Topical Corticosteroids



Fig. 48.1
Chemical structure of cortisol. Note the four-ring structure and the hydroxyl group at position 11



Modifications of the basic GCS structure result in agents with variant potency, mineralocorticoid activity, metabolism, and duration of action (Table 48.1). Important for the therapy of patients with hepatic insufficiency is the fact that the ketone group at the 11 position of cortisone must undergo hepatic conversion to a hydroxyl group to produce the active agent hydrocortisone (cortisol). Likewise, prednisone must undergo the same activation by 11-hydroxylation to become the active prednisolone. Therefore, for patients with liver problems, the use of prednisolone is recommended instead of prednisone. Glucocorticosteroids are absorbed in the jejunum with peak plasma levels occurring within one hour. Of note, administration with food does not decrease peak plasma concentrations but may delay its absorption.


Table 48.1
Glucocorticosteroid agents




























































Compound

Equivalent glucocortico steroid dose (mg)

Mineralocorticoid potency (relative)

Duration of activity (h)

Short acting

Cortisone

25

2 +

8–12

Hydrocortisone

20

2 +

8–12

Intermediate acting

Prednisone

5

1 +

24–36

Prednisolone

5

1 +

24–36

Methylprednisolone

4

0

24–36

Triamcinolone

4

0

24–36

Long acting

Dexamethasone

0.60

0

36–54

Betamethasone

0.75

0

36–54



Molecular Mechanism of Action


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].


Effects on Inflammatory Cells


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.


Potential Indications and Contraindications


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].


Table 48.2
Major indications for systemic GCS use in dermatology























































































Inflammatory dermatoses and allergies

 Contact dermatitis (various)

 Atopic dermatitis

 Photodermatitis

 Exfoliative dermatitis

 Erythrodermas

 Urticaria

 Erythema exudativum multiforme

 Stevens-Johnson syndrome

 Erythema nodosum

 Sweet syndrome

Bullous dermatoses

 Pemphigus (all forms)

 Bullous pemphigoid

 Cicatricial pemphigoid

 Linear immunoglobulin A bullous dermatosis

 Epidermolysis bullosa acquisita

 Herpes gestationis

 Erythema multiforme (major/minor)

 Toxic epidermal necrosis

Vasculitis

 Cutaneous (various types)

 Systemic (various types)

Collagen vascular diseases

 Lupus erythematosus (all subsets)

 Dermatomyositis

 Systemic sclerosis

 Mixed connective tissue disease syndrome

 Eosinophilic fasciitis

 Relapsing polychondritis

Neutrophilic dermatoses

 Pyoderma gangrenosum

 Acute febrile neutrophilic dermatosis

 Behçet’s disease

Miscellaneous dermatoses

 Sarcoidosis Lichen

 Planus Polyarteriitis

 Nodosa Panniculitis

 Urticaria/angioedema

 Arthropod bites/stings

 Hemangiomas

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.


Dosing and Administration


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].


Modes of Application


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.


Drug Interactions


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.


Side Effects


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.


Table 48.3
Important side effects of glucocorticosteroid therapy







































































Musculoskeletal effects

 Osteoporosis

 Osteonecrosis

 Growth retardation

 Myopathy

Ophthalmologic effects

 Cataract

 Glaucoma

 Ocular bacterial, fungal, and viral infections

Nervous system effects

 Euphoria

 Psychosis

 Neuropsychiatric changes (anxiety, insomnia, and emotional lability)

 Pseudotumor cerebri

Metabolic effects

 Hyperglycemia

 Hyperlipidemia

 Weight gain

Cardiovascular effects

 Hypertension

 Atherosclerosis

Infection

Obstetric and gynecologic effects

 Pregnancy and lactation

 Amenorrhea

Gastrointestinal effects

 Nausea and vomiting

 Peptic ulcer disease

Cutaneous effects

 Striae, purpura, telangiectasias, and atrophy

 Cushing syndrome

 Impaired wound healing

Hypothalamic-pituitary-adrenal axis suppression


Musculoskeletal



Osteoporosis


Osteoporosis is the most prevalent of the extremely important and severe musculoskeletal effects of long-term GCS therapy, but can be reduced or prevented with early physician intervention. Osteoporosis develops in 30–50 % of patients treated with long-term GCS therapy [17]. The typical patients suffer from chronic diseases such as rheumatoid arthritis, chronic destructive pulmonary disease, and asthma, or have had an organ transplantation. Postmenopausal women are especially at a significantly increased risk of fractures [18].

