**4. New drug development in glucocorticoid therapy**

There are several exciting developments in the world of GC therapy which aim to maintain the now well described benefits of this class of drugs whilst minimising adverse events. A better understanding of the mechanisms involved in GC action has made this goal a realistic one and there are already new licensed drugs on the market which are available for use in rheumatological practice. Broadly speaking there are two research strategies which are being pursued. The first approach aims to develop new GC analogues which can selectively reduce inflammation while minimising adverse effects (Kirwan & Power, 2007). This class of drugs are known as selective glucocorticoid receptor agonists or SEGRAs. This approach is based on the notion that the majority of therapeutic GC effects are due to the repression of gene transcription while the majority of the adverse effects are due to gene activation. Dissociating these two actions of GC is an attractive goal. The second approach utilises the improved understanding of the circadian HPA axis and its interaction with the inflammatory pathways and aims to develop new GC therapies that are better targeted to augment the natural diurnal variation.

#### **4.1 SEGRAs**

12 Rheumatoid Arthritis – Treatment

GC have a mixture of genomic and non-genomic therapeutic effects depending on the dosage used. Broadly speaking genomic effects occur at lower doses while non-genomic effects become relevant at higher doses with the combined effect of the two mechanisms accounting for the total effect of GC therapy (Fig 7). This has implications for therapeutics as at the lower doses not all the mechanisms are activated therefore the adverse effect profile may significantly differ. In essence low dose GC therapy is a very different treatment compared to high dose therapy both in terms of therapeutic effects and safety (Kirwan & Power, 2007).

Fig. 7. Contribution of genomic and non genomic therapeutic effects of GC action is dose

There are several exciting developments in the world of GC therapy which aim to maintain the now well described benefits of this class of drugs whilst minimising adverse events. A better understanding of the mechanisms involved in GC action has made this goal a realistic one and there are already new licensed drugs on the market which are available for use in rheumatological practice. Broadly speaking there are two research strategies which are being pursued. The first approach aims to develop new GC analogues which can selectively reduce inflammation while minimising adverse effects (Kirwan & Power, 2007). This class of drugs are known as selective glucocorticoid receptor agonists or SEGRAs. This approach is based on the notion that the majority of therapeutic GC effects are due to the repression of gene transcription while the majority of the adverse effects are due to gene activation. Dissociating these two actions of GC is an attractive goal. The second approach utilises the improved understanding of the circadian HPA axis and its interaction with the inflammatory pathways and aims to develop new GC therapies that are better targeted to

**4. New drug development in glucocorticoid therapy** 

augment the natural diurnal variation.

dependent.

Dissociating the beneficial and adverse effects of GC was suggested over 10 years ago but has so far proved largely elusive. The first such compound was RU24858 which was described in 1997 by Vayssiere et al (Vayssière et al., 1997). Despite showing initial promise in dissociation of GC mediated gene activation and repression, the in-vivo effects were more disappointing and the drug did not make it into clinical trials (Belvisi et al., 2001). Other drugs such as A276575 have again shown promise but fared little better (Lin et al., 2002). The only SEGRA in clinical trials at the moment is ZK 245186 which is in Phase III trials for topical use post cateract surgery after initial results from animal models showed promise (Proksch et al., 2011). The Pahse II trail was concluded at the end of 2010 but results have not yet been released. The struggle to take SEGRAs from the bench to the bedside has been quite disappointing but not entirely surprising given the sheer number of biological mechanisms influenced by GC in vivo.

