Early intervention with inhaled corticosteroids is currently considered first-line anti-inflammatory therapy in patients with asthma. Even though adverse effects are not commonly associated with inhaled corticosteroids, the trend toward higher dosing has led to a greater awareness of possible dose-related systemic adverse effects. The comparative risks and benefits of newer and older agents continue to be debated, with the realization that long-acting beta2-agonists, theophyllines or antileukotrienes can still play a role in therapy. Lipworth conducted a literature search to assess the efficacy of inhaled corticosteroid therapy in patients with asthma, along with associated systemic adverse effects.
The results of the search were primarily qualitative and included evaluations of adrenal suppression, the effects of therapy on growth and bone metabolism, and adverse effects on the eyes and skin. Where appropriate, a given end point was analyzed to produce a comparable response across different studies; however, this was possible only for adrenal suppression. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies.
Studies that evaluated the effects of at least three doses of inhaled corticosteroid on adrenal suppression were included in the analysis. Two types of tests are generally used to evaluate adrenocortical function: screening tests of basal adrenocortical activity and dynamic stimulation tests to assess adrenocortical reserve. Obtaining a 24-hour measurement of plasma cortisol levels or urinary free cortisol excretion is the most sensitive way to evaluate basal activity. Measuring overnight or early morning urinary cortisolcreatinine excretion appears to be as sensitive as an integrated 24-hour urinary free cortisol collection and is more sensitive than a spot measurement of 9 a.m. plasma cortisol levels.
Marked adrenal suppression occurs with dosages of inhaled corticosteroids greater than 1.5 mg per day (0.75 mg per day for fluticasone propionate), although there is a significant degree of interindividual susceptibility. Meta-analysis of 21 studies of urinary cortisol levels and 13 studies of suppression of 8 a.m. plasma cortisol levels revealed that fluticasone demonstrated significantly steeper dose-related systemic bioactivity than beclomethasone, budesonide or triamcinolone. The effects were most apparent at dosages above 0.8 mg per day, because of the differences in slope gradients between fluticasone and the other drugs.
The effects of inhaled corticosteroids on bone age and growth rate are important considerations. The results of long-term studies suggest that suppressing asthmatic disease activity in children usually outweighs any potential systemic bioactivity of inhaled corticosteroids in determining long-term growth. However, the U.S. Food and Drug Administration (FDA) continues to caution that the use of recommended dosages of intranasal and inhaled corticosteroids may be associated with a reduction of growth velocity.
One concern associated with the long-term use of inhaled corticosteroids is the potential adverse effects on bone metabolism, particularly osteoporosis and fracture. Inhaled corticosteroids have been shown to be associated with dose-related effects on biochemical bone markers that occur less frequently than with oral corticosteroids. Bone markers should not be used as a surrogate for bone density to predict risk of development of osteoporosis. Decreases in bone density have been associated with long-term daily corticosteroid therapy. Supplemental estrogen may have a protective effect against osteoporosis. Supplemental estrogen should be recommended for use in postmenopausal women with asthma, as it guards against bone loss.
Long-term use of inhaled corticosteroids appears to affect the eyes and the skin. The risk of posterior subcapsular cataracts is increased, and a small but significant risk for ocular hypertension and open-angle glaucoma is associated with regular use of high-dose corticosteroids. There is also evidence of a dose-response effect of inhaled corticosteroids on bruising and thinning of the skin, especially in older women.
The author concludes that fluticasone propionate exhibits greater dose-related adrenal suppression than other available inhaled corticosteroids, particularly at dosages above 0.8 mg per day. Because the systemic effects of inhaled corticosteroids vary by individual, it is difficult to predict whether systemic effects will develop in a patient at a given dosage. Therefore, patients on long-term inhaled corticosteroid therapy should undergo regular examinations.