Experimental and clinical pharmacology

The role of corticosteroids in rheumatology

Anna Dorai-Raj, Rheumatology Registrar, and Leslie Schrieber, Associate Professor of Medicine, University of Sydney and Department of Rheumatology, Royal North Shore Hospital, Sydney

Summary

Corticosteroids can improve the symptoms of patients with rheumatic diseases. They may also have a disease-modifying effect in rheumatoid arthritis, but they are not first-line treatment. Adverse effects are related to the dose and duration of treatment. Patients taking long-term treatment should be advised of these and prescribed the lowest effective dose. They should not stop treatment abruptly.

Key words:  rheumatoid arthritis, prednisolone, prednisone.

(Aust Prescr 1998;21:11-4)

Introduction
The substantial anti-inflammatory activity of corticosteroids was recognised soon after their introduction in the 1950s. They were hailed as a `cure' for rheumatoid arthritis (RA), based on uncontrolled observations. However, it subsequently became obvious that unacceptable adverse effects occurred with prolonged use of high-dose corticosteroids. They fell out of favour until recently. Corticosteroids have been reintroduced for the treatment of several rheumatological conditions. There is now a more rational approach to their use and a concerted effort to minimise adverse effects.

What formulations are available?
Oral preparations are the most commonly used, often as adjunctive therapy. Intravenous preparations have a more restricted role. Intra-articular/intralesional preparations are also commonly used in rheumatology for inflammatory rheumatic diseases and regional pain syndromes e.g. tennis elbow (lateral epicondylitis). Different corticosteroids vary with respect to their duration of action and relative glucocorticoid and mineralocorticoid activity. Corticosteroids are divided into short-, intermediate- and long-acting groups (Table 1). Short- and intermediate-acting preparations are more commonly used in practice as there is less inhibition of the hypothalamic-pituitary-adrenal (HPA) axis.

Mechanism of action
Corticosteroids have a wide range of biological activities including anti-inflammatory and immunosuppressive effects. They have major effects on leucocyte movement and, to a lesser extent, on leucocyte function. In general, they have greater effects on cellular than humoral processes. They inhibit the production of arachidonic acid metabolites, e.g. prostaglandins and leukotrienes, as well as that of certain cytokines e.g. interleukin 1.¹

Rheumatoid arthritis

Low-dose daily oral therapy
Non-steroidal anti-inflammatory drugs (NSAIDs) provide rapid symptomatic relief in RA. However, they do not prevent the development of bony erosions. When the diagnosis of RA is established, a disease-modifying anti-rheumatic drug (DMARD) should be introduced to try to prevent the development of bony erosions and to induce disease remission. However, most of these drugs, e.g. sulfasalazine, take a minimum of 6 weeks, and in some cases up to 6 months, to take effect. Patients may require oral corticosteroids for symptomatic relief if NSAIDs produce an inadequate response. This may bridge the gap until DMARDs take effect. The corticosteroid dose can then be tapered off.

In patients who cannot tolerate NSAIDs or in whom the use of DMARDs has proven to be problematic, e.g. adverse effects, monitoring difficulties or poor compliance, the use of a low-dose corticosteroid e.g. prednisolone 5-10 mg/day, may provide good control of symptoms and improved function.

Importantly, with regard to the use of low-dose corticosteroids, a recent placebo controlled trial has shown that prednisolone 7.5 mg/day has a disease-modifying effect by preventing the development of bony erosions.²

Pulse therapy
Pulse intravenous methylprednisolone can be used in major organ-threatening diseases e.g. scleritis, pneumonitis and mononeuritis multiplex complicating RA. Oral prednisolone (up to 1 g) or intravenous methylprednisolone is given as a single dose to settle a severe flare of disease. The clinical effect may last from weeks to months. This may avoid the need to introduce oral daily therapy. More controversial has been whether or not high-dose boluses of corticosteroids used in conjunction with a DMARD, such as a gold compound, result in improved efficacy and less toxicity of the DMARD. Overall, pulse therapy is well tolerated with little toxicity reported.³

Polymyalgia rheumatica and giant cell arteritis
Both polymyalgia rheumatica and giant cell arteritis are treated with oral corticosteroids. Lower doses (15-20 mg) are used initially in polymyalgia, whereas higher doses, e.g. 40-50 mg/day are used in giant cell arteritis. The drugs are continued for a few weeks and then, depending on the symptoms and laboratory indices, e.g. ESR or C-reactive protein, the dose can be reduced to the lowest maintenance dose possible e.g. 5-10 mg/day. Both conditions require treatment with steroids for a period of about two years. Unfortunately, in older patients, the dramatic early relief of symptoms is complicated by a high frequency of adverse effects after prolonged corticosteroid use.

