October 2007 : No 13

Glucocorticoids in Rheumatic Diseases

John R Kirwan

Lynsey L Power

University of Bristol Academic Rheumatology Unit, Bristol Royal Infirmary

Reports on the Rheumatic Diseases Series 5 : Topical Reviews

  • Glucocorticoids have been widely used by rheumatologists for several decades. They remain highly effective treatment for a range of inflammatory conditions and have well-recognised adverse effects
  • Low-dose glucocorticoids have disease-modifying properties in rheumatoid arthritis, and may have less severe adverse effects than is generally thought
  • Greater understanding of the cellular mechanisms of glucocorticoid action has allowed the development of selective glucocorticoid agonists and targeted glucocorticoid therapy, which may further amplify therapeutic benefit with little increase in toxicity

Glucocorticoids – an old drug with new prospects

Glucocorticoids (GCs) (also called corticosteroids, or, more loosely, 'steroids') were first used in 1948 with dramatic results. Patients with inflammatory arthritis found their symptoms melted away, but physicians used high, long-term doses and serious adverse effects were encountered. For 30 years there were no clear guidelines for the use of GCs. As the patents expired the pharmaceutical industry turned to the development of non-steroidal anti-inflammatory drugs (NSAIDs), taking the focus of clinical research with them.1 While high-dose short-term treatment for inflammatory emergencies has continued as a well-recognised treatment option within rheumatology, since 1995 there has been a resurgence of interest in GC effects in rheumatoid arthritis (RA).2 Now, greater understanding of the mechanisms of drug action and of pathological disease processes are opening up new possibilities for the targeted use of GCs and the development of new, selective analogues which offer the prospect of more powerful treatment effects with less likelihood of adverse effects. This review summarises and puts into context the developments of recent years.

Mechanisms of action

The main endogenous GC in man is cortisol (cortisone in the inactive form), the majority of which is bound in the circulation to corticosteroid-binding globulin (CBG). It is secreted from the zona fasciculata of the adrenal gland and regulated by the adrenocorticotropic hormone (ACTH). Endogenous control and regulation comes from the interactions of the hypothalamic-pituitary-adrenal (HPA) axis. There are recognised associations between the immune system, inflammation and HPA control3 such that there is effectively a second negative feedback loop (Figure 1). A number of authors have reported abnormalities in HPA response to stress or other stimuli in RA,3-5 and this area deserves further attention. One current theory, while recognising the often higher than normal plasma cortisol concentrations in many patients, sees this as a blunted response when compared to the normal, much greater rise in cortisol when similar stress to that caused by widespread joint inflammation is placed on the HPA axis. From this point of view RA is a 'glucocorticoid deficient' state, and the HPA axis is unable to respond to additional stressors, such as infection.

FIGURE 1. Cortisol and the immune system in rheumatoid arthritis.

FIGURE 1. Cortisol and the immune system in rheumatoid arthritis.

ACTH adrenocorticotropic hormone; CRF corticotropin releasing factor; IL interleukin; TNFα tumour necrosis factor

The functions of endogenous GCs are numerous and widespread, including effects on homeostasis, metabolism and immune function. At physiological or low GC doses, cortisol diffuses freely across the cell membrane and binds to the cytoplasmic GC receptor-α (cGCRα). On binding, heat shock proteins are released and the cortisol-GCR complex moves to the nucleus and activates genomic signalling by interacting with GC response elements (GREs) (Figure 2). GCs induce synthesis of some proteins through transcriptional activation, and transcriptional repression switches off synthesis of other proteins. Broadly speaking, transcriptional repression leads to anti-inflammatory effects and transcriptional activation leads to many of the recognised side-effects. This distinction is not clear-cut, however, and exceptions include annexin1, an anti-inflammatory protein induced by GCs, and osteocalcin and osteoprotegerin, proteins that are critical to new bone formation and are repressed by GCs.6-7

FIGURE 2. Cellular action of glucocorticoids.