Importantly, the rate of bone loss is highest in the first 6 months of therapy; thereafter, the rate of bone loss is diminished. Upon discontinuation of steroid therapy, patients partly regain bone tissue. Glucocorticosteroid-induced bone loss affects trabecular bone and the cortical rim of vertebrae to a significantly higher degree than cortical bones (“long bones”). This is due to the much higher metabolic turnover rate of trabecular bone. Glucocorticosteroids cause this side effect by reducing intestinal absorption and renal tubular resorption of calcium. The reduced calcium serum concentration causes increased parathormone release that further promotes bone loss (secondary hyperparathyroidism). In addition, GCS can induce decreased gonadal function in both sexes. The most sensitive technique to diagnose osteoporosis is dual-energy x-ray absorptiometry (DEXA) [19].

Bone density studies should be performed every 12 months in patients with long-term corticosteroid therapy. Besides the use of bisphosphonates (alendronate and risedronate) as effective drugs preventing and treating GCS-induced osteoporosis [20], progress in treating GCS-associated side effects has been limited. There are additional data to support the effectiveness of calcium and vitamin D supplementation in preserving bone mass in patients receiving long-term GCS therapy [21].


Osteonecrosis


Osteonecrosis (aseptic necrosis) can also result from GCS therapy. It most commonly occurs on the proximal femur or the humeral head. In contrast to osteoporosis, osteonecrosis more frequently affects active patients and is particularly common in men [22, 23].


Growth Retardation


Growth suppression from GCS usually occurs with systemic therapy and may only occasionally be a consequence of extensive treatment with topical or inhaled potent GCS. When GCSs are given under the age of 2 or at puberty [24], the risk of growth retardation is especially significant. The studied patients were significantly shorter in height, had a significantly greater body mass index, and a higher prevalence of obesity than did the controls [24]. On average, they had received 23 grams of GCS for the treatment of nephrotic syndrome. The causes are multifaceted: interference with nitrogen and mineral retention, bone formation, inhibition of mitosis, and collagen synthesis [25]. Treatment of GCS-mediated growth inhibition with growth hormone shows some promise [26].


Myopathy


There are two forms of myopathy induced by GCS. One form is an acute myopathy seen almost exclusively in patients treated with high-dose intravenous GCS for status asthmaticus. The second form of myopathy is relevant to dermatology and is characterized by progressive symmetric proximal muscle weakness, which is usually painless and begins on the lower extremities after several months of therapy [27]. While the particular mechanism of GCS’s effect on muscle mass has not been determined, hypogonadism (e.g., estrogen and testosterone) is likely to be involved, as it is present in many GCS patients. Diagnosis of GCS myopathy may be difficult in some patients, as muscle biopsies usually show nonspecific findings, and electromyographic studies are usually normal in this condition.


Ophthalmologic Effects


Cataract formation upon extended periods of GCS treatment has been described [28]. To detect initial changes, routine eye examinations twice yearly are recommended for all patients treated with longterm systemic GCS.

Open-angle glaucoma may also occur upon GCS treatment, especially in patients with a history of rheumatoid arthritis, type 1 diabetes, or a positive family history for glaucoma [29]. The detection of elevated intraocular pressure is important, as this condition is usually reversible within 1–4 weeks, when detected early.


Nervous System Effects


Affective disorders (anxiety, insomnia, euphoria, and emotional lability) are more frequent than confusional or psychotic states. The onset of symptoms is usually within 1 or 2 weeks after starting therapy, especially in patients with a prior history of psychiatric diseases [27]. Importantly, patients with systemic lupus erythematosus, who may suffer from lupus and encephalopathy may be difficult to differentiate from patients with steroid-induced psychosis. Discontinuation of GCS is usually the treatment of choice, rather than starting neuroleptic or antidepressive therapy.

