.8 and 1.04 out of a maximum of 3.0.20,21 RA has an early impact on a patient’s ability to work and their socio-economic

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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 rheumatologist, 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, erythrocyte 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-modifying 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 employed as adjunct interventions. 7. Non-steroidal anti-inflammatory drugs (NSAIDS) have to be considered in symptomatic patients after 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 hydrotherapy 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

status. Work capacity is restricted in one-third of patients within 1 year22 and within 3 years about 40 % will be registered as work-disabled. Targets that are most important in the prevention and management of early RA are: e e e e

To To To To

reduce pain and inflammation reduce disability prevent radiological damage and progression reduce the development of co-morbidities

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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.

TREATMENT GOALS The introduction of new drugs that can control disease progression and the demonstration that DMARDs are more effective if used earlier rather than later in disease progression, have led to crucial changes in management goals in early arthritis and early RA.11e16, 23 The objective should now be to achieve remission, in order to prevent structural damage and long-term disability.4 One recent therapeutic strategy in the treatment of RA is the early use of combination therapy with conventional DMARDs (‘intensive’ therapy). Some randomised controlled trials (RCTs) have evaluated the combination of two DMARDs (mainly methotrexate (MTX) esulphasalazine or MTXecyclopsorine) in early RA with controversial results both in clinical efficacy and radiographic evidence of progression.24e27 However, a combination of MTX and sulphasalazine with high-dose steroids in a step-down therapeutic strategy resulted in protracted effects on radiographic progression, compared to sulphasalazine monotherapy in 155 patients with early RA.8 These results are consistent with those from the FIN-RACo study, in which

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197 patients with RA onset within the previous 2 years were randomly assigned to receive either a four-drug therapy, with MTX, sulphasalazine, hydroxychloroquine and prednisolone (5 mg/day), or a single DMARD.9 After 18 months, a greater proportion of the combination-therapy group were in remission. After 5 years, the combination group were less likely to have radiographic progression and the work disability rate 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 arthritis may profoundly affect long-term radiographic progression is also supported by four recent RCTs with tumour necrosis factor (TNF) blockers in early RA. In patients with a disease duration of less than 3 years, the use of a TNF blocking drug, especially in combination with MTX, revealed an increased rate of clinical remissions and slowing of radiographic change when compared with MTX monotherapy.28e30 The effect size of such a combination versus MTX alone on total radiographic score in patients with early RA varied from 0.42e0.96. These data are consistent with those from several RCTs in established RA, showing that intensive treatment with a combination of conventional DMARDs plus steroids or with biological therapy in combination with MTX, may provide better clinical and radiological efficacy compared to monotherapy.6,12 In addition, a recent RCT compared four treatment strategies in early RA, including a progressive step-up regimen, sequential monotherapy, a step-down combination strategy with MTX, sulphasalazine and high-dose prednisone, and infliximab plus MTX.10 The two groups with initially 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 study17, patients with early RA were randomly assigned to an intensive 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 group had 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. 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 relationship between disease activity (DAS and DAS28) and radiological progression, after adjustment for time effects and baseline predictors of radiological destruction and their interactions with time.31 In the PREMIER30, ASPIRE29 and TEMPO (despite being performed in established RA)32 studies, clinical remission was achieved in some patients and higher remission rates were associated with arrest of radiographical progression (there might even be some repair) and better physical function. There is now ample evidence that with treatment combinations with or without biological agents clinical remission is 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 structural damage in early RA is still based on radiographs of the hands and feet. Structural damage 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 the management of early arthritis (to prevent joint destruction) and the observation that radiographic progression is highest during the first 2 years after disease onset. The scientific evidence for the clinical value of using ultrasonography in early arthritis is limited. In one controlled study and in a few comparative studies magnetic

