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Therapeutic strategies in early rheumatoid arthritis

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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 classification 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.

Section snippets

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 first 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

What is early RA?

The definition of early RA is hampered by the lack of diagnostic criteria, given that the classification 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 fulfil the criteria, while others are classified wrongly.5, 14 With the lack of better criteria, it has been suggested that a cumulative fulfilment

What is a clinically relevant response?

Since RA is an inflammatory disease that leads to joint destruction and long-term disability, assessment of response must relate to all three of these characteristics. However, in RA, inflammation is associated with destruction and both features are linked to subsequent disability.1, 9, 27, 28, 29, 30, 31, 32 The inflammatory response is traditionally measured by composite indices.33, 34, 35, 36, 37 In clinical trials, the categorical ACR improvement criteria and the continuous Disease Activity

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, 45, 46, 47, 48, 49 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

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 modification alone is insufficient to cope with the intermediate- and long-term fate of RA, joint damage and disability. Moreover, the most effective symptom modification is currently achieved by therapies that modify the disease process at the same time.

The role of NSAIDS and glucocorticoids

Non-steroidal anti-inflammatory 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 exemplified 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 patient's risk of developing persistent,

The role of DMARDS and combination therapy

DMARDs are the mainstay of RA therapy due to their significant effect on inflammation, 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

Control of effectiveness

Rather than the drug chosen, it appears to be the tight clinical control examinations with frequent (every 2–4 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

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 2–4 months) with respect to the effect of

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