Best Practice & Research Clinical Rheumatology Vol. 19, No. 1, pp.

163177, 2005
doi:10.1016/j.berh.2004.08.009 available online at http://www.sciencedirect.com

10 Therapeutic strategies in early rheumatoid arthritis

Josef S. Smolen* MD Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria 2nd Department of Medicine, Lainz Hospital Vienna, Austria Daniel Aletaha
MD

Klaus P. Machold MD Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
Rheumatoid arthritis (RA) therapy rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). It has been unequivocally shown that DMARD therapy early in the course of RA retards progression of damage and disability to a larger degree compared with delayed institution; the most effective DMARD is methotrexate (MTX). Moreover, combination therapy including intermediate to high doses of glucocorticoids and combinations of MTX with tumour necrosis factor blockers are more effective than monotherapies. However, early DMARD treatment requires early referral of patients and early diagnosis. This is hampered by the current lack of classication criteria for early RA, since the aim is to prevent destruction from occurring, while RA is typically characterized by the presence of erosions. Novel treatment strategies and therapeutic agents allow us to aim for remission rather than improvement of disease activity. Whether a window of opportunity exists during which effective therapy might lead to cure is still an open issue and will be the focus of clinical trials in the near future. Key words: early arthritis; rheumatoid arthritis; DMARDs; methotrexate; combination therapy; biological agents; antitumour necrosis factor; rheumatoid factor; anti-RA33 anticyclic citrullinated peptide; remission; disease activity.

* Corresponding author. Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: C43 1 40400 4300; Fax: C43 1 40400 4331. E-mail address: josef.smolen@wienkav.at (J.S. Smolen). 1521-6942/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

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THE STAGE The erosive nature of rheumatoid arthritis (RA) mandates intensive interference with the pathogenic processes, since increasing joint destruction leads to increasing disability.1,2 Erosions may be seen within the rst few years of disease3,4, and even patients with less than 3 months duration of symptoms may already have evidence of destruction.5 Therapy with disease-modifying antirheumatic drugs (DMARDs) effectively impedes the disease process. In particular, data obtained with tumour necrosis factor (TNF) blockers in combination with methotrexate (MTX) suggest that progression of radiographic changes can be highly retarded, if not halted, in a majority of patients with longstanding RA.6,7 However, patients with long-established RA have already experienced signicant joint damage, and even mild but continuous progression of these changes may deteriorate functional capacity in the long term. This calls for intervention as early as possible in the disease course and such therapy is, in fact, efcacious.812 Approaching treatment of early RA requires consideration of several issues: (1) what is early RA?; (2) are DMARDs employed in early RA more efcacious than when applied later in the disease course?; (3) can DMARD therapy in early RA lead to remission or even cure?; and (4) how does one control for its effectiveness and when should therapy be modied? The latter is an aspect of general importance when discussing DMARD therapy.

WHAT IS EARLY RA? The denition of early RA is hampered by the lack of diagnostic criteria, given that the classication criteria of the American College of Rheumatology (ACR)13 were developed for chronic RA and for research purposes rather than diagnosis. Their application in early disease often fails to classify many patients correctly; some patients do not yet full the criteria, while others are classied wrongly.5,14 With the lack of better criteria, it has been suggested that a cumulative fullment of ACR criteria over time should be used to dene RA in patients with early arthritis.15 Interestingly, older criteria used the term possible RA for those patients who fullled only three of the criteria of those days, and a variety of exclusions were also stipulated16; thus, it may be worthwhile to reconsider the application of older criteria rather than using current criteria.13 Importantly, patients whose polyarthritis persists over more than 12 weeks are unlikely to experience spontaneous remission and are prone to develop erosive (and thus essentially rheumatoid) arthritis.14,17 Presence of rheumatoid factor (RF) was another independent predictor.14,1719 The 12-week limit is also regarded as important by a majority of rheumatologists surveyed in respect of the denition of early RA.20 Thus, polyarthritis persisting over 12 weeks or more may be regarded as early RA, especially if associated with positive RF; the presence of other auto-antibodies may also be supportive21, and prediction models for the development of erosive/destructive arthritis have been formulated based on these components22,23 but need further validation. Recommendations for early recognition and referral of patients at risk of developing RA have been proposed recently.24 Early joint inammation should be labelled as early arthritis or early undifferentiated arthritis in all instances that can neither be classied clearly as RA nor as reactive arthritis, connective tissue diseases, viral arthritis or similar.