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resonance imaging (MRI) has been shown to be more sensitive than radiography for the detection of erosions in early RA.35 There is also evidence suggesting that MRI findings (e.g. synovitis, bone oedema, bone erosions) may predict subsequent radiographic progression.36 However, the level of evidence is rather low and changes resembling mild synovitis or small bone erosions were occasionally found in the joints of healthy subjects, questioning the specificity of this technique.37 Nevertheless, the search for persistent synovitis using ultrasonography or MRI may help in the definition of true remission. Issues of standardisation and reliability of these techniques have been addressed and are ongoing. WHAT CAN BE DONE: THE EVIDENCE FOR DIFFERENT INTERVENTIONS The evidence for different interventions is considered in the context of the agreed targets for the prevention and treatment of RA and for the populations that the evidence applies to.19 Lifestyle interventions A combination of genetic and environmental factors, such as infections, reproductive or hormonal factors and factors related to lifestyle, is considered to be responsible 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 the associated pain and functional limitations of RA.38 The reduction or stopping of smoking could prevent the development of radiological damage and progression of RA. Ensuring an appropriate body weight by following a healthy diet and maintaining physical activity can influence pain in RA. To prevent early, undifferentiated, symmetric arthritis progressing to RA with disability, there is evidence to recommend smoking cessation. The effect of smoking on the occurrence and course of RA has been shown to remain for several years after stopping. To reduce the impact of RA for those with the condition, there is evidence to recommend physical activity.4,19 There is limited evidence that other lifestyle interventions such as vegetarian 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 pain using pharmacological therapies, with improvement in function, activities and participation. Simple analgesics are used to manage pain in all stages of the disease, often in combination with other therapies to control the inflammatory process. Non Steroidal Anti-Inflammatory Drugs (NSAIDs) have an instantaneous effect on pain and stiffness without influencing the disease process. Substantial evidence, including a Cochrane review in established RA, indicates that both classical and cyclo-oxygenase 2 (COX-2) selective NSAIDs are more effective than simple analgesics in relieving the signs and symptoms of active disease.39 However, there are concerns 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 the addition of gastroprotective drugs to classical NSAIDs can significantly reduce GI complications such as the incidence of GI bleeding. In addition, the long-term use of COX-2 selective drugs has been associated with increased cardiovascular risk. Probably, 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 raised recommendations for the use of these drugs. Among others, they recommend the shortest treatment duration that is possible and contra-indications for at risk patients. There is no reason to assume that these observations should not be extrapolated to early RA. Symptomatic patients presenting with early arthritis should, therefore, be treated with NSAIDs after careful evaluation of GI, renal and cardiovascular status. Glucocorticoids are used either intra-articularly or systemically. Several RCTs and three systematic reviews have demonstrated that systemic low-dose glucocorticoids, typically prednisone 10 mg/day, were effective in relieving short-term signs and symptoms in patients with RA.40 Results of a recent open study of 100 patients with undifferentiated arthritis suggested that a single dose of intra-muscular or intra-articular steroids may even induce remission41, although formal evidence for this strategy is lacking. In addition, and despite controversial data, steroids are probably effective in slowing radiographic progression in early and established RA. In a RCT with patients with RA of less than 1 year’s duration, van Everdingen et al42 compared treatment with prednisone, 10 mg daily, versus NSAIDs. Only sulphasalazine was allowed in this study, but only after 6 months, as a rescue medication. The prednisone group showed significantly less radiographic progression at 12 and 24 months. The effect size of low-dose steroids for Larsen score compared to symptomatic treatments was only 0.26 at 24 months. These data are supported by another RCT43 and by two trials in early RA, which indicated that combination-therapy including steroids was more efficient 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.8,9 The positive short-term effects of intra-articular corticosteroid administration in relieving local symptoms of inflammation in RA patients has been shown in two RCTs. Triamcinolone hexacetonide seems to have the higher efficacy.44 In summary, systemic glucocorticoids, either alone or as part of a DMARD combination strategy, are effective, in the short-term, for the relief of signs and symptoms and are probably effective in retarding radiographic progression in early and established RA. The systemic use of glucocorticoids in very early arthritis has not yet been formally investigated. Preferably, therapy 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. Intraarticular steroids may be effective as an adjunct to DMARDs in relieving local joint symptoms. There is still no evidence that intra-articular or intra-muscular steroids alter the course of early arthritis. Disease-modifying anti-rheumatic drugs (DMARDs) have an effect on the disease process within weeks or months. Among the DMARDs, MTX is considered the anchor drug and should be used first in patients at risk of developing persistent disease.4 Underlying this statement is the observation from a meta-analysis of patients with established RA, showing a significantly lower discontinuation rate of MTX compared to other DMARDs (but leflunomide and TNF-blockers were not