FIGURE 2. Cellular action of glucocorticoids.

cGCRα cytoplasmic glucocorticoid receptor-α; DNA deoxyribonucleic acid; ECF extra-cellular fluid; GRE glucocorticoid response element; HSP heat shock protein; IL interleukin; mRNA messenger ribonucleic acid; NFκB nuclear factor κ B; TNFα tumour necrosis factor α

At higher concentrations GCs are thought to interact with membrane-bound receptors or directly with the membrane to induce non-genomic effects. The exact mechanisms of non-genomic signalling remain under debate but are probably responsible for very rapid effects of high-dose GC such as inhibition of arachidonic acid release.8 Non-genomic effects themselves are currently thought to come in two varieties: specific non-genomic effects related to the activation of membrane GC receptors (not normally engaged in physiological circumstances), and non-specific non-genomic effects engendered when very high concentrations of GC swamp all the available receptors and begin to dissolve directly in the cell membrane (and perhaps the membranes of mitochondria), initiating other intracellular metabolic changes. These effects are all engaged when high-dose therapy is used, such as pulsed intravenous methylprednisolone. Therefore, GCs have a mixture of therapeutic effects depending on the dose used (Figure 3).9 This has important implications for consideration of the potential for adverse effects, as a simple extrapolation from effects observed in high-dose regimens to the expectation of similar but lesser effects at lower doses may not be appropriate if the adverse effect is related to mechanisms which are not employed at lower doses. The recognition of different mechanisms of action also provides an underlying rationale to the clinically recognisable differences in effect for different doses, and for the definition of 'low', 'medium' and 'high' doses of GC.9

FIGURE 3. Diagrammatic representation of differ­-ent dose effects of glucocorticoids. Precise cellular mech­anisms are still being elucidated, there­fore this is an inter­pretation of current knowledge. (Reproduced from Ann Rheum Dis 2002;61(8):720 with permission from the BMJ Pub­lishing Group.)

FIGURE 3. Diagrammatic representation of different dose effects of glucocorticoids. Precise cellular mechanisms are still being elucidated, therefore this is an interpretation of current knowledge.

(Reproduced from Ann Rheum Dis 2002;61(8):720 with permission from the BMJ Publishing Group.)

Glucocorticoids in rheumatoid arthritis

Broadly speaking GC use can be divided into high-dose short-course use and longer-term maintenance dosing. High doses may be used for systemic complications (see 'Glucocorticoids in vasculitis, systemic lupus erythematosus and lupus nephritis') or to treat short-term flares (such as the use of intramuscular depomedrone). In effect, intra-articular injection provides high-dose treatment (and hence non-genomic effects) to the synovium of individual joints. The use of longer-term lower-dose GCs simply to control disease symptoms probably remains inappropriate for most patients. While low-dose GCs clearly control symptoms in the short run and are substantially superior to NSAIDs in this respect10,11 there is much debate over their continued success in the longer term.12 However, it was observed in the Arthritis and Rheumatism Council Low Dose Glucocorticoid Study12 that during the treatment phase several patients were withdrawn in order to specifically give treatment with GC. All of these were in the placebo arm. In the blinded, off-treatment follow-up year a similar number of patients were started on GC by their physician, and almost all of these had previously been in the GC arm of the study. Thus it may be that in about 8% of cases rheumatologists find that the patient requires continuing low-dose treatment for symptom control, but further work is needed to be sure of this.

The last 10 years has seen increasing evidence for the disease-modifying properties of low-dose GCs. There are now 14 randomised controlled trials (RCTs) in the literature which measured the effects of GCs on joint damage as revealed by radiographic progression. These have been combined in a recent Cochrane meta-analysis13 which concluded: 'Even in the most conservative estimate, the evidence that glucocorticoids given in addition to standard therapy can substantially reduce the rate of erosion progression in rheumatoid arthritis is convincing.' Indeed, even including studies with very low doses of GC and patients not also taking disease-modifying anti-rheumatic drugs (DMARDs), the average reduction in the rate of progression was 70%. This makes GC by far the most powerful DMARD, particularly when used in combination with other DMARDs.

