In 1952, Sulzberger and Witten published their observation that hydrocortisone applied topically was effective in the treatment of atopic dermatitis.1 Since then, hydrocortisone and its more potent analogs have been used extensively for the treatment of inflammatory dermatoses in children. Armed with only a few grams of a topical corticosteroid, a physician can frequently clear lesions that had been unresponsive to therapy in the pre-corticosteroid era. Dermatoses that are responsive to topical corticosteroids are usually characterized by inflammation, hyperproliferation, or aberrant immunologic phenomenon. In children, these are atopic dermatitis (including nummular and dyshidrotic eczema), seborrheic dermatitis, contact dermatitis, psoriasis, lichen planus, lichen nitidus, lichen simplex chronicus, and granuloma annulare.
The discovery that topical hydrocortisone possesses considerable anti-inflammatory activity quickly stimulated research efforts to develop corticosteroid compounds with increased efficacy. These synthetic analogs are modifications of the hydrocortisone molecule. Fluorination, methylation or acetylation, esterification, and double-bond induction all seem to increase the anti-inflammatory activity of the glucocorticoids.
Physicians frequently consider fluorinated or halogenated corticosteroids to be more potent and to have more risk for side effects than nonhalogenated preparations. It is now recognized that topical corticosteroids lacking fluorine and other halogens may not be significantly safer than the halogenated compounds of similar strength. For example, hydrocortisone esters, such as hydrocortisone butyrate or hydrocortisone valerate, belong in the moderately potent group of steroids with risk-benefit ratios similar to those of other moderately potent topical corticosteroids and are not equivalent to the least potent hydrocortisone formulations.
MECHANISM OF ACTION
The clinical potency and, to an extent, side effects of topical corticosteroids are determined by their solubility in the stratum corneum. The desired solubility is achieved by the various chemical modifications mentioned above. The vehicle in which the corticosteroid is delivered also influences percutaneous absorption considerably. Agents such as propylene glycol may be added to enhance the solubility of the steroid in the stratum corneum. Therefore, the vehicle into which the agent is incorporated may be as important as the corticosteroid molecule itself in determining the strength and the effectiveness of the drug. Because of differences in vehicle, generic preparations are not always equivalent to brand name products in strength and effectiveness.
Besides the intrinsic strength of the corticosteroid molecule and the vehicle into which it is incorporated, other factors greatly influence the ability of these compounds to penetrate the stratum corneum. The first is the condition of the skin. Diseased skin does not have a normal stratum corneum barrier, so penetration is much greater than through normal skin.2 Fortunately, barrier function is restored as the skin improves with treatment. This means that less corticosteroid is absorbed, resulting in a natural tapering of the corticosteroid dosage.
The second factor is hydration of the skin. Greater penetration occurs through well-hydrated stratum corneum, such as the skin in the axillae and the groin areas. Therefore, weaker preparations are preferred in these areas. Ointments, which cause greater hydration of the skin than cream vehicles, allow greater penetration. Thus, the ointment preparation of any particular topical corticosteroid is generally more potent and clinically effective than the cream form. ''Optimized'' vehicles, such as those used in high-potency creams, are an exception to this generalization.
Another factor affecting penetration is the thickness of the stratum corneum in the area of the skin to which a topical corticosteroid is applied. Penetration of hydrocortisone cream is 13 times greater on the face (presumably because of a very thin stratum corneum) and 42 times greater in the groin (due to hydration and a thin stratum corneum) when compared with penetration on the forearm.3 Penetration is further enhanced by an occlusive diaper. This explains why skin atrophy and systemic side effects have been reported most frequently from the use of topical corticosteroids of moderate strength or stronger in the groin area of infants. It is therefore recommended that only weak corticosteroid preparations, such as 1% hydrocortisone, be used on the face and under a diaper, and, if stronger preparations are needed, their use should be limited to 2 weeks or less. The combination of clotrimazole and betamethasone dipropionate contains a potent topical corticosteroid and thus should be avoided in the diaper area.