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evaluated).45 Several RCTs have proven the clinical efficacy of MTX. These RCTs were followed by observational studies clearly establishing that MTX is effective over long periods of time and that MTX has a better toxicity profile than other DMARDs.46 Importantly, MTX is one of the only conventional DMARDs with proven efficacy on radiographic progression in RA.7 In early RA, two RCTs (one 12- and one 18-month study), failed to demonstrate the superiority of MTX over other DMARDs such as sulphasalazine.24,25 However, recent RCTs with TNFblocking drugs have shown that MTX is almost as effective as TNF blocker monotherapy in patients with early (less than 3 years’ disease duration) severe RA.28,30 An important argument for considering MTX 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 MTX, compared with monotherapy.12,29,30 The combination of MTX with TNF blockers appears to convey the maximal therapeutic effect currently obtainable both in established and early RA. The combination of MTX with sulphasalazine has not been shown to be superior to a single drug.24,25 Despite interesting reports, whether the combination of MTX with other DMARDs is more efficient than monotherapy needs further investigation. Leflunomide and, to a lesser extent, sulphasalazine, have a similar clinical efficacy as MTX in established and recent RA (category Ia).4 Leflunomide is as effective as MTX in slowing radiographic damage.7 Sulphasalazine, in contrast, may be inferior to leflunomide and MTX in the long term. In summary, MTX appears to be an anchor drug in RA, both as monotherapy and in combination with conventional DMARDs and/or TNF-blocking drugs for most patients with early RA. Although formal evidence that prioritises MTX as the first DMARD 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 recommendation is based on its clinical and radiological efficacy in combination with the relatively beneficial safety profile and on its beneficial properties in treatment combinations. Leflunomide7 and, to a lesser extent, sulphasalazine are considered the best alternatives. Rehabilitative interventions RA is commonly associated with limited function that can be improved with a wide variety of rehabilitation interventions aimed at the whole person and not just at the painful area. These are part of the multidisciplinary approach to the management of a person with early RA.19 The effect of non-pharmaceutical therapy has not been investigated in early RA and can only be extrapolated from the results of several RCTs and eight Cochrane reviews in established RA.4,19 RCTs have shown that joint-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 exercise programme has not yet been determined. One recent RCT and a Cochrane review49 reported a positive effect of occupational therapy on functional ability and self-management, but without an effect on disease activity. Hydrotherapy in RA patients has been evaluated in two recent meta-analyses, with positive findings but insufficient evidence to support a strong recommendation. Nine RCTs have been undertaken to investigate the efficacy of diet.4 The results are 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 patients could be recruited. A 1 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 clinical variables, including the ACR20 response, compared to the non-vegetarian group.50 Two other RCTs found a positive effect of a vegetarian diet on pain and parameters of disease activity. Numerous other non-pharmaceutical interventions have been investigated in RA patients including acupuncture, laser therapy, use of compression gloves, transcutaneous electrical nerve stimulation (TENS), ultrasound, thermotherapy, use of splints or ortheses and homeopathy. Controversial effects have been reported and, if positive, the RCTs demonstrated 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 was maintained.19 Three RCTs have demonstrated that written information may increase knowledge about the disease. One systematic review, four RCTs and two controlled trials showed that a self-management education programme resulted in improved clinical outcome in RA patients, producing short-term effects on disability, joint count, patient global assessment, anxiety and depression, but without any evidence of long-term benefit.4,51 There was only weak evidence that group education is better than individual education. In summary, some non-pharmaceutical interventions, such as dynamic exercises, occupational therapy and hydrotherapy, have shown symptom-relieving effects in established RA. There is limited evidence that a vegetarian diet may have a modest effect on symptoms. Patient information should be considered important, since the benefits of educational interventions have been shown in clinical trials. However, it is considered difficult to prioritise a single educational intervention, because all interventions have only shown short-term benefits and are subject to cross-national and cultural variation. The efficacy of non-pharmaceutical interventions in early arthritis has not been formally tested and there is no indication that such interventions would improve long-term outcome such as radiographic progression. Non-pharmaceutical interventions should only be applied as an adjunct to pharmaceutical therapies in patients with early arthritis.

