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Treating very early rheumatoid arthritis

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Rheumatoid arthritis (RA) is common and leads to joint damage due to persistent synovitis. The persistence of inflammation is maintained by hyperplastic stromal tissue, which drives the accumulation of leukocytes in the synovium. Aggressive treatment after the first 3–4 months of symptoms, with either disease modifying anti-rheumatic drugs or anti-tumor necrosis factor (TNF)-α therapy, reduces the rate of disease progression. However, it rarely switches off disease such that remission can be maintained without the continued need for immunosuppressive therapy. There is increasing evidence that the first few months after symptom onset represent a pathologically distinct phase of disease. This very early phase may translate into a therapeutic window of opportunity during which it may be possible to permanently switch off the disease process. The rationale for, and approaches to, treatment within this very early window are discussed.

Introduction

Early inflammatory arthritis is remarkably common. However, in up to half of patients the disease resolves spontaneously over a few months.1, 2 In the rest, the processes driving the natural resolution of inflammation are disrupted, leading to a switch to chronic persistent disease characterised by the accumulation of large numbers of lymphocytes, macrophages and fibroblasts in the synovium. Rheumatoid arthritis (RA) is the most prevalent of the persistent inflammatory arthritides, affecting 0.81% of adults in the UK.3 The disease typically manifests as a symmetrical peripheral inflammatory polyarthritis that leads to joint destruction and may be associated with extra-articular features. RA causes significant disability4, 5 and enhanced mortality, predominantly related to accelerated cardiovascular disease.6, 7

In the 1980s treatment decisions in RA were guided by a ‘pyramid approach’, with non-steroidal anti-inflammatory drugs (NSAIDs) being used as initial therapy, and disease modifying anti-rheumatic drugs (DMARDs) being added later, usually after the development of erosive disease. The development of this therapeutic approach was based on two assumptions. First, that RA was a benign, non-life threatening disease, in which damage occurred late. Secondly, that DMARDs were too toxic for widespread use. Identifying that these assumptions were false8 led to an important shift in the management of RA in the early 1990s. It became apparent that bone erosion, an important feature of established RA, actually began early in the course of disease9 and was due to active synovitis.10, 11, *12 These and other observations led to the use of DMARDs and anti-tumor necrosis factor (TNF)-α therapy earlier in the course of RA to limit damage by reducing the cumulative inflammatory burden to which patients were exposed.13, 14 Nevertheless, therapy was restricted to patients in whom it was clear that established RA had developed (typically with symptoms of more than 3 months duration) and in whom the chances of the disease resolving spontaneously were slim.

Over the last 5–10 years we, and others, have shown that the persistence of chronic inflammation in the rheumatoid synovium is associated with hyperplastic stromal tissue, which inhibits leukocyte apoptosis leading to the accumulation of inflammatory cells in the joint.15, 16, 17, *18, 19 Once symptoms have been present for more than 3 months the immunopathological processes operating in the rheumatoid synovium appear to become stereotyped and become very similar in patients with markedly different disease durations. Therapy after the first 3 months of symptoms with conventional DMARDs (reviewed in Smolen et al)20 as well as with drugs targeting TNF-α21, 22, reduce disease activity and so limit the development of damage, but do not cure RA. However, there is accumulating evidence that the very early phase of synovitis in patients destined to develop RA (within the first 12 weeks of symptoms) represents a pathologically distinct stage of disease.23, 24, 25, *26 This suggests that late disease is not just more of early disease and gives, for the first time, a clear rationale for suggesting that very early intervention may have a qualitatively different effect compared with later intervention – a genuine therapeutic window of opportunity during which the potential for therapies to permanently switch off inflammation needs to be explored.27, 28 In this article we will discuss those studies that have treated RA patients with symptoms of less than 2 years duration, review why intervention within this time frame fails to switch off inflammation permanently and outline the rationale and prospects for intervention within the first 3 months of symptoms.

Section snippets

The treatment of ‘early’ RA

The time frames within which the effects of therapy have been studied in most trials of ‘early’ intervention in RA have been somewhat arbitrarily defined and have been based on the principle of ‘the earlier the better (assuming the patient has definitely developed RA)’.

Most trials of ‘early’ therapy have chosen a maximum symptom duration of 2 years. Therapeutic approaches studied to date have included intra-articular and systemic steroid, DMARD monotherapy, DMARD combination therapy and

Why is it so difficult to permanently switch off rheumatoid synovitis in patients with symptoms of more 3 months duration: lessons from pathology

Physiological inflammation is not a stable state. During the early stages of a local inflammatory response, large numbers of leukocytes are recruited from peripheral blood into the inflamed tissue. In the absence of extrinsic stimuli such inflammation resolves and the tissue reverts to normal. Resolution is mediated by the cessation of recruitment of further inflammatory cells and the clearance of unwanted effector cells. The clearance of inflammatory cells results, at least in part, from the

Very early therapy within the first 3 months of symptoms

The first 12 weeks of symptoms represents a potentially important therapeutic window in patients with very early synovitis destined to develop RA. However, treating patients within this phase presents three challenges: (1) getting patients with symptoms of such short duration to clinic; (2) predicting which patients with very early synovitis will develop RA and thus require treatment; (3) determining how such patients should be treated.

Future directions

As the last 15 years have seen a move towards the introduction of DMARDs (singly or in combination) within the first year of disease, the next 5 years are likely to see studies assessing the effects of therapy within the first few months of symptoms. A desire to introduce therapy earlier in the course of disease will stimulate research into predictors of the development of RA in patients with very early synovitis in an attempt to improve on the sensitivities of current tests.

Studies in early

Conflicts of interest

K.R. has received honoraria from Wyeth, Pfizer and UCB Celltech. C.D.B. acts as a consultant for Wyeth and UCB Celltech. K.R., C.D.B. and M.S. hold research grants from Wyeth.

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