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In fact, arthritis may have to be categorized as undifferentiated even in many patients with inammatory joint disease of more than 3 months duration.5,23,25 For research purposes, such preliminary categorization may be advantageous, since it allows further investigations into risk and prognostic factors.26 For the individual patient who will develop RA and thus for the fate of her/his disease, it may, however, be important to make the decision towards labelling a disease as RA and initiation of the best therapy at the best time, i.e. early. Most clinical trials investigating DMARD therapy of early RA have employed timelines that started within 3 months of diagnosis (sic!) and varied in terms of maximal duration for up to 3 (or even more) years. Whether this can be regarded as early or whether results of such studies allow us to extract sufcient information on the therapeutic fate of truly early RA (i.e. 36 months of symptoms) must be left open at present.

WHAT IS A CLINICALLY RELEVANT RESPONSE? Since RA is an inammatory disease that leads to joint destruction and long-term disability, assessment of response must relate to all three of these characteristics. However, in RA, inammation is associated with destruction and both features are linked to subsequent disability.1,9,2732 The inammatory response is traditionally measured by composite indices.3337 In clinical trials, the categorical ACR improvement criteria and the continuous Disease Activity Score (DAS)/European League against Rheumatism (EULAR) response criteria are valid measures3841, and a continuous simplied disease activity index (SDAI) has also been shown to correlate very well with these two scores.42 Radiographic progression is assessed by the Larsen or Sharp scores43 and quality of life is assessed by the Health Assessment Questionnaire (HAQ)44 or related measures, such as Short Form-36 or EuroQuol. Minimal improvements compared with placebo have been dened for each of these measures; for example, the ACR response requires a minimum of 20% improvement of tender and swollen joint counts and three of ve additional core-set variables. However, these minimal response rates are a compromise at the very low end of response and are insufcient to account for relevant improvement in terms of damage and disability. In fact, the aim is to achieve low disease activity as categorized by the DAS or SDAI; this would correspond to at least a 70% improvement in the ACR response. In fact, the aim should ideally be remission.

SHOULD WE GO FOR REMISSION? IS CURE POSSIBLE? In established RA, full and sustained remission is rare even when biological agents are employed. However, in early disease, remissions appear to be more frequently achievable.10,12,4549 Although remission in very early disease may be spontaneous rather than induced by therapy, this is unlikely to occur beyond 12 weeks (see above) it may be assumed that the process leading to joint destruction is still reversible in many patients with early RA, in terms of both reversal from a destructive to a non-destructive form of the disease as well as reversal of inammation. Although there are notions that joint destruction might continue to progress in RA patients even if they have achieved a remission-like state50,51, these observations need further evaluation, especially among early RA patients. Given that destruction as assessed by radiography reects past