HOW TO IDENTIFY THOSE WHO WILL BENEFIT MORE FROM INTERVENTIONS? Risk factors for RA can be divided into risk factors for susceptibility and risk factors for 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 been shown that the shared risk for RA development between a pair of identical twins is 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 accounting for this risk.

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The incidence is influenced by age and gender. It is a rare disease in men under the age of 35, but females reach an incident peak approximately 10 years earlier than men and, overall, it is more common among woman than men. There is some connection to female hormonal factors and reduced occurrence of RA in younger women has been connected to the use of oral contraceptives. Infection or immunisation might act as a trigger for RA onset, but there is no connection to a single infectious 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 relate the onset of RA to some traumatic event, physical or psychological, but there is no clear evidence to support this hypothesis. Risk factors for severity of RA After exclusion of diseases other than RA, the third step in the diagnostic procedure of early arthritis should be to try to determine which patients are at risk of developing persistent and/or erosive arthritis. This prognostic typing is considered crucial for guiding the optimal therapeutic strategy. At least 45 studies have evaluated the prognostic factors in early arthritis (n ¼ 5) or early RA (n ¼ 40).4,5 They were all observational or caseecontrol studies. Most prognostic factors were analysed in a multivariate manner in these studies, so that their independent contribution could be tested. In most of these studies, the variable to predict was radiographic progression. The presence of IgM or IgA rheumatoid factor, high erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level and early radiographic evidence of erosions, according to most of the reports, independently predicted long-term radiographic progression.52e54 The number of swollen joints probably correlates better with radiographic progression than the number of tender joints. Recently, several studies have demonstrated that presence of anti-CCP antibodies is also an independent prognostic factor for radiographic progression in early arthritis and early RA.55 The presence of HLA-DRB1*0401 and DRB1*0404 is also consistently associated with joint damage in different ethnic groups.53 This association appears to be dose-dependent, since patients with two RA-associated genes show more radiographic evidence of destruction than patients with nonassociated alleles. HLA-DRB1*01 genes alone are not associated with RA severity. However, when DRB1*04 genes are included in logistic regression analyses, they do not frequently contribute to explaining variation in the model, which makes DRB1 genotyping a less suitable tool for prognostic purposes.52,54 Duration of cigarette smoking has also been shown to be an interesting susceptibility factor and accelerator of disease progression in RA, but this variable has been infrequently investigated and selected as an independent parameter in multivariate studies. Smoking is also associated with a higher risk for the development of extra-articular disease. It has also been shown that the prognosis may be worse in socially deprived areas. Abnormalities seen on MRI may be of prognostic interest.36 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 markers.5,52,53 Although 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.