Pseudotumor cerebri, presenting with headache, nausea, vomiting, and papillary edema, is a rare complication of long-term GCS administration and occurs predominantly in boys. It usually occurs when steroids are rapidly tapered or stopped [27].


Metabolic Effects


The manifestation of hyperglycemia and secondary diabetes is a typical complication of GCS therapy [30]. Relative insulin resistance is produced by decreasing the insulin affinity of cellular receptors and possibly by diminishing postreceptor effects of insulin [31, 32]. In addition, GCSs effect insulin-mediated increases in blood flow to muscles and increases in glucose output by increasing the rate-limiting enzyme of gluconeogenesis (i.e., phosphoenolpyruvate carboxy kinase). Therefore, following patients’ regular blood glucose levels during continued GCS therapy is important [33]. If needed, insulin is the therapy of choice, as oral antidiabetics often take weeks before the onset of effects.

Hyperlipidemia may be worsened by GCS, especially in patients with diabetes mellitus, obesity, hypothyroidism, or family history of lipid disorders.

Weight gain may occur as a consequence of increased appetite and fluid retention with GCS therapy. Facial, supraclavicular, and posterior cervical fat depots are particularly sensitive to GCS, resulting in the moon face and buffalo humps that are characteristic of long-term GCS treatment. These symptoms severely impact on patients’ well-being by negatively affecting their appearance and by predisposing them to obesity-related health issues.


Cardiovascular Effects


Excess GCSs can lead to increased blood pressure as they affect several points of blood pressure regulation. Hypertension may develop as a consequence of the mineralocorticoid activity of exogenous GCS. Usually, the kidney is protected from the effects of excess cortisol through the oxidizing effect of 11β-hydroxysteroid dehydrogenase-2, a tissue-specific enzyme capable of converting cortisol to cortisone. However, aldosterone as well as synthetic steroids with modifications and different positions are not susceptible to this activity and exert a major effect directly on the kidney through both mineralocorticoid receptors and GR, leading to transepithelial sodium transport and sodium reabsorption in the proximal tubule [34]. A similar mode of action may be present in brain, where the 11β-hydroxysteroid dehydrogenase-2 is expressed along with mineralocorticoid receptors in selected areas that are involved in central regulation of salt, water balance, and blood pressure [35].

These processes trigger intravascular and extracellular volume expansion. In addition, a decrease in vasodilatory prostaglandins and prostacyclins has been detected upon GCS therapy [36], which contributes to hypertension.


Infection


Patients on GCS therapy are at an increased risk for infections, including bacterial, fungal, viral, and protozoal infectious agents. Making the diagnosis is sometimes difficult, as fever and many other signs of inflammation may be masked. Although neutrophilia is induced by GCS, the presence of greater than 6 % band forms suggests a coexistent infection [37]. Opportunistic infections such as Pneumocystis jirovecii and Toxoplasma gondii may occur in patients on chronic GCS therapy who are not HIV-positive. In addition, reactivation of tuberculosis remains a concern in this patient population [38]. Concomitant isoniazid has been advocated in patients with a positive tuberculin skin test undergoing long-term GCS therapy.


Inhibition of Wound Repair


The inhibition of wound repair results from inhibiting the natural and critical process of inflammation as part of the normal wound-healing process to remove debris and bacteria [39]. Moreover, GCSs inhibit collagen synthesis and collagen cross-linking, and thereby affect structural components of a healing wound [40].


Obstetric and Gynecologic Effects


Clinical experience in several trials has shown minimal adverse effects in pregnant and lactating women during GCS therapy [41, 42]. The American Academy of Pediatrics has determined prednisone to be compatible with breast-feeding, even though there is an excretion in breast milk [43].

Despite the fact that systemic GCS can cross the placenta to various degrees, there is no proof of the detrimental effect on the developing human brain or on vascular disease such as hypertension and atherosclerosis [44, 45]. However, pregnant or lactating women should be monitored for complications such as osteoporosis and glucose intolerance (gestational diabetes).


Gastrointestinal Effects


Nausea and vomiting may occur with oral GCS therapy. These side effects can be minimized if the GCS is taken with food. The association of GCS therapy and peptic ulcer disease remains controversial [46]. In particular, the simultaneous intake of GCSs with nonsteroidal anti-inflammatory drugs as well as smoking and alcohol use have to be considered. Concurrent therapy with proton pump blockers is advised in patients with a history of peptic ulcer disease.