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inammation, the relationship between remission and damage needs to be established between two timepoints in which remission-like states have been achieved and maintained (with the rst of these time points being at least 6 months in remission, the minimal time to assuring progression radiographically from past inammation). Many RA patients in remission are when DMARD therapy is stopped52, but it is currently unknown if (or how frequently) remissions in early RA mean cure (i.e. no evidence of active disease off therapy). There is yet another issue related to the denition of remission. The remission criteria of the ACR are very stringent and, for example, would not allow patients with joint pain from osteoarthritis or a raised erythrocyte sedimentation rate (ESR) for other reasons than RA to be called in remission.53 This is in contrast to the DAS28 remission criteria54, which may be too loose as they also allow patients with many swollen joints to full them. In any case, achieving remission is one prerequisite to best interfere with joint destruction and long-term disability. The best odds for such a goal ought to be in early disease, i.e. when destruction is still absent or minimal. Nevertheless, a note of caution is necessary: it should be borne in mind that no study on early RA has yet revealed a halt of disease in a large majority of patients, let alone all patients.55 This may be due to the inherent nature of RA or, alternatively, because clinical trials in early RA have not approached the disease early enough and/or intensively enough. Clearly, it is not only important to reveal predictors of bad outcome, but also predictors of remission of disease. Persistence of arthritis for R12 weeks is a prognostic factor of further persistence. In a recent study, remission among 191 treated patients with RA of !1 years disease duration was related to clinical and functional variables as well as RF negativity, but not negativity for anticyclic citrullinated peptide (antiCCP).56 These data will need further conrmation in larger cohorts but do suggest that prediction is possible. Another recent investigation suggested that a high acutephase response and the degree of radiographic damage at baseline was highly predictive of increased joint destruction even on gold-standard therapy, MTX, and that this may be mitigated by the use of TNF blockers.57

WHEN TO START THERAPY AND HOW AGGRESSIVE SHOULD IT BE? Joint pain, swelling and stiffness are the main presenting clinical symptoms of patients with RA. Accordingly, these symptoms require appropriate therapeutic intervention. Such intervention, however, must pay attention to the fact that symptom modication alone is insufcient to cope with the intermediate- and long-term fate of RA, joint damage and disability. Moreover, the most effective symptom modication is currently achieved by therapies that modify the disease process at the same time. Delay of DMARD initiation by just a few months is associated with much more rapid progression of damage during the rst year of observation compared with very early DMARD institution, while after the rst year of DMARD therapy, damage in patients who started DMARD therapy later in the course of their disease appears to approach or even parallel that in patients treated very early.12,58 These observations indicate that very early DMARD treatment prevents much of the damage accrued during the initial months. Although, it may not be unequivocally proven that this matters with respect to long-term outcome, it must be assumed that any retardation of damage, and thus also the relatively modest effects achieved by appropriate therapy in the very early stages,

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will materialize at least by delaying the ultimate degree of damage and consequently disability in the long term. In fact, recent Finnish data conrm this assumption with respect to work disability and economic loss.59 Thus, aggressive DMARD therapy ought to be initiated as early as possible once the diagnosis of RA is made or suspected. Glucocorticoids that have rapid anti-inammatory as well as disease-modifying qualities60 but are aficted with signicant long-term adverse effects may then be used as bridging therapy until DMARDs are fully efcacious. However, when is RA diagnosed? As stated above, the current classication criteria may be misleading in early disease and it is particularly important to exclude the presence of other arthritis, such as those associated with connective tissue diseases or reactive or other infection-associated forms of arthritis. Provided that no diagnostic criteria for early RA are established, and as long as results of currently planned trials to treat early (unclassied) arthritis (oligo- or polyarthritis) aggressively are not available, it will be at the rheumatologists judgement whether a given form of early disease ought to be labelled early rheumatoid arthritis and thus whether DMARDs should be initiated or not. A worthy approach would be to start DMARD therapy if (patientreported) symptoms have persisted for 12 weeks, since this appears to be the borderline of spontaneous reversibility (see above) and conforms with the increasing judgement of a majority of rheumatologists for the rheumatoid nature of early arthritis.20,61 However, this time line may have to be reduced if patients are positive for RF (and/or auto-antibodies for CCP), since these auto-antibodies have been found to allow differentiation between (destructive) RA and milder forms of unclassied arthritis, to be associated with joint destruction and even to antedate the development of clinical symptoms.17,19,23,6264 Whether the presence of the shared epitope of the HLA-DR4 cluster is truly helpful for differentiation of RA remains an open issue, since several lines of evidence have suggested that HLA-DR4 may be associated with the presence of RF rather than severe disease.65,66 Thus, while symptomatic therapy and glucocorticoids, at low to high doses (see below), should be started as soon as a patient presents with symptoms, current evidence indicates that DMARDs should be initiated in patients with RF-positive unclassied oligo- or polyarthritis (unequivocally conrmed joint swelling) even if they have !3 months of disease duration; in RF-negative unclassied arthritic patients, this evidence would suggest a DMARD start after 3 months of symptoms. The type of DMARD will be discussed below.