Furthermore, some very encouraging observations of medium-term follow-up of two of these studies have been reported which raise the possibility that GC might have enduring or even permanent effects on disease progression long after therapy with GCs has been discontinued. The first was the COBRA regimen.14,15 In this trial in early RA patients there were two treatment groups, one treated with sulfasalazine (2 g/day) monotherapy and the other with methotrexate (7.5 mg/week), sulfasalazine (2 g/day) and prednisolone, initially 60 mg/day but reducing over 6 weeks to 7.5 mg/day for 5 months. During the 4–5 year follow-up period, the Sharp progression rate was 8.6 points per year in the sulfasalazine group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during follow-up, the between-group difference in the rate of radiographic progression was 3.7 points per year. This continuing response, years after stopping GCs, showed a sustained suppression of the rate of radiographic progression in patients with early RA, independent of subsequent anti-rheumatic therapy. The second study followed up patients in the Utrecht trial16 after they had been treated with 10 mg/day prednisolone or placebo for 2 years. This study showed that during an additional 3 years of follow-up, radiographic scores showed significantly less progression in the original prednisolone group than in the original placebo group. These observations of the sustained disease-modifying properties of GCs constitute the first hard evidence that it may be possible to fundamentally alter the long-term course of RA by a specific and limited intervention early in the disease.

Used in an appropriate way, GCs have a much more profound effect on symptoms than is generally realised. In the COBRA trial15 symptomatic benefit in the group receiving methotrexate, sulfasalazine and prednisolone was dramatic – much more so than in the other studies of GC where no initial high-dose therapy was used. This regimen was subsequently directly compared to anti-tumour necrosis factor (anti-TNF) therapy in patients with early RA, in the BeSt study.17 The authors concluded that initial combination therapy including either prednisolone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy. While an economic analysis was not presented, it seems very likely that the GC combination would be the more cost-effective approach.

TREATMENT TIP

Based on the evidence reviewed here, and in patients with a secure expert diagnosis of RA, one logical approach to treatment in the first few years would be to establish within a few weeks if the patient's symptoms could not be adequately controlled with full-dose NSAIDs (which will be the case in about 80% of hospital outpatients), then initiate combined DMARD therapy including methotrexate and either low-dose glucocorticoids (7.5 mg/day prednisolone) or the short-term high-dose followed by medium-term low-dose treatment used in the COBRA regimen. It is difficult to see the justification for monotherapy without glucocorticoids unless there are specific contraindications in a particular patient. Consultation time will be required to educate the patient (and their GP) about the nature of the treatment and the necessity of carefully controlled management of their medication.

Glucocorticoids in polymyalgia rheumatica and temporal (giant cell) arteritis

The signs and symptoms of polymyalgia rheumatica (PMR) and temporal arteritis (TA) overlap and can often be confused, but both are treated with GCs. No trials have been conducted which allow an adequate definition of the best treatment regimen, but four substantial cohorts of patients have been reported in the literature.18-22 Although there are some differences, the overall pattern suggests the need to treat PMR initially with about 15 mg/day prednisolone, reducing slowly over 18–24 months.

About two or three times that dose will be required to treat coexisting or separate TA and for perhaps 6 months longer. All series reported a few complications, including some patients with PMR who become more definite cases of TA while on treatment. The main pitfalls seem to be the use of too high a dose of GCs initially, with too rapid a reduction in treatment thereafter.23,24 This criticism could also be directed towards some controlled trials of treatment that have shown disappointing results.25-28

Higher doses of 40–60 mg are required to treat giant cell arteritis (GCA), and therefore in suspected cases a temporal artery biopsy is recommended to confirm the diagnosis.29 The high doses of GC required initially and the duration of treatment can be associated with GC side-effects, and epidemiological studies have shown a high incidence of fractures.30 We now know that these risks can be substantially reduced with concurrent osteoporosis prophylaxis and this should now be routine practice.