Three major phenomena occur after application of topical corticosteroids: vasoconstriction, reduction of inflammation, and decreased mitosis of epidermal cells. The ability to reduce inflammation and the ability to constrict blood vessels have been thought to correlate with each other, although this correlation may be far from perfect.4 Topical corticosteroids have been placed into seven groups using the vasoconstriction assays of McKenzie and Stoughton,5 which measured the blanching effects of steroids on the healthy skin of adult volunteers. This ranking does not measure safety or clinical outcome.4 Relative strengths of some commonly used topical corticosteroids are listed in the table, which is a modification of a similar table recently published by Burkholder.6
POTENTIAL SIDE EFFECTS OF TOPICAL CORTICOSTEROIDS
Serious side effects from the use of topical corticosteroids have rarely been reported in children. However, as preparations of greater potency have become available, the potential for side effects has increased.
Systemic Side Effects
Clinically apparent systemic side effects have been reported more frequently in children than in adults. This is partly because the ratio of body surface area to body weight is greater in children. Systemic side effects include adrenal insufficiency and growth retardation. Cushing's syndrome, intracranial hypertension, arterial hypertension, and osteoporosis have been reported rarely. Systemic effects are most common after continuous, long-term (more than 3 months), generalized application of a moderate strength or stronger topical corticosteroid, or after such application for 1 month or longer to the diaper area of infants.7
Adrenal suppression occurs rapidly after the generalized application of very high potency topical corticosteroids. However, this has also been reported after generalized application of hydrocortisone (one of the weakest topical corticosteroid preparations) in a small number of young children with acute generalized dermatoses.8 Infants younger than 18 months have the highest systemic levels of corticosteroids following topical application. This results in a greater degree of adrenal suppression than is seen in older children.2 Therefore, if effective, the use of weak corticosteroids or relatively short-term application (2 to 3 weeks to induce remission of moderatestrength preparations) is preferred for very young patients. Caution should be used for children with liver or renal disease because they may have difficulty metabolizing and excreting steroid compounds.
When topical corticosteroids are used carefully, systemic effects are rarely a problem. Several studies have demonstrated that the short-term use of mild to moderately potent topical corticosteroids had no clinically significant effects on the Cortisol level in the plasma of children.910 Patel et al.n also found no evidence of adrenal suppression in children with moderate to severe atopic dermatitis treated intermittently for 3 to 10 years with topical corticosteroids of mild to moderate potency.
Fortunately, most children with a generalized inflammatory skin disease such as atopic dermatitis respond rapidly to treatment. This usually leaves only limited areas of skin, such as the flexural areas, that require long-term therapy, making systemic side effects unlikely. When longer-term generalized treatment is needed, adrenal suppression is much less likely if intermittent therapy can be used once improvement from daily therapy has been attained. Intermittent regimens include application of corticosteroids every other day,12 twice weekly application for maintenance,13 or 2 weeks of therapy followed by a 2-week "rest" period during which patients are treated topically with emollients. Routine generous use of emollients (creams or ointments rather than lotions), in addition to topical corticosteroid therapy, often reduces the frequency and duration of treatment.
Even when suppression of the hypothalamic-pituitary-adrenal axis is detectable biochemically, it may not become clinically significant unless suppression is prolonged. However, pediatricians should be aware that when young patients who have received extensive, continuous topical corticosteroids are severely stressed by a major illness or a surgical procedure, they could potentially have clinical signs of adrenal insufficiency and require emergent replacement therapy.
Relative Potencies of Some Commonly Used Topical Corticosteroids
Growth retardation from topical corticosteroids is uncommon, but has been reported after long-term use for extensive areas of the skin or the diaper area of infants.14 Fortunately, a period of rapid "catch up" growth generally occurs when the steroid is discontinued. Long-term effects on growth have been assessed by reviewing the adult heights of 35 patients who had the onset of atopic dermatitis before 5 years of age.15 The disease continued into adulthood and was severe enough to require the care of a specialist and the frequent use of topical corticosteroids. The adult heights of these patients were not significantly different from those of control subjects. Although apparently rare, permanent short stature resulting from extensive, continuous use of a topical corticosteroid during childhood and through adolescence has been reported.16 Therefore, continuous, extensive use of highpotency preparations should be avoided if possible, especially during the rapid growth period of adolescence.