#### **4.2 Modified release glucocorticoids**

Modelling of the diurnal variation of the HPA axis and its effects on the secretion of systemic inflammatory cytokines in RA has been a novel approach which has yielded positive results. The cytokine IL-6 has been unequivocally shown to have a diurnal variation which causes an increase in serum concentrations during the night, before the natural increase in serum cortisol, and which reaches a peak at the time of morning waking (Perry et al., 2009). This has opened the door for the development of a modified release form of GC tablet which is taken at night and releases the active ingredients in the early hours of the morning (approximately 2 am) in order to target the peak in IL-6 levels (Kirwan, 2011). The rationale behind this approach suggests that better targeting of glucocorticoids within the HPA axis may produce better efficacy hence allowing clinicians to use smaller doses of GC. Indeed a multi-centre RCT comparing a modified release GC preparation with the equivalent prednisolone dose showed significant improvements in the duration of early morning stiffness in RA (Buttgereit et al., 2008). Interestingly, a recent study by Clarke et al. (Fig 8), which measured overnight cortisol concentrations as well as IL-6 in RA patients treated with modified release GC, showed the normal pre-treatment cortisol response to be suppressed in active RA and this suppression was reversed using the correctly timed modified release therapy with a corresponding decrease in IL-6 levels and clinical symptoms (Clarke et al., 2011).

Fig. 8. Effects of modified release GC on 24 hour diurnal variation of systemic IL-6 and cortisol in RA patients

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis 15

GCR-β is an alternatively spliced form of the GC receptor and its over-expression has been linked with GC resistance in asthma, RA and inflammatory bowel disease (Hamid et al., 1999; Sousa et al., 2000; Kozaci et al., 2007; Orii et al., 2002). GCR-β does not bind GC and in fact its natural ligand (if it has one) remains unknown (Lewis-Tuffin, 2006). However, it does compete with GCR-α for the GRE binding sites on DNA, thus acting as a dominant negative inhibitor. Another anti-GC mechanism may be the disruption of active GCR-α translocation to the nucleus since the down regulation of GCR-β in the alveolar macrophages of patients with asthma leads to enhanced GCR-α localization and a greater response to GC. Moreover, it has been shown that various pro-inflammatory cytokines can up regulate the expression of GCR-β and this may explain why patients seem to develop clinical GC resistance with worsening of their inflammatory disease (Webster et

The role of defective histone acetylation in acquired GC resistance has emerged principally from studies on patients with asthma and chronic obstructive pulmonary disease (COPD). As described previously, inflammatory stimuli ultimately lead to the activation of NFκB which binds to specific κB recognition sites on the promoter regions of inflammatory genes in addition coactivators which cause acetylation of core histones. This leads to their unravelling and opens up the genes for transcription. Activated GCRs inhibit this effect directly by binding the coactivators and recruiting histone deacetylase (HDAC) 2 which reverses the acetylation (Rhen & Cidlowski, 2005). GCRs themselves become acetylated upon ligand binding to allow them to bind GREs and can be targeted directly by HDAC2. HDAC2 activity has been shown to be reduced in alveolar macrophages of GC resistant asthma patients and patients with COPD (Ito et al., 2005; Hew et al., 2006). This reduced activity is thought to be secondary to the oxidative stress resulting from smoking (Rahman & Adcock, 2006). Smoking and obesity, both causes of oxaditive stress, are both risk factors for developing rheumatoid arthritis (Symmons et al., 1997). In COPD it has been shown that low dose oral theophylline can reverse GC resistance by restoring HDAC2 activity (Ito et al., 2005). This effect is independent of phosphodiesterase inhibition and is mediated via the selective inhibition phospho-inositide-3-kinase-δ (PI3Kδ). This is an enzyme which is activated by oxidative stress in patients with COPD (To et al., 2010). This pathway has not been studied in rheumatoid arthritis and presents a

T helper (Th) cells differentiate into distinct phenotypes under the influence of the inflammatory cytokine milieu which is largely dictated by cytokines released from monocyte derived macrophages. IL-17 producing T-helper cells (TH-17 cells) have recently been identified as a distinct pro-inflammatory T-helper subset and their role in various autoimmune processes including RA (Kirkham et al., 2006), multiple sclerosis (Matusevicius et al., 1999), psoriasis and inflammatory bowel disease (Duerr, 2006) is becoming more apparent. They seem to have a reciprocal relationship with regulatory IL-10 secreting T helper cells (McGeachy, 2007) and drive an inflammatory response which is dominated by

**5.3 Glucocrticoid receptor β expression** 

**5.4 Defects in histone acetylation** 

novel way of reversing GC resistance.

**5.5 T Helper-17 cells and glucocorticoid resistance** 

al., 2001).
