**5.1 The problem of glucocorticoid resistance**

GC resistance has been observed in the clinical setting for a long time and represents a challenge for clinicians as treatment requires larger doses of GC associated with an increased risk of adverse events. GC resistance may occur in a quarter to a third of RA patients. The emergence of this subgroup was first reported in a paper by Van Schaardenburg et al in 1995 (Van Schaardenburg et al., 1995). This study looked at elderly onset RA patients treated with oral prednisolone and a 30% discontinuation rate due to lack of efficacy was reported. Further confirmation of this phenomenon came in a study by Sliwinska-Stanczyk et al (Sliwinska-Stanczyk et al., 2007) who showed a 25% resistance rate in their 44 patients who had moderately active RA and who were not taking other disease modifying agents. This group went on to show that clinical GC resistance seemed to correlate with a failure of GC to adequately suppress in vitro peripheral blood mononuclear cell (PBMC) proliferation in the affected individuals.

The problem of GC-resistance is not unique to RA and has been observed in a range of inflammatory conditions including ulcerative colitis (UC), asthma and uveitis (Creed & Probert, 2007; Lee et al., 2009; Sousa et al., 2000; Barnes & Adcock, 2009). The proportion of 25-33% GC resistance seems to be preserved across the various diseases and the possible mechanisms underlying this are explored in the following sections.