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WHAT STRATEGIES SHOULD BE USED FOR PREVENTION AND TREATMENT IN EARLY RA? To prevent the impact of RA on quality of life, individuals at greatest risk must be selected and encouraged to take measures to reduce their risk.19 Patients with early inflammatory arthritis should be identified and assessed as soon as possible, as many will progress to develop persistent and erosive arthritis such as RA.4,19 There should be education programmes to encourage self management. These should include information on the conditions, lifestyle and treatment. Patients presenting with arthritis of more than one joint should be referred to and seen by a rheumatologist, ideally within 6 weeks of the onset of symptoms4, although the 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 early arthritis, especially if it includes involvement of at least two joints and/or morning stiffness >30 mins duration and/or involvement of metacarpophalangeal and/or metatarsophangeal joints.18 Involvement of hand and foot joints can be identified by a positive ‘squeeze test’. The evaluation of the impact of a delay in the start of treatment on the outcome of arthritis is difficult. Using the evidence in the literature and clinical experience, it is usually recommended that drug treatment should start within a relatively short period after the onset of complaints, ‘ideally within 6 weeks’.4,19 Several comparative studies27e33 have shown a better functional status and earlier DMARD start by rheumatologists, which further supports the idea that patients with clinical presentations suggesting arthritis should be referred early to a rheumatologist.4,18,56,57 The choice of treatment should take into account the presence of prognostic indicators supporting the use of more intensive therapy. Patients at risk of developing persistent and/or erosive arthritis should be started with DMARDs (in addition to symptomatic therapy and rehabilitative interventions) as early as possible even if they do not yet fulfill established classification criteria for inflammatory rheumatological diseases.4 Early arthritis is frequently undifferentiated at presentation and six studies have shown that classification criteria for established disease have little discriminant value during the early months of the disease. Recent studies have shown that joint erosion occurs early in RA and that more than 80% of patients with a disease duration of less that 2 years may already have radiographic evidence of joint damage. The concept of a ‘window of opportunity’ for effective treatment of recent-onset RA has been supported by one meta-analysis23, six RCTs and several comparative or observational studies.14e16 Among patients with recent-onset polyarthritis, those who received DMARD therapy early had a better outcome with regard to radiographic progression, function and ability 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 duration at the time of DMARD initiation was shown to be the main predictor of the response to 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 activity should include tender and swollen joint count, patient’s and physician’s global assessments, ESR and CRP. Arthritis activity should be assessed at 1e3-month intervals, for as long as remission is not achieved. Structural damage should be assessed by X-ray every 6e12 months during the first few years. Functional assessment (e.g. HAQ) can be used to complement the disease activity and structural damage monitoring.4

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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 early treatment. Recent studies have shown that early, intensive treatment for RA can delay the onset of joint destruction. For the at risk population, that is those with early inflammatory arthritis, there is evidence that early diagnosis and treatment (early start with DMARDs, systemic or intra-articular corticosteroids) prevents the full occurrence of RA. The early use of DMARD treatment can reduce pain and stiffness and prevent joint erosions, as defined by radiological changes. This improves the long-term outcome of the disease, as assessed by joint damage, pain and disability. Initial intensive treatment provides a better outcome than DMARD monotherapy including MTX in patients with recent-onset chronic arthritis, but mainly in a subset of patients with severe disease. Consequently, regarding the risk:benefit ratio and the cost-effectiveness of these strategies, a reasonable course of action should be initial DMARD monotherapy with MTX (or leflunomide or sulphasalazine). 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. Since 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.

Practice points  Reduction or cessation of smoking could prevent the development and progression of early rheumatoid arthritis (RA)  Early referral to a specialist is key to guaranteeing the patient’s early and appropriate 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 encouraged to take measures to reduce their risk  A reasonable course of action based on the risk:benefit ratio and the costeffectiveness of the available medications should be initial DMARD monotherapy 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 traditional DMARD strategy

Prevention and management of early rheumatoid arthritis 39

Research agenda  Ultrasonography and power Doppler should be validated for the diagnosis of early synovitis  Magnetic resonance imaging (MRI) should be validated for the diagnosis of synovitis, for showing early erosions and for the prognosis of further joint destruction  Accurate classification and diagnostic criteria for early rheumatoid arthritis (RA) are still lacking and need to be developed  The available prediction algorithms for persistent and/or erosive arthritis and for long-term disability should be further evaluated  Randomised controlled trials of non-pharmacological interventions in early arthritis are needed  The most efficient and effective information/education interventions and exercise programmes for early arthritis need to be determined  The role of glucocorticoids in very early arthritis should be evaluated  Whether the temporary use of glucocorticoids can prevent the progression of joint destruction if started in early arthritis should be further investigated  The effects of the temporary use of intensive treatments, such as biological agents in early arthritis should be investigated to test whether prevention of erosions and cure (a long-term remission) of the disease is possible  Therapeutic strategies in early arthritis should be tested on the basis of prediction models  Studies with an appropriate design to determine the comparative effectiveness and cost-effectiveness of different therapeutic strategies are required

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