**2. Glucocorticoid use in rheumatoid arthritis**

GC are still widely used in the management of RA and between 25-75% of patients with RA are treated more or less continuously with GC (Johannes et al., 2010). They are used in high doses (including intra-articular injection which provides a high dose to the synovium) to rapidly control acute disease flares. Moreover, the anti-inflammatory effects of lower dose GC can also be beneficial for a large number of patients especially when starting standard disease modifying anti-rheumatioc drugs (DMARDs) which often take weeks to months to have their full effect. Whether this anti-inflammatory effect persists in the long term over and above that achieved by standard DMARDs is a matter of debate.

The most recently confirmed role of GC is their use in preventing long term joint erosions as measured through radiological progression. In the last 10-15 years this observation (Kirwan et al., 2007) has put GC firmly back on the map as effective disease modifying agents in their own right.

#### **2.1 High dose short term therapy**

The use of high dose GC therapy to control life threatening complications of rheumatic diseases such as rheumatoid vasculitis is widespread. Intravenous methyprednisolone is often used in "pulsed therapy" at doses of around 1000mg. At these doses all GC receptors are saturated and there are undoubtedly non-genomic effects as discussed later in this chapter (Tyrrell & Baxter, 1995).

The necessity of such high doses in clinical practice remains a matter for debate due to the lack of large randomized controlled trials in rheumatoid arthritis which specifically address this question. The practice has been inherited largely from success in managing life threatening systemic lupus erythematosus and from transplant rejection rescue. In the clinical setting however, such doses seem to be successful and this success is captured in small non controlled and retrospective trials (Jacobs et al., 2001; Weusten et al., 1993). These small trials also demonstrate that short term pulsed therapy is relatively safe but there remains the concern over significant infection from profound immunosupression. A review by Badsha et al in 2003 suggested that lower (but still high) doses may be just as effective (Badsha & Edwards, 2003).

#### **2.2 Anti-Inflammatory effects of low dose therapy**

GC therapy is often initiated shortly after diagnosis in RA usually in combination with disease modifying agents. Many patients find GC to be very effective in controlling their symptoms and continue the therapy long term. A recent Cochrane review confirmed the effectiveness of low dose (<15mg per day) GC therapy compared to traditional NSAIDs and placebo. It analysed 10 studies with 320 patients and the overall results showed an improvement in all parameters with GC therapy. These included pain scales, joint scores, morning stiffness, fatigue and improvement in acute phase reactant levels (Criswell et al., 2000; Gotzsche & Johansen, 2004). The therapeutic benefit is much greater than that of

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

GC are still widely used in the management of RA and between 25-75% of patients with RA are treated more or less continuously with GC (Johannes et al., 2010). They are used in high doses (including intra-articular injection which provides a high dose to the synovium) to rapidly control acute disease flares. Moreover, the anti-inflammatory effects of lower dose GC can also be beneficial for a large number of patients especially when starting standard disease modifying anti-rheumatioc drugs (DMARDs) which often take weeks to months to have their full effect. Whether this anti-inflammatory effect persists in the long term over

The most recently confirmed role of GC is their use in preventing long term joint erosions as measured through radiological progression. In the last 10-15 years this observation (Kirwan et al., 2007) has put GC firmly back on the map as effective disease modifying

The use of high dose GC therapy to control life threatening complications of rheumatic diseases such as rheumatoid vasculitis is widespread. Intravenous methyprednisolone is often used in "pulsed therapy" at doses of around 1000mg. At these doses all GC receptors are saturated and there are undoubtedly non-genomic effects as discussed later in this

The necessity of such high doses in clinical practice remains a matter for debate due to the lack of large randomized controlled trials in rheumatoid arthritis which specifically address this question. The practice has been inherited largely from success in managing life threatening systemic lupus erythematosus and from transplant rejection rescue. In the clinical setting however, such doses seem to be successful and this success is captured in small non controlled and retrospective trials (Jacobs et al., 2001; Weusten et al., 1993). These small trials also demonstrate that short term pulsed therapy is relatively safe but there remains the concern over significant infection from profound immunosupression. A review by Badsha et al in 2003 suggested that lower (but still high) doses may be just as effective

