Experimental and clinical pharmacology
Corticosteroids in autoimmune diseases
Bruce M. Hall, Professor of Medicine, University of New South Wales, and Head, Division of Medicine, Liverpool Hospital; Suzanne J. Hodgkinson, Senior Lecturer in Medicine, University of New South Wales, and Head of Neurology, Liverpool Hospital; and John

Summary

Corticosteroids can be used to induce a remission or reduce the morbidity in autoimmune diseases. Although high doses can be given for short periods, the aim is to achieve specific targets with the minimum effective dose. Patients who require long-term treatment should be advised about the adverse effects of corticosteroids, particularly the risk of adrenal insufficiency, osteoporosis and cataracts.

Key words: prednisone, prednisolone, toxicity.

Aust Prescr 1999;22:9-11

What are corticosteroids?
All corticosteroid drugs are chemical modifications of natural glucocorticosteroids (see `Corticosteroids - mechanisms of action' Aust Prescr 1996;19:41-4). Prednisone and prednisolone are commonly used. They only differ from cortisone and hydrocortisone by the addition of a double bond in the 1,2 position (Fig. 1). To become active, prednisone must be converted to prednisolone by changing the 11-keto group to 11-hydroxyl. The glucocorticoid activity of prednisone and prednisolone is 3-4 fold greater than hydrocortisone (Table 1). The addition of a 6a-methyl group to prednisolone creates methylprednisolone, which has 5-6 times the activity of hydrocortisone.

How do corticosteroids act in autoimmunity?
Corticosteroids induce a transient lymphocytopenia by altering lymphocyte recirculation. They also induce lymphocyte death. The most important immunosuppressive effect of corticosteroids is on T cell activation, by inhibition of cytokine and effect or molecule production. In this action, they are similar to cyclosporin, although the intracellular pathways by which the two classes of drug achieve this effect are quite separate.

Starting treatment with corticosteroids
Corticosteroids are widely used for a variety of inflammatory and non-inflammatory conditions that are not a result of hydrocortisone deficiency. The evidence, in well-controlled trials, for their benefit in curing diseases or improving outcome often does not exist. However, the outcome for patients since steroids were introduced is far better than the results of the natural progression of these diseases. When prescribing steroids, an adequate dose must be used for long enough to achieve an effect. The patient must be aware of the risks of therapy and the potential benefits. Care must be taken to prevent, minimise and appropriately treat complications of steroid therapy. In many cases, additional immunosuppressive drugs will be required to control immune aggression and inflammation or, in the long term, minimise corticosteroid usage. There should be a plan to minimise the dose in long-term maintenance therapy if this is required.

Giving high-dose corticosteroid therapy for a few days to a critically ill patient, or for a few weeks in a patient with a condition such as asthma which should settle, is relatively safe. Patients with chronic incurable diseases such as systemic lupus erythematosus or nephritis need a clear plan of when, how much and for how long corticosteroid therapy is required.

Fig. 1

Sites on the basic glucocorticoid structure (hydrocortisone) that are chemically modified to produce the common therapeutic agents are numbered and the chemical groups added are in bold.

Cortisone has a = 0 group in position 11

Fluorohydrocortisone is hydrocortisone with a 9a fluorine

Prednisolone is hydrocortisone with a double bond in 1,2 position

Prednisone is cortisone with a double bond in 1,2 position

Methylprednisolone is prednisolone with a 6a methyl group

Dexamethasone is prednisolone with a 16a methyl group

Betamethasone is prednisolone with a 16b methyl group

/upload/issue_files/2201_285_1.gif

Reducing morbidity or inducing remission in chronic progressive diseases
In diseases which respond to corticosteroids (see box), oral therapy, usually beginning with 1-2 mg/kg prednis(ol)one, is started with a plan to taper over time to a maintenance dose or to cease the therapy. Clear therapeutic goals can be set such as reduction in proteinuria, reduction in weakness and muscle enzymes, improved blood counts or lung function studies. The risks and complications of long-term corticosteroid therapy should be discussed with the patient and minimised by attempts to lower the dose or use adjunct immunosuppression to spare steroid usage. Alternate day therapy may be of use to minimise adverse effects, particularly to allow maximal bone growth in children.