THE ROLE OF NSAIDS AND GLUCOCORTICOIDS Non-steroidal anti-inammatory drugs (NSAIDs), including selective cyclo-oxygenase 2 (COX-2) inhibitors, are symptomatic agents that do not affect the propensity of RA towards destruction and thus do not change its long-term fate; this is clearly exemplied in dozens of clinical trials in which one group of patients received a DMARD and the control arm received placebo including NSAIDs. The fact that NSAIDs reduce swelling and pain may even obscure a patients risk of developing persistent, destructive disease.67 There is no evidence that the recently introduced selective COX-2 inhibitors behave differently. Glucocorticoids, on the other hand, are not only more potent anti-inammatory agents than NSAIDs, but also appear to have disease-modifying effects even at low doses60,68,69, although this remains a controversial issue.70 In early disease, oral or

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parenteral glucocorticoid application of high doses, or intra-articular injection17,67, may lead to more rapid remission of non-persistent forms of arthritis and thus allow better differentiation of RA from non-RA, or at least of persistence of disease: among 63 patients with early arthritis, those with !12 weeks of disease duration had a high frequency of remission after intramuscular or intra-articular glucocorticoid injections.17 These data are under current validation in a large clinical trial in Europe in the Stop Arthritis Very Early (SAVE) trial.71 The most important aspect of glucocorticoid therapy in early RA is its employment as an induction and bridging therapy. High doses of glucocorticoids (e.g. 60 mg/day) are likely to be the major effective component of aggressive combination therapies that have been shown to be advantageous in retarding radiographic progression as well as frequency of remission among early RA patients (see below).45,7274 Given these effects, one wonders whether studies showing a slightly better efcacy of biological agents compared with MTX75 in the early treatment phase would give the same result if glucocorticoids had been applied de novo in intermediate or short-term high doses at the start of MTX therapy. Thus, the role of glucocorticoids may be three-fold: in very early disease, intramuscular depot glucocorticoids may allow us to induce remission, or at least enhance the propensity towards remission, and patients with active disease despite such treatment must be regarded as very likely to have RA. When DMARDs are started, a short course of intermediate-dose glucocorticoids for 12 months (or intramuscular depot steroid) may rapidly reduce disease activity and thus improve prognosis by induction and bridging until DMARDs become effective76, while low-dose glucocorticoids could be used thereafter as consolidation and bridging therapy until the maximal effects of DMARDs are seen.9,17,58 As with bridging therapy, patients with reactivation of disease will benet from glucocorticoids while DMARDs are switched. Once patients have achieved a low disease activity state on DMARDs, glucocorticoids should be tapered and only employed further to inject single joints with continuing activity.

THE ROLE OF DMARDS AND COMBINATION THERAPY DMARDs are the mainstay of RA therapy due to their signicant effect on inammation, damage and function. Meta-analyses and retrospective analyses of large patient cohorts revealed that response to DMARDs or their retention rates are better in early stages of disease.77,78 Two important studies suggested that delay of the institution of DMARDs leads to impaired clinical, radiographic and functional outcome. Egsmose et al79 treated patients with RA !2 years duration in a double-blind placebo-controlled trial within 1 year from diagnosis with auranon or delayed such treatment employing placebo for 8 months; clinical and radiological benet was seen for the DMARD-treated group at 2 and 5 years. In an open trial, van der Heide et al randomized 238 consecutive patients with early RA to receive DMARDs either immediately or with delay; functional and clinical results signicantly favoured the early DMARD treatment group, and the control group had almost four times more treatment discontinuations.8 Since the days of these two studies, many investigations have revealed the advantage of treating RA early9,11,55,58,73,80,81 or even very early, i.e. within the rst 3 months from symptom onset12 with DMARD therapy compared with delayed institution. Although, it is not yet clear whether non-biological DMARDs and their combinations affect the disease process itself more effectively in early stages than