GC therapy is often initiated shortly after diagnosis in RA usually in combination with disease modifying agents. Many patients find GC to be very effective in controlling their symptoms and continue the therapy long term. A recent Cochrane review confirmed the effectiveness of low dose (<15mg per day) GC therapy compared to traditional NSAIDs and placebo. It analysed 10 studies with 320 patients and the overall results showed an improvement in all parameters with GC therapy. These included pain scales, joint scores, morning stiffness, fatigue and improvement in acute phase reactant levels (Criswell et al., 2000; Gotzsche & Johansen, 2004). The therapeutic benefit is much greater than that of

pathophysiology of RA itself.

agents in their own right.

**2.1 High dose short term therapy** 

chapter (Tyrrell & Baxter, 1995).

(Badsha & Edwards, 2003).

**2.2 Anti-Inflammatory effects of low dose therapy** 

**2. Glucocorticoid use in rheumatoid arthritis** 

and above that achieved by standard DMARDs is a matter of debate.

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 symptoms.

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

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 balance clearly falls in favour of treatment with GC.

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, 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

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis 7

The adverse effects of GC therapy should be considered and discussed

This advice should be reinforced by giving information regarding

 If GC are to be used for a more prolonged period of time, a ''glucocorticoid card'' is to be issued to every patient, with the date of commencement of treatment, the initial dosage and the

Initial dose, dose reduction and long-term dosing depend on the underlying rheumatic disease, disease activity, risk factors and individual

Timing may be important, with respect to the circadian rhythm of

When it is decided to start GC treatment, comorbidities and risk factors for adverse effects should be evaluated and treated where indicated; these include hypertension, diabetes, peptic ulcer, recent fractures, presence of cataract or glaucoma, presence of (chronic) infections, dyslipidaemia and

For prolonged treatment, the GC dosage should be kept to a minimum, and a GC taper should be attempted in case of remission or low disease activity; the reasons to continue GC therapy should be regularly checked

During treatment, patients should be monitored for body weight, blood pressure, peripheral oedema, cardiac insufficiency, serum lipids, blood and/or urine glucose and ocular pressure depending on individual

If a patient is started on prednisone >7.5 mg daily and continues on prednisone for more than 3 months, calcium and vitamin D

 Antiresorptive therapy with bisphosphonates to reduce the risk of GC-induced osteoporosis should be based on risk factors, including

Patients treated with GC and concomitant non-steroidal antiinflammatory drugs should be given appropriate gastro-protective medication, such as proton pump inhibitors or misoprostol, or alternatively could switch to a cyclo-oxygenase-2 selective inhibitor

All patients on GC therapy for longer than 1 month, who will undergo surgery, need perioperative management with adequate GC replacement

Children receiving GC should be checked regularly for linear growth and considered for growth-hormone replacement in case of growth impairment

GC during pregnancy have no additional risk for mother and child 87

Fig. 3. Summary of EULAR recommendations for the use of GC in rheumatological practice.

subsequent reductions and maintenance regimens

both the disease and the natural secretion of GC

comedication with non-steroidal anti inflammatory drugs

with the patient before GC therapy is started

**Strength of Recommendation (0-100 VAS)** 

92

93

79

86

57

92

86

93

100

93

93

93

93

**Proposition** 

GC management

responsiveness of the patient

patient's risk, GC dose and duration

supplementation should be prescribed

bone-mineral density measurement

to overcome potential adrenal Insufficiency

(VAS=visual analogue score)

after discontinuation of the prednisolone). This continued benefit of GC in preventing joint erosions long after their anti-inflammatory benefits have subsided is noteworthy. There is increasingly an appreciation in the literature for several simultaneous pathogenic processes taking place in the RA joint. In particular joint erosions and synovitis seem to be two distinct processes and their apparent dissociation in the case of GC therapy is therefore not surprising (Kirwan, 2004).