Table 1 Corticosteroid preparations - half-life and potency
Drugs	Anti-inflammatory potency	Equivalent doses (mg)	Sodium retaining	Biological half-life (hours)
Short-acting
- cortisone acetate	1	20	2+	8-12
Intermediate-acting
- prednisolone	3-5	5	1+	18-36
Long-acting
- dexamethasone	20-30	0.75	0	36-54
- betamethasone	20-30	0.6	0	36-54

Connective tissue diseases
Diseases such as systemic lupus erythematosus, vasculitis and polymyositis require systemic corticosteroid therapy for effective control. These diseases vary greatly in the extent and severity of organ system involvement so there is a need to individualise treatment. In severe flares, high-dose oral or intravenous corticosteroids are usually required. Management should be under the guidance of a consultant physician e.g. a rheumatologist experienced in treating these complex disorders.

Considerations before starting oral corticosteroids¹
1. Are corticosteroids really necessary and have safer alternatives, e.g. NSAIDs, been tried?

2. Are there any relative contraindications or precautions e.g. diabetes mellitus, hypertension, osteoporosis?

3. Duration of treatment - short or long term?

4. Timing of dose - early morning if possible, as there is less HPA axis suppression. However, when the disease is severe and active, a split dose given in the morning and in the evening may be necessary.

5. Aim to use the lowest possible dose for the shortest period of time as adverse effects are time and dose related.

6. Consideration as to whether a safer alternative route can be used e.g. intra-articular steroids.

7. Patients need to be advised about the adverse effects, against ceasing corticosteroids suddenly and about wearing medic-alert badges while on long-term treatment.

Local corticosteroid therapy⁴
An injection of a corticosteroid into the site of inflammation can avoid most of the problems caused by large oral doses. Intra-articular and intralesional corticosteroids are of use when a high concentration in a particular joint, tendon sheath or bursa is required. The indications for intra-articular/intralesional preparations are shown in Table 2. There are, however, situations where a local corticosteroid injection is contraindicated and these are:

• periarticular sepsis

• bacteraemia

• unstable joints

• intra-articular fractures

• septic joints

• bleeding disorders (relative contraindication)

Adverse effects of local corticosteroid therapy include:

• local/intra-articular infection if inadequate aseptic precautions are taken

• rupture of a tendon if corticosteroid is inadvertently injected directly into the tendon

• superficial injection can lead to local skin atrophy and hypopigmentation

• local, transient post-injection flare of arthritis (thought to be due to microcrystalline formation)

Table 2 Intra-articular and intralesional therapy
Joints	Rheumatoid arthritis Seronegative spondyloarthritis Crystal arthritis Osteoarthritis - in acute flares Traumatic arthritis
Soft tissues e.g. bursa, tendon sheath, tenosynovium, entheses	Local - inflammation, injury, overuse Systemic inflammatory disorders - e.g. rheumatoid arthritis, gout
Nerve entrapment	e.g. carpal tunnel syndrome

Epidural corticosteroids
The use of epidural corticosteroids for back pain is controversial, with reports of arachnoiditis complicating this application. They are not recommended.

