**1. Introduction**

In 1949 Hench & Kendall published the first report of a treatment that was to revolutionise the management of rheumatoid arthritis (RA) (Hench & Kendall, 1949) and indeed, much of medicine. Their work was based on the observation that RA seemed to improve in patients who were pregnant or jaundiced. The adrenal cortex extract they used contained the hormone 17-hydroxy-11-dehydrocorticosterone, and they set the scene for the use of glucocorticoid (GC) therapy in the management of RA. In the 62 years since that seminal publication, our knowledge of the mechanisms of action of GC has increased markedly. The extent of GC use has ebbed and flowed because of concerns about adverse effects and in the light of the subsequent discovery of new anti rheumatic agents, but nevertheless the role of GC in the clinic has endured and around 10 million new prescriptions for oral GC are written each year in the USA alone (Schäcke et al, 2002)

In recent years the importance of GC in preventing long term joint erosions has been confirmed (Kirwan et al., 1995). Today they are seen as an important "disease modifying" agent in their own right and are recommended by the UK National Institute for Health and Clinical Excellence (NICE) for the early treatment of rheumatoid arthritis (Rudolph, 2009). Moreover, they remain an effective clinical tool for achieving short term control of disease flares especially in high doses administered intravenously. Their use in intra-articular injections is also a mainstay for targeting disease flares in particular joints and thus GC continue to form an important part of the therapeutic armoury of rheumatological practice (van Vollenhoven, 2009).

The main clinical problem associated with the use of GC is the numerous adverse effects. The most serious of these include the development of glucose resistance or in some instances type 2 diabetes. Other important adverse effects include hypertension, osteoporosis, skin changes, sleep disturbance, weight gain and changes to body fat distribution (Schäcke et al., 2002). This wide spectrum of actions reflects the many physiological roles of endogenous GC.

As our knowledge of the action of GC increases, we can begin to tackle the two key challenges that lie ahead. Firstly, how can the benefits of these drugs be utilised while minimising their many adverse effects. Secondly, is it possible to identify a distinct subset of patients with inflammatory disorders who are resistant to GC. Apart from RA, clinical GC resistance can be found in a range of inflammatory conditions including asthma, inflammatory bowel disease and uveitis (Barnes & Adcock, 2009). GC-resistant disease is the

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis 5

other anti-inflammatory treatments, with an effect size of about 1.25. However, these results do not seem to be sustained in most patients after 6 to 12 months. In practice some patients are unable to completely come off GC therapy as they experience a recurrence of

The first report of the disease modifying effects of long term low dose glucocorticoids was in 1995. The Arthritis and Rheumatism Council Low Dose Glucocorticoid Study was a double blind placebo controlled trial which studied the effects of 7.5mg of prednisolone (in addition to standard therapy for RA ) on radiographic joint erosions. The results showed a significant benefit in the prednsiolone group but no statistically significant difference in adverse events between treatment and placebo (Kirwan et al., 1995). This observation again confirms that low dose GC is relatively safe in clinical practice and in this case the risk versus harm

There are now 14 randomised controlled trials included in a Cochrane meta-analysis (Kirwan et al., 2007) which concludes that low dose GC therapy in addition to standard therapy in rheumatoid arthritis significantly reduces the rate of joint erosions (Fig 1). The doses needed to achieve these effects are modest and hence associated with less adverse effects. Even in studies of patients not taking other conventional DMARDs alongside GC,

**2.3 Role of low dose glucocorticoids in prevention of joint erosions** 

balance clearly falls in favour of treatment with GC.

the average reduction in the rate of joint progression was 70%.

Fig. 1. Summary of data from Cochrane meta-analysis (Kirwan et al., 2007)

Subsequent analysis of longer term follow up data from some of these studies shows that the anti-erosive effects of GC persist several years after the treatment has been discontinued (Fig 2). In particular the data from the COBRA trial which compared sulphasalazine alone with combination sulphasalazine, methotrexate and a tapering dose of prednisolone showed anti-erosive benefits at 5 years in the GC group, long after the GC had been discontinued (Landew et al., 2002). The Uterecht trial (Johannes et al., 2006) which looked at the effects of 10mg prednisolone in a DMARD naïve group of patients also demonstrated a significant reduction in radiological joint progression at 2 years which was sustained at 5 years (2 years

symptoms.

cause of considerable morbidity, as affected individuals are subject both to the adverse sequelae of on-going inflammation, and the systemic adverse effects of GC. The mechanisms underlying this phenomenon are becoming more apparent and understanding and overcoming GC resistance in a subset of RA patients may offer further insight into the pathophysiology of RA itself.
