Glucocorticosteroids exert their effect by binding to glucocorticoid receptors (GRs) and by modification of transcription of corticosteroid-responsive genes. Free GCSs readily diffuse through the plasma membrane to bind to GRs in the cytoplasm, which leads to release of the heat-shock protein (hsp) 90. Upon release of hsp90, two nuclear localization signals are exposed, which allow the nuclear accumulation of the GR complex.

The GR forms a dimer that binds to glucocorticoid response elements within the promoter region of steroid-responsive genes. From this interaction, transrepression or transactivation of regulatory proteins may occur. It has become increasingly clear that many adverse effects of GCS are predominantly caused by transactivation (e.g., diabetes and glaucoma, osteoporosis, skin atrophy, growth retardation, and Cushing syndrome) [3]. By contrast, antiinflammatory effects are mostly mediated by transrepression of proinflammatory cytokines or cyclooxygenase-2 (COX-2) [3, 4].

The discovery that activation and repression of the GR are genetically separable has fueled intense research on more selective receptor ligands [5]. The precise confirmation that the receptor assumes after ligand binding is determined by the structure of the given binding partner. Upon binding, structural alterations occur that allow interactions of the DNA-binding surface with specific glucocorticoid response elements such as the formation of homodimers and the binding of different co-activators and co-repressors at the ligandbinding domain that induce either activation or repression of gene transcription [6]. In particular, transcriptional repression activity is sensitive to the glucocorticoid-mediated antiinflammatory and antiproliferative effects [7]. Several mechanisms of transcriptional repression such as interactions of the GR with DNA or with nonreceptor protein– protein complexes have been described [6]. Recently, a number of more selective GR ligands have been discovered; they are called selective GR agonists (SEGRAs) or dissociating GCSs [6]. The SEGRAs predominantly induce the desired transrepression effects, whereas transactivation properties are significantly reduced [3]. While some of these compounds have an encouraging side-effect profile, equivalent anti-inflammatory efficacy as compared with prednisone and dexamethasone still has to be demonstrated for compounds such as deflazacort [8].

Glucocorticosteroids induce neutrophilia, lymphopenia, eosinopenia, and monocytopenia. They also reduce access of inflammatory cells at the sites of active inflammation. However, important neutrophil functions such as phagocytosis and bactericidal activity remain largely unaffected by pharmacologic doses of GCSs. Transient lymphopenia occurs through redistribution of T lymphocytes to other lymphoid compartments, possibly through a change in adhesion molecule expression.

The list of potential indications for use of GCS in dermatology is long (Table 48.2). Primary indications are severe forms of eczema and autoimmune diseases, including bullous and collagen vascular diseases. In addition, GCSs are extremely useful drugs in the treatment of graft-versus-host disease [9].

Moreover, a number of cancers such as certain lymphomas and leukemias (e.g., multiple myeloma) respond well to combination therapy that includes GCSs. In these diseases, cancer cells are killed through GCS-mediated induction of apoptosis.

Contraindications include herpesvirus keratitis, active viral infections, invasive mycosis, and allergy to GCSs as well as administration following vaccination. Relative contraindications include hypertension, cardiac insufficiency, peptic ulcers, psychosis, tuberculosis, diabetes, osteoporosis, glaucoma, cataracts, and pregnancy.

Dermatologists most often prescribe GCSs for short periods of time to treat acute dermatoses such as contact dermatitis or different kinds of disorders. The therapeutic principle is to start at a high dose and to reduce the dose upon effect to maintenance dosing below the Cushing equivalent. Many corticoid-sensitive conditions are treated by oral burst therapy followed by a 2- to 3-week tapering course with a drug of intermediate duration of action such as prednisone; typically initial doses are in the range of 40–60 mg per day. From a pharmacoeconomic standpoint, GCSs have a very high cost effectiveness ratio; however, this is hampered by the costs of management of side effects. For example, prednisone is convenient as it is inexpensive and available in many dosages. The drug is usually given as a single dose in the morning rather than dosing being divided over the course of the day in order to minimize HPA axis suppression.