Minimising symptoms in chronic inflammatory conditions
Classical examples of this are rheumatoid arthritis and polymyalgia rheumatica. The place of steroids in rheumatoid arthritis remains vexed (see `The role of corticosteroids in rheumatology' Aust Prescr 1998;21:11-4). In these diseases, the aim should be to use the minimum dose required to gain symptomatic relief. A typical starting dose is 5-7.5 mg/day of prednis(ol)one or up to 20 mg to gain initial control of symptoms. Corticosteroids are also used for intra-articular injections of painful joints.

Saving lives and saving organs
Very high-dose therapy might be indicated for several days in critically ill patients with an aggressive acute presentation or a life- or organ-threatening relapse. Experience with treating organ allograft rejection showed that daily doses of 1 g of intravenous methylprednisolone could be given safely. The infusion has to be given slowly as it can induce an anaphylactoid reaction. This regimen has been utilised in a variety of other non-transplant situations, often with a lower daily dose of 500 mg or 250 mg for 3-5 days.

In acute relapses of multiple sclerosis and optic neuritis, a short course of parenteral treatment can significantly shorten the time the patient is symptomatic. In the Optic Neuritis trial1, the only benefit was seen in the group given intravenous methylprednisolone. The group given oral prednisone had an increased risk of new episodes of optic neuritis in either eye. In general, oral treatment with prednisone should not be used in multiple sclerosis.

In patients who present with aggressive vasculitis such as Wegener's granulomatosis, polyarteritis nodosa, Good pasture's syndrome and idiopathic rapidly progressive glomerulonephritis, daily pulses of methylprednisolone can be used to try to control the immune injury. In these diseases, corticosteroids should be combined with other immunosuppressive drugs, e.g. an alkylating agent such as cyclophosphamide. These drugs take days to weeks to work, whilst the corticosteroids will start to have an effect in hours. For this reason, high-dose corticosteroids are required immediately to control disease and, later, the immunosuppressant allows minimisation of the steroid dosage. These patients, on completing treatment with intravenous methylprednisolone, need high doses of oral prednis(ol)one (usually 1-2 mg/kg body weight). Critically ill patients with these diseases will often relapse unless a dose of around 120 mg/day is given. In this situation, the risk of disease progression outweighs the risk of the high-dose steroids.

Hazards associated with such therapy are reduced resistance to infection, especially bacterial, and relapse of latent infection such as Herpes simplex and zoster, as well as Pneumocystis carinii and Helicobacter pylori. There is also a risk of acute myocardial ischaemia in pre-disposed patients.

Minimising corticosteroid toxicity
Toxicity relates to cumulative dose, so all therapy must aim to find the minimum dose which will maintain the desired therapeutic effect. Adjunctive therapy with a corticosteroid sparing immunosuppressive drug should be considered early rather than after irreversible complications have occurred.

Cardiovascular disease
Patients should be closely monitored for glucose intolerance and hyperlipidaemia. Dietary restriction to avoid weight gain should begin immediately, together with exercises to minimise muscle weakness. Blood pressure should be monitored as hypertension may develop because of the mineralocorticoid activity of the drugs. Patients on steroids have accelerated atherosclerosis and all risk factors should be reduced, especially smoking. There is an increased risk of acute vascular events, including myocardial infarction, shortly after starting high-dose steroids.

Table 1

Comparison of relative functional activity of glucocorticoids used in therapy *

Drug Liver
glycogen
Salt
retention
Anti-inflammation Receptor
affinity
Relative
dose
(mg)
Therapeutic
half-life
Hydrocortisone/ cortisone 1 1 1 1 100 <12 hours
Prednis(ol)one 3 0.75 3-4 2 20-25 12-36 hours
Methylprednisolone 10 0.5 5-6 11 17-20 12-36 hours
Fludrocortisone 12 125 10-12 not used
Beta/dexamethasone - 0 25/30-40 5/7 4 48 hours

* Relative effects compared to hydrocortisone for liver glycogen (glucocorticoid activity), salt retention (mineralocorticoid activity), anti-inflammatory effects and receptor affinity. Relative receptor affinity compared to hydrocortisone for budesonide is over 50x and for fluticasone 140x.