Local Side Effects
Local changes in the skin from topical corticosteroids have been reported less frequently in children than in adults. Changes in children include rosacea and perioral dermatitis, atrophy of the skin with striae, and changes in pigmentation.17
Rosacea and perioral dermatitis are the most common local side effects reported in children. These may result from even the short-term use of corticosteroids of any strength on the face of susceptible individuals.18 Weston and Morelli18 noted that immediate discontinuation of the corticosteroid and treatment with oral erythromycin and topical clindamycin resulted in resolution of these conditions.
Atrophy is most likely in areas where the stratum cornea is thin, such as the face and the groin. In children, most reports of atrophy followed continuous application of topical corticosteroids of moderate strength or stronger to the diaper area or the groin for longer than 4 weeks. Mild atrophy appears to be largely reversible. However, striae, should they develop, are permanent. Areas treated with corticosteroids should be examined regularly for signs of atrophy. These include thinning of the skin, shininess, telangiectasia, and loss of normal skin markings. In adolescents who may be prone to striae formation, topical corticosteroids should be used with caution in areas where striae commonly develop (eg, the thighs, buttocks, and breasts).
Allergic contact reactions to topical corticosteroids most commonly result from sensitization to preservatives or fragrances in the vehicle, but occasionally are due to the corticosteroid itself. Patients with contact dermatitis from topical corticosteroids generally present with a chronic dermatitis that is not exacerbated by, but fails to respond to, corticosteroid therapy.19 The diagnosis is confirmed by patch testing, although improvement may occur by simply switching to an unrelated compound. Contact allergic reactions are most commonly observed with esters such as hydrocortisone butyrate and prednicarbate.19
How Frequently Should Topical Corticosteroids Be Applied?
For several years, twice daily application has been recommended most often for topical corticosteroids. For the treatment of dermatitis, recent studies have revealed no significant difference in efficacy between once daily and twice daily application.20,21 Once daily application of topical corticosteroids for atopic dermatitis should have three advantages: reducing the risk of adverse effects, halving the cost of therapy, and possibly improving patient compliance.
Which Topical Corticosteroid Should Be Used?
In general, preparations that are mild or moderate in strength are recommended for children. High-potency corticosteroids may be appropriate for short-term use (particularly in older children) to bring disease under control, and for use on the palms and the soles, where the stratum corneum is thick. Very high potency compounds are used only under special circumstances for children. It is frequently appropriate to recommend two or more strengths of topical corticosteroids for different areas of the body.
Since the early 1980s, attempts have been made to modify the basic corticosteroid molecule to produce agents that have little systemic activity but retain a high degree of topical anti-inflammatory activity. Three moderate-strength preparations have been designed to have low systemic bioavailability because of rapid biotransformation into inactive metabolites. These are fluticasone propionate, which was recently approved for use in children 3 months of age or older; mometasone furoate, approved for children 2 years or older; and prednicarbate, approved as a cream for 3 weeks of use in children 1 year or older and as an ointment for children 10 years and older. When moderate-strength corticosteroids are needed, they may offer some safety advantage, although they are more costly than compounds available in generic formulations.
Physicians should be aware of the strength of the topical preparations they prescribe, but should also educate parents and older children to use topical corticosteroids safely and effectively. In a recent study, 31% of patients thought 1% hydrocortisone was either strong or very strong and 41% of patients graded clobetasol propionate, one of the most potent topical corticosteroids available, as weak.22
Topical corticosteroids continue to be among the safest and most effective therapies for inflammatory skin diseases. When they are used appropriately, side effects are rare. The consequences of underutilization of these agents (eg, severe itching, negative social feedback resulting in physiological distress, loss of sleep, and family disruption) may be much more harmful than the small risks of the side effects. In the future, we can expect an improvement in potency rankings based on clinical outcome measures, which will aiiow more precise selection of agents.6 The increasing understanding of structure-function relationships and molecular mechanisms also holds promise for the development of agents that have even greater safety profiles.