Fig. 2. X-ray progression after stopping trial therapy

#### **2.4 Adverse effects of glucocorticoids in rheumatology practice**

In 2007 Hoes et al published the EULAR evidence-based recommendations on the management of systemic GC therapy in rheumatic diseases (Hoes et al., 2007). The table of their key recommendations is reproduced below (Fig 3) but as part of their review process they quantified the incidence of reported adverse events in the glucocorticoid treated arms from 18 studies which included 963 patients taking 30mg or less of prednisolone (or equivalent) for the treatment of rheumatic diseases. The average dose across all studies was 8mg of prednisolone and the mean duration of follow up was 19.6 months. The results (Fig 4) are reported as adverse events per 100 patient years and provide an overview of the types of adverse events reported in GC use at these doses. (Not all these will actually be attributable to GC).

An important point to note when considering cardiovascular and osteoporotic fracture risk in the context of GC use is the underlying risk posed by the inflammatory disease itself. It has been shown that chronic inflammatory conditions are associated with an increased fracture risk and bone mineral density loss (Cooper et al., 1995; Staa et al., 2006; Hoff et al., 2007). Moreover, the increased cardiovascular risks associated RA and other inflammatory conditions are now very well established (Peters et al., 2010). Clearly the relationship between the beneficial effects of GC in controlling inflammation which, drives adverse events in these settings, and the GC contributions to the above risks are quite complex.

after discontinuation of the prednisolone). This continued benefit of GC in preventing joint erosions long after their anti-inflammatory benefits have subsided is noteworthy. There is increasingly an appreciation in the literature for several simultaneous pathogenic processes taking place in the RA joint. In particular joint erosions and synovitis seem to be two distinct processes and their apparent dissociation in the case of GC therapy is therefore not

surprising (Kirwan, 2004).

attributable to GC).

Fig. 2. X-ray progression after stopping trial therapy

**2.4 Adverse effects of glucocorticoids in rheumatology practice** 

In 2007 Hoes et al published the EULAR evidence-based recommendations on the management of systemic GC therapy in rheumatic diseases (Hoes et al., 2007). The table of their key recommendations is reproduced below (Fig 3) but as part of their review process they quantified the incidence of reported adverse events in the glucocorticoid treated arms from 18 studies which included 963 patients taking 30mg or less of prednisolone (or equivalent) for the treatment of rheumatic diseases. The average dose across all studies was 8mg of prednisolone and the mean duration of follow up was 19.6 months. The results (Fig 4) are reported as adverse events per 100 patient years and provide an overview of the types of adverse events reported in GC use at these doses. (Not all these will actually be

An important point to note when considering cardiovascular and osteoporotic fracture risk in the context of GC use is the underlying risk posed by the inflammatory disease itself. It has been shown that chronic inflammatory conditions are associated with an increased fracture risk and bone mineral density loss (Cooper et al., 1995; Staa et al., 2006; Hoff et al., 2007). Moreover, the increased cardiovascular risks associated RA and other inflammatory conditions are now very well established (Peters et al., 2010). Clearly the relationship between the beneficial effects of GC in controlling inflammation which, drives adverse events in these settings, and the GC contributions to the above risks are quite complex.