† Relative dose is compared to 100 mg of hydrocortisone.

Diseases which respond to corticosteroids

– nephrotic syndrome

– myasthenia gravis

– lupus nephritis and cerebritis

– dermatopolymyositis

– temporal arteritis

– immune thrombocytopenia

– immune haemolytic anaemia

– sarcoidosis

Infection and vaccination
Corticosteroids are relatively contraindicated in patients with uncontrolled infection. All patients with a risk of prior exposure to tuberculosis should be assessed. If previous infection is confirmed and they have not received a curative course of antimycobacterial drugs, they should be treated.

Patients on steroids are at increased risk of infection, and symptoms such as fever and pain may be masked by the steroids. Bacterial infections, such as urinary and respiratory infections, are the most common. Opportunistic infections should also be considered e.g. Pneumocystis carinii. Immunisation with standard vaccines such as influenza should be undertaken, although the protective effect may be reduced. Live vaccines, including BCG, measles, rubella and chicken pox are contraindicated.

Peritonitis should be considered in patients with minor abdominal symptoms as clinical signs may be masked.

Osteoporosis
Corticosteroids accelerate bone loss. Screening for osteoporosis and therapies for bone loss prevention should be considered in all patients who require long-term corticosteroids. Preventative therapy includes calcium, vitamin D and a bisphosphonate, as well as hormone replacement therapy in postmenopausal women.

Others
Other major adverse effects are aseptic necrosis of bone, psychosis, sleep disturbance, skin fragility and poor wound healing. The eyes should be checked for glaucoma and cataracts.

Hypothalamic-pituitary-adrenal suppression
Inhibition of the hypothalamic-pituitary-adrenal axis may lead to adrenal insufficiency when steroids are ceased after long-term use. It requires corticosteroid supplements in episodes of severe acute illness. Therapy for under 3 weeks or with less than 10 mg of prednis(ol)one is unlikely to suppress the hypothalamic-pituitary-adrenal axis. This axis will be suppressed in anyone with Cushingoid features. Low early morning cortisol levels, after omitting therapy for 24 hours, suggest suppression. Evening doses of steroids increase the risk of suppression. Alternate day therapy probably does not reduce the risk.

Patients should be advised of the risk of adrenal insufficiency and wear a bracelet indicating their corticosteroid usage. For major illnesses and surgical procedures, a short course of corticosteroids should be started. Minor illness, such as upper respiratory infection, and superficial trauma do not require additional/replacement therapy.

Stopping corticosteroid therapy
In autoimmune disease, clear end-points should be set before starting therapy. Corticosteroids may improve mood and give patients a feeling of general well-being unrelated to the effect on the disease being treated. Subjective assessments can therefore be misleading. Objective clinical parameters should be used to monitor the need for continuing or restarting therapy e.g. proteinuria in nephritis, spirometry in asthma and creatinine kinase in myositis. Therapy should be tapered off. For example, with prednis(ol)one, the dose is reduced in steps of 2.5-5 mg every 3-7 days down to 15 mg/day. At that point, switch to alternate day therapy and reduce in 2.5 mg steps over 2-3 weeks. This minimises the impact on mood and lessens the drop in general well-being.

Reference

1 . Beck RW, Cleary PA, Trobe JD, Kaufman DI, Kupersmith MJ, Paty DW, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 1993;329:1764-9.

Self-test questions

The following statements are either true or false (click here for the answers)

1. Patients with features of Cushing's syndrome probably have suppression of the hypothalamic-pituitary-adrenal axis.

2. Immunosuppressant drugs can be used to reduce the dose of corticosteroids.



First published online: February 1999