In addition to the dangers associated with long-term use of corticosteroids in supraphysiological concentrations, withdrawal of steroid therapy presents problems. The suppression of the hypothalamic-pituitary axis observed with modest doses and short courses of gluco-corticoid therapy is usually readily reversible. However, steroid therapy with modest to high doses for 2 weeks or longer will depress hypothalamic and pituitary activity and result in a decrease in endogenous adrenal steroid secretion and eventual adrenal atrophy. These patients have a limited ability to respond to stress and an enhanced probability that shock will develop. Long-acting steroids, such as dexamethasone and betametha-sone, suppress the hypothalamic-pituitary axis more than do other steroids. The functional state of the hypothalamic-pituitary axis can be evaluated by tests involving basal plasma Cortisol determinations, low and high doses of cosyntropin (peptide fragment of corticotrophin), insulin hypoglycemia, metyrapone, and corticotrophin-releasing hormone.
Glucocorticoids are not withdrawn abruptly but are tapered. The doses are altered so that the condition being treated will not flare up and recovery of the hypothalamic-pituitary axis will be facilitated. Tapering the dose may reduce the potential for the development of Addison-like symptoms associated with steroid withdrawal. Alternate-day therapy will relieve the clinical manifestations of the inflammatory diseases while allowing a day for reactivation of endogenous corticosteroid output, thereby causing less severe and less sustained hypothalamic-pituitary suppression. This is feasible with doses of shorter-acting corticosteroids, such as pred-nisolone. The usual daily dose is doubled and is given in the early morning to simulate the natural circadian variation that occurs in endogenous corticosteroid secretion. The benefits of alternate-day therapy are seen only when steroids are used for a long period and are particularly useful for tapering the dose of glucocorticoid.
Although not always predictable, the degree to which a given corticosteroid will suppress pituitary activity is related to the route of administration, the size of the dose, and the length of treatment. The parenteral route causes the greatest suppression, followed by the oral route, and finally topical application. Hypothalamic-pituitary suppression also may result if large doses of a steroid aerosol spray are used to treat bronchial asthma. Patients given high concentrations of steroids for long periods and subsequently exposed to undue stress (e.g., severe infection, surgery) face the danger of adrenal crisis. These patients must be given supplemental steroids to compensate for their lack of adrenal reserve and to sustain them during the crisis.
Acute adrenal insufficiency will, of course, occur from an abrupt cessation of steroid therapy. The causation of fever, myalgia, arthralgia, and malaise may be difficult to distinguish from reactivation of rheumatic disease. Steroid treatment should be reduced gradually over several months to avoid this potentially serious problem. Also, continued suppression may be avoided by administering daily physiological replacement doses (5 mg prednisone) until adrenal function is restored. Although tapering of dose may not facilitate recovery of the hypothalamic-pituitary-adrenal axis, it may reduce the possibility of adrenal insufficiency. This is important, since severe hypotension caused by adrenal insufficiency may evoke a medical emergency. Adrenal insufficiency should always be considered in patients who are being withdrawn from prolonged glucocorti-coid therapy unless metyrapone or insulin hypo-glycemia tests are performed to exclude this possibility.
An additional problem associated with glucocorti-coid therapy is that certain side effects can be caused by the diseases for which glucocorticoids are administered. Thus, osteoporosis can be a sequela of rheumatoid arthritis, and the physician is left to determine whether the untoward effect is iatrogenic or is merely a sign of the disease being treated. In addition to these problems, the physician must also be aware of the patient's natural reluctance to reduce the dose of steroid because of its salutary effects, both on the inflammatory process and on the psyche. Thus, the problems associated with withdrawal from long-term steroid therapy in rheumatoid arthritis are additional reasons steroid treatment should be initiated only after rest, physiotherapy, and nonsteroidal antiinflammatory drugs or after methotrexate, gold, and D-penicillamine have been used.
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