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late, it is at least evident that disease progression and health-related quality of life are inuenced earlier by early compared with delayed DMARD therapy and, therefore, disability will be signicantly delayed. Several studies have shown advantages of certain DMARDs over others, such as sulphasalazine over hydroxychloroquine82, and a metaanalysis has conrmed such differences.83 While, aside from auranon, the leasteffective DMARDs appear to be the antimalarials, there are still some patients who respond well to these drugs.84 A more recently introduced DMARD, leunomide, has not yet been formally studied in early RA, but subanalyses of patients with short disease duration who entered large clinical trials have revealed this drug to be at least equally effective in early compared with longstanding RA.85 The role of combination DMARD therapy is still controversial, if one disregards the addition of intermediate- or high-dose glucocorticoids. Hitherto, many studies have shown that combination DMARD therapy is not superior to monotherapy8689 if only low-dose glucocorticoid therapy is employed in both treatment arms.90 In most studies showing advantages of combination DMARD therapies over monotherapy, the control groups received either no glucocorticoids or doses of comparator DMARDs that were tto nen et al10 studied 195 insufcient to obtain signicant clinical effects.10,45,74,91 Mo patients with early RA in several treatment arms: those treated with combinations of DMARDs plus prednisolone achieved similar remission rates at 2 years (approximately 42%) regardless of whether treatment was delayed by O4 months or not; in contrast, patients treated with single DMARDs, many of whom had no addition of prednisolone, fared better when treatment was started early (!4 months of delay, remission rate 35%) compared with a treatment delay of O4 months (remission rate of 11%). Likewise, in the COBRA trial, Boers et al72 demonstrated, in 155 early RA patients with a median duration of 4 months from diagnosis, that a combination of sulphasalazine and MTX with 60 mg prednisolone was superior to sulphasalazine alone during the period of steroid and MTX application; the clinical difference between the groups decreased and was no longer signicant after prednisolone was stopped, and there were no further changes after MTX was stopped.72 However, a radiographic benet in favour of the combination treatment arm continued to be seen for several years92, although the patients originally treated with sulphasalazine plus MTX plus prednisolone also had signicant progression of radiographic damage. Finally, in the recently performed Best trial, patients started on a combination of MTX, sulphasalazine and high-dose glucocorticoids had similar efcacy as patients treated with MTX and a TNF blocker.93 Taken together, the data in the literature suggest that addition of intermediate- to highdose prednisolone to DMARDs, whether as mono- or combination therapy, is benecial if introduced early in the course of RA. The only apparent exception to the controversial data on combination DMARD treatment in the absence of high doses of glucocorticoids is the combination of TNF blockers with MTX. Double-blind controlled trials have shown this to be signicantly superior to MTX alone, even when the latter is employed at high doses.7,94 However, TNF blockers are currently not employed in very early, DMARD-naive RA. This may change as more information is accruing on predictors of aggressive disease.57 (see also Chapter 8). On the other hand, the current gold-standard DMARD is MTX, accelerated in dosing to achieve 2025 mg/week within 68 weeks and with folate substitution.95 In clinical practice, it will be important to start patients with a poor prognosis, such as high-titre RF, antiCCP or other predictors, on high-dose MTX or combination therapy with glucocorticoids at sufcient dose. In patients with a good prognosis, alternative

