H02: Corticosteroids for systemic use

How do glucocorticoids work?

Glucocorticoids act through genomic and possibly nongenomic mechanisms. In the genomic route, the drug activates the glucocorticoid receptor in the cytosol, which switches the synthesis of proteins up or down, including cytokines, chemokines, inflammatory enzymes and adhesion molecules. In this way, glucocorticoids may modify inflammation and the immune response. Nongenomic mechanisms might play an additional role in short courses of very high doses (pulse therapy) [2].

Endogenous cortisol

In a model of the hypothalamic-pituitary-adrenal (HPA) axis built on data from 30 healthy volunteers, adrenocorticotropic hormone (ACTH) from the pituitary drove a time-dependent production of cortisol, the body’s own glucocorticoid, and cortisol inhibited ACTH secretion in turn [3].

When the drug is hydrocortisone, which is cortisol, the assay measures the dose and the body’s own cortisol together. In one healthy-volunteer study, endogenous cortisol was therefore suppressed with dexamethasone before and after the hydrocortisone doses, and the final model still carried a constant endogenous baseline [4].

Efficacy

What is measured depends on why the drug is given.

In 50 patients with underactive adrenal glands (adrenal insufficiency) on their usual hydrocortisone replacement regimen, dosed on clinical evaluation, plasma cortisol was compared with the physiological range, and 79%, 55% and 45% of them were over- or under-treated at 08:00, 16:00 and midnight [5].

In rheumatoid arthritis, an inflammatory disease, the SEMIRA trial compared tapering with continuing prednisone (H02AB07) on the mean change in a clinical score, the Disease Activity Score for 28 joints with erythrocyte sedimentation rate (DAS28-ESR). In patients with low disease activity on tocilizumab (L04AC07), continuing 5 mg prednisone daily gave better disease control than tapering it to zero, although two-thirds of patients tapered safely [6].

In a study in 48 healthy women given single doses of dexamethasone or betamethasone (H02AB01), the effects were followed on six continuous biomarkers: cortisol, T helper cells, basophils, glucose, neutrophils and T cytotoxic cells, four of which had circadian rhythms. Each was described with an indirect response (turnover) model, in which the drug inhibited or stimulated the production or influx of the biomarker, and cortisol was the most sensitive [7]. Simulations with T helper cells and endogenous cortisol as biomarkers suggested that low-dose methylprednisolone might be more effective given twice daily [2].

Safety

Glucocorticoids cause severe adverse reactions, particularly when taken systemically at high doses for long periods [8]. In a survey of 2446 long-term users in a US managed care population, more than 90% reported at least one adverse effect associated with glucocorticoids. Weight gain was the most common, reported by 70%, and cataracts (15%) and fractures (12%) were among the most serious. All eight adverse effects studied showed a dose-dependent association with cumulative glucocorticoid use, and among users of 7.5 mg prednisone per day or less, longer use was associated with acne, skin bruising, weight gain and cataracts [9].

Suppression of the HPA axis causes adrenal insufficiency, which is potentially life-threatening and can become symptomatic when treatment is withdrawn. Long-term systemic glucocorticoids should therefore be withdrawn slowly [8]. In a meta-analysis of 74 studies of corticosteroid users, the proportion with adrenal insufficiency among patients with asthma rose from 2.4% at low doses to 21.5% at high doses, and from 1.4% after less than 28 days of treatment to 27.4% after more than a year. No dose, duration, route or disease excluded adrenal insufficiency with certainty [10].

References