Cutaneous Effects


Cutaneous side effects consist of atrophy of the dermis and subcutaneous tissue, striae, rarefaction of elastic tissue (frequently causing corticoid purpura and steroid acne), telangiectasias, and hirsutism. These and other cutaneous side effects are discussed in the section on topical GCS below.


Hypothalamic-Pituitary-Adrenal



Axis Suppression


The onset of HPA axis suppression is usually evident within 5 days of high-dose prednisolone therapy, suppressing ACTH and cortisol secretion. With longer treatment duration, clinically important adrenal suppression becomes a concern. Full recovery of adrenals may require up to 1 year in certain cases [38]. In addition, patients with chronic adrenal suppression, including HIV patients, may need GCS supplementation in critical conditions such as perioperative stress or sepsis.

A more common clinical problem than adrenal crisis is the steroid withdrawal syndrome. Patients’ symptoms generally include arthralgias, mood swings, headache, lethargy, nausea, and vomiting, and are most frequently noted on rapidly tapering of GCS after extended periods of treatment [47].


Topical Corticosteroids


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.


Table 48.4
Potency of selected topical corticosteroid preparations

























































































Class 1 (superpotent)

Betamethasone dipropionate ointment, cream 0.05 % (Diprolene, Diprosone)

Clobetasol propionate ointment, cream 0.05 % (Temovate, Dermoxin)

Diflorasone diacetate ointment 0.05 % (Florone, Psorcon)

Halobetasol propionate ointment, cream 0.05 % (Ultravate)

Class 2 (potent)

Amcinonide ointment 0.1 % (Cyclocort)

Desoximetasone ointment, cream, gel 0.25 % (Topicort, Ibaril)

Diflorasone diacetate ointment 0.05 % (Florone, Maxiflor)

Fluocinonide ointment, cream, gel 0.05 % (Lidex)

Halcinonide cream 0.1 % (Halog)

Mometasone furoate ointment 0.1 % (Elocon, Ecural)

Triamcinolone acetonide ointment 0.5 % (Kenalog)

Class 3 (less potent)

Amcinonide cream, lotion 0.1 % (Cyclocort)

Betamethasone valerate ointment 0.01 % (Valisone)

Diflorasone diacetate cream 0.05 % (Florone, Maxiflor)

Fluticasone propionate ointment 0.005 % (Cutivate)

Fluocortolone 0.25 % cream (Ultralan)

Fluocinonide cream 0.05 % (Lidex E cream, Topsyn)

Halcinonide ointment 0.1 % (Halog)

Triamcinolone acetonide ointment 0.1 % (Aristocort A)

Triamcinolone acetonide cream 0.5 % (Aristocort-HP)

Class 4 (mid-strength)

Betamethasone valerate lotion 0.01 % (Valisone, Luxiq)

Desoximetasone cream, gel 0.05 % (Topicort-LP)

Fluocinolone acetonide cream 0.2 % (Synalar-HP)

Fluocinolone acetonide ointment 0.025 % (Synalar)

Flurandrenolide ointment 0.05 % (Cordran)

Halcinonide cream 0.025 % (Halog)

Hydrocortisone valerate ointment 0.2 % (Westcort)

Mometasone furoate cream 0.1 % (Elocon, Ecural)

Triamcinolone acetonide ointment 0.1 % (Kenalog)

Class 5 (less mid-strength)

Betamethasone dipropionate lotion 0.05 % (Diprosone)

Betamethasone valerate cream 0.01 % (Valisone)

Fluocinolone acetonide cream 0.025 % (Synalar)

Fluocinolone acetonide oil 0.01 % (Derma-Smoothe/FS)

Flurandrenolide cream 0.05 % (Cordran)

Fluticasone propionate cream 0.05 % (Cutivate)

Hydrocortisone butyrate cream 0.1 % (Locoid)

Hydrocortisone valerate cream 0.2 % (Westcort)

Triamcinolone acetonide lotion 0.1 % (Kenalog)

Class 6 (mild)

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Oct 14, 2017 | Posted by in Dermatology | Comments Off on Topical Corticosteroids

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