Glucocorticoids in vasculitis, systemic lupus erythematosus and lupus nephritis

Life-threatening complications of rheumatic diseases require higher doses of GC to achieve disease control. These higher doses are usually given intravenously at doses of 0.5–1 g methylprednisolone. Often three pulses are given on alternate days and single pulses can also be used for rapid control of RA or other inflammatory arthritides. There are no definitive studies to guide us on optimum doses in the treatment of systemic lupus erythematosus (SLE) flares,31 but it has been suggested that using lower doses (1–1.5 g compared to 3–5 g) is efficacious and complication rates, particularly infections, are reduced.32 A recent review33 suggests doses of 500 mg/day methylprednisolone for 3 days are as efficacious and associated with fewer infectious complications than 1 g/day.

Renal complications of SLE are associated with significant mortality and morbidity. Once again, first-line treatment for lupus nephritis is intravenous GC. Not all patients respond adequately and further intravenous immunosuppression such as cyclophosphamide may need to be added, but with additional risk of gonadal suppression and malignancy. Kanno and Hotta34 looked for possible predictive factors of those who will respond to GC. There were no clinical characteristics that were predictive; however a longer pre-treatment period was associated with a worse outcome. The chronicity index (a histological severity measure) was also useful, but the main message was that prompt diagnosis and initiation of treatment is important to improve outcome. A recent Cochrane review concluded that the combination of GC and cyclophosphamide should be used until further RCTs of other immunosuppressant therapies are available.35 As experience increases and evidence accumulates it may be that mycophenylate replaces cyclophosphamide as a drug with a more favourable side-effect profile.36

TREATMENT TIP

One regimen in use for dealing with acute vasculitic emergencies is:

Day 1

  • IV mesna 200 mg
  • IV cyclophosphamide 1000 mg in 500 ml normal saline over 1 h
  • IV methylprednisolone 1000 mg in 250 ml normal saline over 1 h
  • Oral mesna 400 mg 4 h after infusion
  • Oral mesna 400 mg 6 h after infusion

Day 3

  • IV methylprednisolone 1000 mg in 250 ml normal saline over 1 h

Day 5

  • IV methylprednisolone 1000 mg in 250 ml normal saline over 1 h


Glucocorticoids in gout

GCs (and in the past ACTH) have been used in gout mainly in treating an acute attack. Clinical practice varies between one-off intramuscular doses, short-term oral courses or intra-articular injection – particularly in monoarticular disease. Evidence for the effectiveness of GCs in gout is based on clinical experience and some case series reports, but there is little in the literature and certainly no up-to-date trials. In an open-label study of tapering prednisolone therapy (starting at 30–50 mg/day), 11 of 12 patients had significant clinical improvement within 48 hours with a single adverse event (transient hyperglycaemia) reported.37 In a trial comparing a single dose of parenteral ACTH to oral indometacin, ACTH was associated with a shorter time to symptomatic relief.38 Alloway et al39 reported quicker symptom resolution with intramuscular triamcinolone than with indometacin, although the results did not reach statistical significance. In a trial comparing single doses of ACTH and triamcinolone both treatment arms were well tolerated and resulted in similar clinical benefit.40 It seems likely that GC use in gout is effective and well tolerated for the short-term treatment of flares.41

Dose-related adverse effects of glucocorticoids

The wide range of adverse effects associated with GCs is well known and includes (for example) cardiovascular effects, HPA axis suppression, muscle wasting, hyperglycaemia, effects on the skin and central nervous system (CNS), and infection risk. However, the rate of side-effect occurrence depends on daily and cumulative dose,42 and the potency of GC prescribed, as well as duration of exposure. Further, it may also depend upon the underlying pathology of the disease being treated, a factor which has not been adequately considered in the development of GC treatment guidelines in the past. Two areas that are currently hotly debated, particularly in low-dose GC use in RA, are increased risks of osteoporosis and cardiovascular disease. The extent of these risks has been difficult to establish and remains in question,43 partly because RA itself is a risk factor for these conditions. Indeed there is increasing evidence (see below) that (at least in RA) the increased risk comes more from uncontrolled inflammation and that low-dose GC might actually be protective.