1. Sulzberger MB, Witten VH. The effect of topically applied compound F in selected dermatoses. J Invest Dermatol. 1952;19:101-102.
2. Turpeinen M. Influence of age and severity of dermatitis in the percutaneous absorption of hydrocortisone in children. Br J Dermatol. 1988;118:517-522.
3. Feldman RJ, Maibach HI. Regional variations in percutaneous penetration of C-cortisol in man. J Invest Dermatol. 1967:48.181-183.
4. Hepburn DJ, Aeling JL, Weston WL. A reappraisal of topical steroid potency. Pediatr Dermatol. 1996;13:239-245.
5. McKenzie AW, Stoughton RB. Method for comparing percutaneous absorption of steroids. Arch Dermatol. 1962; 86:608-610.
6. Burkholder B. Topical corticosteroids: an update. Curr Probi Dermatol. 2000;12:222-225.
7. Johns AM, Bower BD. Wasting of napkin area after repeated use of fluorinated steroid ointment. BM]. 1970;1:347348.
8. Turpeinen M, Salo OP, Leisti S. Effect of percutaneous absorption of hydrocortisone on adrenocortical responsiveness in infant with severe skin disease. Br J Dermatol. 1986;115:475-484.
9. Rasmussen JE. Percutaneous absorption of topically applied triamcinolone in children. Arch Dermatol. 1978; 114:1165-1167.
10. Crespi HG. Topical corticosteroid therapy for children: alclometasone dipcopionate cream 0.05%. Clin Ther. 1986;8:203-210.
11. Patel L, Clayton PE, Addison GM, Price DA, David TJ. Adrenal function following topical steroid treatment in children with atopic dermatitis. Br J Dermatol. 1995; 132:950-955.
12. Queille C, Pommarede R, Saurat JH. Efficacy versus systemic effects of six topical steroids in the treatment of atopic dermatitis of childhood. Pediatric Dermatol. 1984; 1:246-253.
13. Van der Meer JB, Clazenburg EJ, Mulder PGH, et al. The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. Br J Dermatol. 1999;140:1114-1121.
14. Vermeer BJ, Heremans GF. A case of growth retardation and Cushing's syndrome due to excessive application of betamethasone-17-valerate ointment. Dermatologica. 1974;149:299-304.
15. Patel L, Clayton PE, Jenney MEM, et al. Adult height in patients with childhood onset atopic dermatitis. Arch Dis Child. 1997;76:505-508.
16. Bode HH. Dwarfism following long-term topical corticosteroid therapy. JAMA. 1980;224:813-814.
17. Pierard GE, Piérard-Franchimont C, Mosbah TB, Estrada JA. Adverse effects of topical corticosteroids. Acta Dermatol Venereol Suppl (Stockh). 1989;69(suppl 151):26-30.
18. Weston WL, Morelli JG. Steroid rosacea in prepubertal children. Arch Pediatr Adolesc Med. 2000;154:62-64.
19. Goossens A, Matura M, Degreef H. Reactions to corticosteroids: some new aspects regarding cross-sensitivity. Cuti's. 2000;65:43-45.
20. Tharp M. Comparisons of twice daily and once daily administration of fluticasone propionate cream 0.05% in the treatment of eczema. Cutis. 1996;57:19-26.
21. Lagos BR, Maibach HI. Frequency of application of topical corticosteroids: an overview. Br J Dermatol. 1998;139: 763-766.
22. Charman CR, Morris AD, Williams HC Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol. 2000;142:931-936.
Relative Potencies of Some Commonly Used Topical Corticosteroids