Fig. 3. Summary of EULAR recommendations for the use of GC in rheumatological practice. (VAS=visual analogue score)

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis 9

GC have a lipophilic structure and low molecular mass. They therefore pass easily through the cell membrane and exert their effects mainly through binding with the glucocorticoid receptor (GCR) in the cytoplasm (Rhen & Cidlowski, 2005). There are two isoforms of the GCR, α and β. GCR-α is the biologically active form of the receptor and mediates the intracellular effects of GC. GCR-β is an alternativley spliced form which may act as dominant neagtive inhibitor of GC action (Lewis-Tuffin, 2006). Over expression of GCR-β

The GCR-α in the cytoplasm is associated with various heat shock proteins (HSPs) including HSP40, HSP56, HSP 70 and HSP90 (McLaughlin & Jackson, 2002) which are released when the receptor binds to GC After binding, the complex translocates to the neucleus where it exerts its effects on gene transcription (Davies et al., 2002). At the neucleus GCRs homodimerise and bind to GC response elements (GREs) in the promoter region of the target genes and lead to activation or inhbition of gene transcription. In addition the DNA bound GCR can also directly bind transcription co-activator molecules and exert further

In activated inflammatory cells there is an additional route for GC action. This is because inflammatory stimuli ultimately lead to the activation of neuclear factor κB (NFκB) which binds to specific κB recognition sites on promoter regions of inflammatory genes in addition to coactivators such as cyclic AMP response element binding protein (CBP). The coactivators cause acetylation of core histones which leads to their unravelling and opens up the genes for transcription. Activated GCRs and the HSPs that are released when the GC binds to the receptor inhibit this effect directly by binding the coactivators and recruiting histone deacetylase (HDAC) 2 which inhibits acetylation (Rhen & Cidlowski, 2005). GC also switch on the transcription of certain genes including mitogen-activated protein (MAP) kinase phosphatase 1 (MKP1) hence inhibiting the MAP kinase pathway which is involved in proinflammatory gene transcription (Clark, 2003). The existence of this pathway has led to a search for ways of enhancing this GC effect, which would apply only in activated inflammatory cells and would therefore not be relevant to other body tissues, and hence

Some of the effects of GC occur within minutes of their administration especially at high intravenous doses (Croxtall et al., 2000). The mechanisms involved in mediating this rapid action are non-genomic as they are transcription independent. So far three such nongenomic actions of GC have been described. The first involved the observation of the rapid reversal by dexamethasone of epidermal growth factor-stimulated activation of phospholipase A2. It is thought that this effect is medicated by chaperone molecules such as Src which are rapidly released from the GCR-GC complex on ligation (Croxtall et al.,

Non-specific non-genomic effects are seen at very high doses of GC therapy and are thought to be due the saturation of all available GCRs in the cells at doses above 100mg perdnisolone or equivalent (Tyrrell & Baxter, 1995). At these doses it is thought that GC molecules dissolve into the membranes and alter proton leak hence influencing membrane transport

may be implictaed in GC resistance as will be discussed later in this chapter.

**3.1 Genomic mechanisms** 

actions this way (Barnes, 2006).

would not contribute to adverse effects.

**3.2 Non-genomic mechanisms** 

(Buttgereit & Scheffold, 2002).

2000).

Indeed a cohort study examining the interaction between GC therapy and cardiovascular risk in RA showed GC therapy to be associated with an increased risk only if patients were rheumatoid factor (RF) positive (Davis et al., 2007). In fact in RF negative patients GC were not associated with increased risk regardless of the cumulative dose and indeed showed a trend towards being protective.


Fig. 4. Reported adverse events in GC treated patients with rheumatological diseases.

In summary, GC are widely used in the management of RA and rheumatologists have over 60 years experience in their use. At low doses they act as to reduce the symptoms of RA in the first 6 to 12 months but in addition, their use early in the disease process substantially slows the progression of joint destruction and results in less disability in the long term. Remarkably this joint protective effect seems to be sustained years after GC are discontinued and for this reason GC can both be considered to be true "disease modifying" antirheumatic drugs (Bijlsma et al., 2010) and to have some kind of effect on the underlying long term disease process. At higher doses they are effective in treating severe and life threatening flares of disease. Adverse effects remain a significant problem but in the balance of risk versus benefit, GC (especially at lower doses) can be considered relatively safe. The summary of the EULAR recommendations in GC use are reproduced below and are a useful tool for clinicians to refer to in their daily practice.