Osteoporosis

There is no doubt that long-term GC use even in moderate doses is associated with reduced bone mineral density, particularly loss of trabecular bone, and increased fracture risk at the hip and spine.44 The mechanisms of GC-induced osteoporosis are multiple but include disturbed calcium homeostasis, osteoblast dysfunction and osteocyte apoptosis.45 Although fracture risk rises soon after GCs are commenced it also rapidly declines when treatment is stopped and this is independent of effects on bone mineral density.46 However, the extent to which lower doses of GC (<7.5 mg prednisolone) contribute to increased fracture risk remains in debate. Chronic inflammatory conditions such as RA are themselves associated with an increased fracture risk47,48 and bone density loss,49 and therefore distinguishing disease effects from GC effects at low doses is complicated. Doses of 5 mg have been found to suppress bone formation as measured by serum and urine markers,50 but this was in healthy volunteers. Other studies that suggested an increased fracture risk at low doses of GC did not include patients with untreated inflammatory diseases.51 A recent review further illustrated conflicting conclusions/opinions of low-dose GC-induced osteoporosis risk.52 Guidelines have now been produced for GC-induced osteoporosis.44,53 The UK guidelines restrict primary prevention to those aged 65 and over, or younger patients with a T-score of –1.5 or lower.

Cardiovascular risk

Cardiovascular risk, like osteoporosis, is difficult to quantify in the context of inflammatory diseases. Studies of cardiovascular risk and GC suggest an association due to effects on blood pressure, glycaemic control and lipid profiles.54,55 However, active inflammation itself leads to increased risk of cardiovascular disease,56-58 so low doses of GC used to control inflammation may result in an overall reduction in cardiovascular risk in these patients. A recent study of immunosuppressant medication and cardiovascular events in patients with RA suggested GCs did increase risk but may have been confounded by factors such as GC use being associated with more severe disease.59 A small study of early RA patients demonstrated that treatment with methotrexate and prednisolone improved lipid profiles.60 A recently published cohort study61 reviewed 603 RA patients, their GC exposure and cardiovascular events over a 13-year period compared to patients with RA who had never been exposed to GC. In rheumatoid factor (RF)-negative patients, GC exposure was not associated with increased risk of cardiovascular events whatever the cumulative dose – indeed there was a suggestion that GCs might be protective. However, in the RF-positive group increased cardiovascular event risk was observed and was related to both cumulative doses and recent exposure. In contrast, a population-based cohort study of PMR patients showed that treatment with GCs was not associated with an increased risk of cardiovascular events, and a non-significant trend suggested that they might even be protective.62 While more detailed study is needed before firm conclusions can be drawn, taking all the evidence together it seems likely that in inflammatory rheumatic disease, control of the disease process should be the priority in reducing cardiovascular risk, GCs are probably efficacious in this context, and low-dose GC therapy may offer no additional cardiovascular risk while reducing that due to the underlying disease.

Drug delivery and targets: new glucocorticoid developments

GCs continue to be vital and valuable in treating rheumatic diseases. However, the adverse effects of higher doses combined with very useful but clearly suboptimal benefits of low-dose therapy have sparked the search for a GC or GC analogue that will provide amplified therapeutic benefits with a more attractive side-effect profile. This search is developing in several directions.

New non-steroidal anti-inflammatory agents

Non-GC compounds with GC-like effect, such as ZK21634863 and Abbott-Ligand 438,64 may activate GC receptors selectively, suppressing inflammation but not changing other aspects of intracellular metabolism, and have shown promise in murine models. Other selective GC receptor agonists (SEGRAs) are under development.65-68 In most reports, separating therapeutic effects from side-effects has not yet been perfected, but it will be interesting to see how these compounds perform in human studies.