Adverse effects associated with corticosteroid use
Corticosteroid therapy has many possible complications (Table 3).¹ More common adverse effects with long-term use include:

• weight gain and Cushinghoid features e.g. moon face
• hirsutism
• skin atrophy
• bruising
• posterior subcapsular cataract
• mood changes
• osteoporosis

Some of the adverse effects are more serious and may require monitoring:

• elevation of blood glucose level, especially if the patient is a diabetic
• hypertension
• increased susceptibility to infection
• avascular necrosis of bone

Table 3 Adverse effects of corticosteroids
Metabolic	Obesity, electrolyte imbalance, glucose/protein/lipid metabolism
Predisposition to infection
Musculoskeletal	Osteoporosis, myopathy, osteonecrosis
Gastrointestinal	Peptic ulcer disease, pancreatitis
Ophthalmic	Cataract, glaucoma
Central nervous system	Psychosis, depression, benign intracranial hypertension
Dermatological	Acne, striae, alopecia, bruising, skin atrophy, hirsutism
Growth retardation	In children
Hypothalamic-pituitary-adrenal axis suppression
Corticosteroid withdrawal syndrome

Osteoporosis
The bone loss associated with long-term (>6 months) corticosteroid treatment mainly affects trabecular bone. To minimise this effect, reduce the dose to the lowest possible and withdraw corticosteroids if possible. If long-term corticosteroid therapy is planned, bone mineral density (BMD) should be measured. Consideration should be given to preventive strategies, especially in high-risk patients. Adequate calcium intake and hormone replacement therapy in postmenopausal women who have no contraindication are appropriate. Where a patient has had a previous fracture, or has a reduced BMD at baseline, a bisphosphonate, e.g. etidronate or alendronate or active vitamin D metabolite, calcitriol, is appropriate to prevent bone loss. Prevention may be most effective when given at the start of therapy since bone loss is most rapid when corticosteroids are first commenced.

A recent 12-month clinical trial reported that the use of intermittent etidronate at the start of corticosteroid therapy prevented bone loss and reduced the risk of new vertebral fractures. Long-term studies are required to determine if these effects will be sustained.⁵

Practical prescribing tips

Withdrawal of corticosteroids
Patients treated with long-term moderate or low doses of corticosteroids should have their corticosteroid dose reduced and withdrawn slowly. The reasons for this are to:

• allow time for the HPA axis to recover as it can be suppressed by only 3 weeks of systemic treatment

• reduce the likelihood of relapse of the underlying condition being treated, particularly symptomatic inflammatory disease e.g. RA

• avoid the `corticosteroid withdrawal syndrome' which some patients develop if their dose is suddenly reduced. Symptoms include myalgia, fatigue, anorexia, nausea and weight loss. This may be confused with poor control of the primary disease process e.g. polymyalgia rheumatica or polymyositis.

To avoid these problems with withdrawal of corticosteroids, the dose should be reduced gradually. A suggested rate of reduction for prednisolone is 2.5 mg every 4-8 weeks until a dose of 7.5 mg is reached. Subsequent reduction should be by 1 mg decrements over the same interval.

Alternate day administration
Inhibition of linear growth and delay in epiphysial closure occur in children on long-term corticosteroids. Alternate day administration of the same total dose may reduce this adverse effect and is now preferred in children where possible.⁶ This regimen is also possible in adults when their disease is stable. The adverse effects associated with this form of therapy are less compared to daily administration. However, in symptomatic disorders, e.g. RA, patients often experience a flare in their symptoms on the day off treatment and may be unable to tolerate this regimen.

Conclusion
Corticosteroids have a clear role in the management of rheumatic disease. Their toxicity requires that they are used only when necessary, at the lowest dose possible and for the shortest duration of time. Consideration should be paid to the measures that can be taken to limit toxicity. No compound has yet been developed that dissociates the anti-inflammatory properties of corticosteroids from their adverse effects.

(See also Dental implications)

R E F E R E N C E S
1. Alexrod L. Glucocorticoids. In: Kelley WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th ed. Philadelphia: WB Saunders Company, 1993:779-96.

2. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:142-6.

3. Arnold M, Schrieber L, Brooks P. Immunosuppressive drugs and corticosteroids in the treatment of rheumatoid arthritis. Drugs 1988;36:340-63.

4. Owen DS. Aspiration and injection of joints and soft tissues. In: Kelley WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of rheumatology. 4th ed. Philadelphia: WB Saunders Company, 1993:
545-61.

5. Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997;337:382-7.

6. Reimer LG, Morris HG, Ellis EF. Growth of asthmatic children during treatment with alternate day steroids. J Allergy Clin Immunol 1975;55: 224-31.

Availabillity of Therapeutic Guidelines: Antibiotic, 10th edition

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