Severe and life-threatening dermatoses such as pemphigus vulgaris or severe drug reaction require higher doses of GCSs to suppress and control the disease. Especially for high-dose treatment, the doses can be separated by 4 to 6 hours to achieve better early control. The next step is to consolidate the drug to a single morning dose, prior to tapering. Alternatively, every-other-day administration may also be used as it has been shown to minimize suppression of the HPA axis. The addition of a steroid-sparing agent (e.g., mycophenolate mofetil or azathioprine) is often necessary for long-term GCS treatment such as for pemphigus vulgaris prior to tapering. Typical tapering is accomplished by 20-mg steps when the initial dose was more than 60 mg per day. Smaller tapers are used for lower initial doses until the physiologic dose range of 7.5 mg per day of prednisone is reached.

Intravenous pulse therapy is used for lifethreatening dermatoses using methylprednisolone in doses of 0.5–1 g per day for 5 days with a subsequent change to oral therapy. Cardiac conditions due to acute electrolyte shifts and arrhythmias are the most significant complications of a high-dose regimen. Due to the mineralocorticoid activity, potassium substitution may also be necessary.

To minimize corticosteroid side effects associated with GCS use, local application (e.g., inhalation) or fine-tuned dosing regimens have been developed to improve the benefit-risk ratio. One additional progress report includes the development of liposomal GCSs, which selectively accumulate at the site of inflammation [10]. Another current approach to optimize therapy with conventional GCS is to change the timing of glucocorticoid delivery (timed-release capsules) and the combination with 11β-hydroxysteroid dehydrogenase that increases the level and action of endogenous GCSs. For an additional improvement, new drugs such as selective GR agonists or nitroso-glucocorticoids (nitrosteroids) are in development. The nitrosteroids are characterized by an aliphatic or aromatic molecule, which links a conventional GCS derivative with nitric oxide (NO). Representatives of this class are NO-prednisolone and NO-hydrocortisone, which slowly release NO, exerting antiinflammatory effects [11]. The NO effect is synergistic to the effect of prednisolone, leading to an up to tenfold more potent antiinflammatory response than those of prednisolone alone [12].

Glucocorticosteroids can be applied as topical and systemic treatment, but may also be administered locally to the nasal mucosa or be inhaled for the treatment of asthma. Recent studies suggest that inhaled steroids may also exhibit comparable side effects, including growth retardation in children [13] and reduction of bone markers in adolescents [14].

Local injections of triamcinolone are frequently being used to treat keloids. In addition, intraarticular injection represents a local application against rheumatic diseases.

As several drugs, such as rifampin, phenytoin, and phenobarbital, induce the hepatic cytochrome P-450 system, the clearance of GCSs may be accelerated in patients taking these medications. Dose-lowering adjustments may be necessary with enzyme inhibitors such as ketoconazole. Estrogens also potentiate the effect of GCS, because the two agents are metabolized similarly and have similar protein-binding characteristics [15].

The dose of GCS needs to be adjusted in patients with chronic active hepatitis and reduced renal function [16]. Conversely, in patients with hyperthyroidism, the biologic effect of prednisolone is reduced and may require higher doses.

The side effects of GCS are strictly dose-dependent. In addition, some side effects are known to depend on age and sex. In general, the side effects of GCS therapy show different degrees of severity. Table 48.3 contains a list of relevant side effects of GCS.

Topical corticosteroids (TCSs) have a particular adverse-effect profile, primarily directed at the treated skin area, that occurs regularly with prolonged treatment. The severity depends on the potency of the drug, the vehicle, and the location of its application (Table 48.4). The most frequent adverse effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura (Table 48.5). With lower frequency, hypertrichosis, pigmentation changes, delayed wound healing, and exacerbation of skin infections are observed. Of particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher than generally believed. Systemic reactions following topical application such as hyperglycemia, glaucoma, and adrenal insufficiency have also been reported, especially in children.