Combination drugs

Another avenue of exploration is the combination of GC with drugs whose intracellular actions effectively amplify the therapeutic effects of GCs, but only in activated inflammatory cells. One such drug has combined prednisolone with dipyridamole.69,70 Usually used as an anti-platelet drug, in this combination dipyridamole seems to enhance the ability of GC to influence the transrepression of nuclear factor κB (NFκB) and the nuclear factor of activated T-cells (NFAT) while not affecting the direct interaction with deoxyribonucleic acid (DNA) at GREs, which is where the toxicity arises. As these pro-inflammatory pathways are up-regulated in activated inflammatory cells, but not up-regulated in other tissues, this should provide a selective increase in potency as an anti-inflammatory agent while not increasing the potential for adverse effects in other cells. Cellular studies have found a 30-fold increase in anti-inflammatory potency. Early clinical studies of this 'selective steroid amplifier' suggest that this enhanced benefit does indeed occur, but its full extent and the true improvement in the benefit:risk ratio remain to be determined.70 A similar approach has used paroxetine to alter the same pathway but through different signalling effects. Laboratory results look interesting, and clinical studies are under way.71

Targeting therapy

By targeting therapy to the site of inflammation, systemic exposure (and hence risk of adverse effects) could be reduced. One way of achieving this is being investigated in the form of encapsulating GC in liposomes.72 Initially formulated in topical form for dermatological conditions, long-circulating liposomes have enabled intravenous administration. Modification of the coating of the liposomes has been shown to be effective in targeting to sites of inflammation in rat models of arthritis through interaction with the vascular wall at sites of inflammation. Human studies are awaited.

Timing therapy

Recent clinical investigations have provided more detailed information about circadian variations of hormones (particularly GC) and cytokines in RA. The diurnal nature of symptoms and signs in RA may be linked to the circadian variations that have been observed in the HPA axis and in inflammatory cytokines, particularly interleukin-6 (IL-6). This has led to targeting the timing of administering GC to the time of greatest change in serum IL-6 (during the night), and we are currently investigating this in more detail. More information on circadian rhythms in other conditions will inform us if this approach would be viable in other diseases.

Understanding glucocorticoid resistance

Clinicians will recognise that there is a subgroup of patients who either do not respond to GC or who develop resistance to GCs. Sliwinska-Stanczyk et al73 have confirmed that a quarter of patients with RA will be GC-resistant and have correlated this clinical measure to peripheral blood mononuclear cell (PBMC) proliferation responses providing a laboratory-based predictor of GC responsiveness. This is likely to be true for other inflammatory diseases.

There are several possible mechanisms by which GC resistance could occur.

  • First, there are two forms of the GCR, α and β. GCRα is the active form which binds cortisol and has transcriptional activity. GCRβ does not bind GC and is therefore an inactive receptor. Imbalances in the expression of these receptors could conceivably lead to resistance in some patients.
  • Second, the way that GCs are metabolised when they enter the cells is a likely candidate. 11β-hydroxysteroid dehydroxylase has two forms and is responsible for activation (11β-HSD 1) and deactivation (11β-HSD 2) of GC. Normally 11β-HSD 1 has the greater influence so that GCs are activated as soon as they enter the cell, but a change in the relative activity of these two forms may be responsible, or partly responsible, for GC resistance.
  • Finally, variations in the number and affinity of GC receptors, transcription factors and cofactors may also play a role in GC resistance,74 but whatever the mechanisms are they are likely to be multiple and/or complex. Several researchers are trying to characterise these mechanisms, which may help us in selecting patients for treatment or even provide new drug targets.

Conclusion

Glucocorticoids remain an important treatment option in many circumstances in rheumatology, and new understanding of disease-specific and dose-specific effects has resulted in renewed effort to make full use of their potential. It is a challenge for both clinicians and patients to look beyond the well-known dangers of long-term high-dose treatment and take full advantage of these developments.

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