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DMARDs may be tried initially but should be rapidly switched (after a maximum of 34 months) if remission (or at least very low disease activity) is not achieved.96

CONTROL OF EFFECTIVENESS Rather than the drug chosen, it appears to be the tight clinical control examinations with frequent (every 24 months) assessment of disease activity and consequent changes of regimens in patients with continuing active disease that allow achievement of the best results.97 In this study, 110 patients with active early RA (!5 years) were started on sulphasalazine and were to be switched to triple-combination DMARD therapy, then to increased prednisolone and then to other DMARDs or combinations in the course of randomization to routine clinical care or intensive care which aimed at a DAS44!2.4 with monthly control examinations; the tight control (TICORA) arm fared much better clinically (ACR70 of 67 vs 18%), functionally (twice as much HAQ improvement) and radiographically, although the retardation of radiographic progression was only borderline, statistically, and even in the TICORA group, patients progressed signicantly over the 18 months of observation; this latter result may have been due to the late introduction of higher-dose glucocorticoids. The advantage of tight control was also seen in the Best study93, where even patients randomized to sequential monotherapy, although statistically inferior to other regimens, could achieve low disease activity states in 50% of cases and remission-like states in almost 30% of

Early RA: Early DMARD therapy MTX dose 20-25 mg/week (within 2 months) (+ steroids)

Longstanding RA: High-dose DMARD (combination) therapy (+ steroids)

DAS28 improvement >1.2 or SDAI improvement > 20 or HAQ<0.5 within 34 months NO

YES

DAS28 < 2.6 or SDAI < 5 or HAQ<0.5 within 34 months NO

YES

Continue aggressive DMARD therapy

Add another DMARD +/ corticosteroids or Add a biological agent (e.g. TNF antagonist)

Add another DMARD +/ corticosteroids or Add a biological agent (e.g. TNF antagonist)

Figure 1. Algorithm for achieving therapeutic success in rheumatoid arthritis (RA). DMARDs, diseasemodifying antirheumatic drugs; MTX, methotrexate; DAS, Disease Activity Score; SDAI, simplied disease activity index; HAQ, Health Assessment Questionnaire; TNF, tumour necrosis factor. Source: Smolen et al Clin Exp Rheumatol 2003; 21(supplement 31): S209S210.96

Therapeutic strategies in early rheumatoid arthritis 171

cases. On the other hand, early institution of combination therapy with high-dose glucocorticoids (COBRA type) or biological agents was more effective statistically. The tight control concept has already previously been proposed on the basis of the many previous studies on early RA, recent clinical practice and our understanding of the pathogenesis and the implications of continuing disease activity on the course of RA.96 This proposed treatment algorithm, as it is in line with the current state of evidence, is shown in Figure 1.96 Based on such attempts to achieve the lowest possible disease activity today compared with just signicant improvement in earlier years, future observational studies of DMARD strategies in early RA will not be comparable with previously published ones.98,99 Nevertheless, recent observational evidence suggests that the gold-standard DMARD, MTX, has been employed more frequently, at increasingly higher doses and with shorter lag time over more recent years.78,99,100 In fact, given its high efcacy, the fact that it is the major constituent of most combination therapies and also serves as a treatment basis for combination with biological agents, MTX is todays major anchor drug and should, with few exceptions, be employed as the treatment of choice in early RA.101 A proposed treatment algorithm, as it is in line with the current state of evidence, is shown in Figure 1.96 Importantly, early therapeutic intervention requires early referral, and early referral must be met by short delays in the specialty clinics, which is rarely the case.20,61 To fully cope with the challenge of early arthritis in general and early RA in particular, more early arthritis clinics and respective infrastructures for enhanced possibilities of clinical examination and diagnostic work-up are needed (see Chapter 1).102

