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What have we learnt about the development and progression of early RA from RCTs?

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Most randomized controlled trials (RCTs) investigating the treatment of early rheumatoid arthritis (RA) use the core set of measures proposed by consensus meetings in the 1990s; these include tender and swollen joint counts, pain, global assessments, disability, and acute-phase responders such as the erythrocyte sedimentation rate (ESR). Trials in early RA generally assess three key outcomes based on this core data set: symptoms and signs of inflammatory arthritis, progression of disability, and erosive damage. Adverse events are also recorded. This chapter considers the lessons learned from the various trials in terms of benefits and adverse effects of different treatment regimens.

Introduction

It was little more than 30 years ago that randomized controlled trials (RCTs) started to examine the treatment of early RA. Although it is problematic crediting any one RCT as being the first to study early RA, the evidence points towards the trial by Dwosh et al acting as the forerunner of future research in the field [1]. In this RCT the effects of azathioprine were compared with those of gold and chloroquine in RA of <5 years' duration. Thirty-three patients were enrolled and randomized to receive azathioprine, gold or chloroquine. All groups showed similar changes over time. The following year Mäkisara et al[2] reported a series of 100 patients with RA of up to 3 years' duration that were treated for the first time with either penicillamine or gold for 12 months. Both groups improved by similar amounts.

These two studies, only one of which was a definite trial, set the scene for future research in this field. Their key characteristics were examining patients with up to 5 years' disease duration treated with disease-modifying drugs for up to 12 months, during which time a variety of clinical outcomes was assessed. Over the years, the maximum disease duration has fallen, sometimes to no more than 12 months, and the numbers of patients have increased. However, the general ethos of the trials remains unchanged.

The dominant focus of treatment is improving the symptoms of early RA. Initially trials used joint counts, the erythrocyte sedimentation rate (ESR), and measures such as grip strength. These have changed over time, but only marginally. Almost all RCTs now use the core set of measures proposed by consensus meetings in the 1990s. These include tender and swollen joint counts, pain, global assessments, disability, and the ESR or another acute-phase responder. American College of Rheumatology (ACR) responder rates or disease activity scores (DAS) are usually calculated from these.

In the main, trials in early RA assess three key outcomes based on the core data set. The first is the symptoms and signs of inflammatory arthritis, which are usually assessed by ACR responder rates or changes in DAS. The second is the progression of disability, which is usually assessed by changes in a self-assessed measure such as the health assessment questionnaire (HAQ). The third is erosive damage, which is usually assessed on x-rays and measured using a standardized scoring system such as the Sharp or Larsen scores.

In addition to these conventional outcomes, trials invariably record adverse events. These are described in detail but rarely quantified, making comparisons of trials more difficult. One approach used in a systematic review is to compare withdrawals due to lack of effect.

There have been a number of systematic reviews that have dealt entirely or partially with early-RA patients treated with disease-modifying anti-rheumatic drugs (DMARDs), steroids or biologics, especially tumour necrosis factor (TNF) inhibitors [3], [4], [5], [6], [7], [8], [9], [10], [11]. These used broadly comparable search strategies to identify trials in Medline and other databases using terms such as early rheumatoid arthritis, randomized controlled trial, DMARD, and the names of individual drugs. We have followed this search strategy to identify trials for this review. We have also excluded trials that use drugs not available in Europe, studies that have no obvious control group, very small studies, and papers that were not written in English. We divided the studies into four broad groups: placebo-controlled trials of DMARDs, delayed treatment studies, comparator trials, and combination studies. We have used descriptive methods rather than formal meta-analyses to compare the results.

Section snippets

Placebo-controlled trials of disease-modifying drugs

There have been seven placebo-controlled trials of disease-modifying drugs in early RA. These have involved oral gold [12], sulphasalazine [13], [14], [15] and hydroxychloroquine [16], [17], [18]. These trials, which enrolled 790 patients, are summarized in Table 1.

All seven trials show evidence of clinical benefits, assessed by higher falls in joint counts, ESR, or combined measures such as DAS with active treatment. Three trials evaluated falls in HAQ; two showed a significant difference, and

Delayed treatment

Five studies have specifically examined the impact of delayed treatment [22], [23], [24], [25], [26]. Some but not all of them were randomized; in this analysis we have combined both randomized and non-randomized studies. The studies involved intramuscular gold, oral gold, or a range of DMARD treatments. These five studies enrolled 982 patients who were followed for up to 2 years. They are summarized in Table 2.

Four studies evaluated clinical outcomes; two showed a benefit from early treatment

Comparator studies

Eight trials have compared one DMARD with another to compare effectiveness. In two trials sulphasalazine was compared to hydroxychloroquine [28], [29] or intramuscular gold [30]; one of these studies reported the clinical outcomes separately from the radiological outcomes, and for this analysis the reports have been considered together as representing a single trial. Two trials compared methotrexate with intramuscular gold [31], [32]; one of these trials involved oral methotrexate and the other

Combination therapies

Twenty six trials have evaluated combination therapy with DMARDs, biologics or steroids in comparison to DMARD monotherapy. Eighteen trials used a parallel design, in which the combination therapies were started immediately. Six of these parallel-group trials studied only DMARDs [37], [38], [39], [40], [41], [42], six studied glucocorticoid/DMARD combinations *[43], [44], [45], [46], [47], [48], and six studied biologic/DMARD combinations [49], *[50], [51], [52], *[53], [54] (all the biologics

Adverse effects

All the studies show a tendency for more adverse reactions with increasing treatment intensity, though the differences between studies are small. Choy et al, in a systematic review of combination therapy, showed approximately a 50% increased rate of withdrawals due to toxicity in all trials, and this was also seen in early RA combinations. This excess appears to be replicated across most trials. Some studies suggest no increase at all in toxicity, but these are in the minority.

Heterogeneity of early RA

Irrespective of the benefits of treatment, RA remains a highly variable disease in which some patients do well with very little treatment and others do badly with the most intensive treatment available. Consequently no treatment is correct for all patients. It is currently impractical to identify specific groups of patients most at risk of poor outcomes, although patients with many active joints who are positive for rheumatoid factor do less well. Ideally clinical and laboratory tests could be

Conclusion

The balance of evidence now favours starting early intensive treatment for active RA with DMARDs given in combination. The optimal combination is uncertain and there is support for both intensive treatment with two DMARDs and steroids and for methotrexate with TNF inhibitors. In some countries, such as the UK, access to early biologic treatment is restricted and therefore intensive DMARDs and steroids are recommended. Elsewhere there may be immediate access to methotrexate and TNF inhibitors.

Acknowledgments

The authors' ongoing research in rheumatoid arthritis is supported by the Arthritis Research Campaign and he is grateful for their continuing help.

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