SUMMARY Early recognition of RA (or arthritis with a poor prognosis) and early intervention with DMARDs in conjunction with glucocorticoid therapy appear to be key to optimal management of early RA. With the currently available therapeutic armamentarium, very early therapy has been demonstrated to be superior to more traditional, delayed treatment. Such treatment primarily rests on the use of MTX. Importantly, patients ought to be followed intensively (every 24 months) with respect to the effect of therapy on reduction of disease activity using established composite disease activity indices. If the therapeutic aim to achieve low disease activity or even remission is not achieved, therapeutic strategy must be changed by employing other or additional DMARDs or biological agents, especially TNF blockers. The ideal drug or combination of drugs for starting treatment early (rheumatoid) arthritis remains to be determined, particularly in view of the necessity to develop diagnostic and prognostic criteria. These will allow us to obtain optimal treatment algorithms for individual patients. In fact, an individualized therapeutic approach is of particular importance in early arthritis. Current evidence suggest that a poor prognosis is associated with persistent (O12 weeks of symptoms) arthritis, high number of involved joints, high acute-phase response, high-titre RF and antiCCP. It is likely that the most important aspect in the context of treating early arthritis is early referral to the rheumatologist for diagnostic and prognostic evaluation, which ought to ensure optimal patient care.

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Practice points early arthritis is often undifferentiated in nature, once other diagnoses are excluded; it may remit spontaneously or under symptomatic therapy, or may persist; synovitis when present for 12 weeks or more is regarded as persistent and is likely to evolve into RA it is not easy to diagnose RA at very early stages, since current RA classication criteria are often not fullled or misleading; in fact, RA may start as mono-, oligo- or polyarthritis prognostic markers of destructive disease in patients with persistent arthritis are: high number of swollen joints, high C-reactive protein (CRP)/ESR, and presence of RF and/or autoantibodies to cyclic citrullinated peptide once arthritis is persistent, DMARDs should be started as soon as possible, MTX, accelerated in dosing to reach 2025 mg once weekly within 68 weeks with folate substitution (5 mg/week), is the gold-standard therapy; sulphasalazine and leunomide or combination therapy are alternatives institution of DMARD therapy early in the disease retards its progression and, in some patients, may lead to sustained remission; this is especially true if such therapy starts at !12 weeks of symptom duration; NSAIDs alone are insufcient to interfere with the disease process, whether early or late in its course glucocorticoids are effective in rapid reduction of disease activity, especially until full efcacy of DMARD therapy develops, and should be added at least initially measuring disease activity at short (24 monthly) intervals and guiding therapeutic decision making according to preset levels of improvement in disease activity confers better results than traditional patient care disease activity indices are composite scores that allow us to follow the disease activity of RA patients; the higher the disease activity, the more likely and rapidly RA will progress with respect to joint damage and disability: the DAS is calculated as follows: DAS28 K 0.56*SQRT(28TJC C 0.28*SQRT(28SJC)C0.7*In(ESR)C0.014*PGA (TJC, tender joint count; SJC swollen joint count; 28, employing the 28-joint count; PGA, patient assessment of global disease activity); remission: !2.6, low disease activity: !3.2, high disease activity: O5.1; moderate and good responses have been dened; the SDAI is obtained by numerical summation: SDAIZSJC(28)CTJC(28)C PGA(VAS in cm)CMDGA (VAS in cm)CCRP (in mg/dl) (VAS, visual analogue scale; MDGA, observers assessment of global disease activity); remission: !5, low disease activity: !20, high disease activity: O 40; moderate and good responses have been dened the optimal approach to early RA requires early referral of patients with arthritis to specialists and early diagnosis of the disease using mainly clinical and serological investigations, although diagnostic criteria for early RA do not yet exist the major aim of therapy is remission or, at least, very low disease activity

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Research agenda classication or diagnostic criteria for early RA are still missing and need to be developed prognostic criteria for rapidly progressive disease have been suggested and require validation treatment algorithms must be consolidated on the basis of prognostic markers clinical trials in very early arthritis are needed to test if cure or prevention of the development of RA can be achieved

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