Department of Dermatology, University Hospital, Leuven, Belgium
Corticosteroids have dominated the class of anti-inflammatory agents for the past 50 years. In the last ten years, seven new corticosteroids have been developed for topical use. Characteristics common to these several chemically different corticosteroids are their class III, or high potency (USP) designation and their improved safety profile. Allergic contact dermatitis is an unexpected adverse effect that is caused by some of them, in particular budesonide and, to a somewhat lesser degree, the labile “prodrug” corticosteroids, such as prednicarbate and prednisolone acepontate.
corticosteroids, anti-inflammatory agents
No drugs have dominated this class of anti-inflammatory agents as successfully as the corticosteroids. Since their introduction to dermatology a half-century ago, these molecules have been developed both as topical and systemic agents. However, the side effects associated with their use, including percutaneous absorption and cutaneous atrophy, have become increasingly unacceptable. The pharmaceutical industry has responded by introducing a new generation of topical corticosteroids which are “softer”, and early indications are that they are safer1.
Not long after Sulzberger and Witten demonstrated the effectiveness of hydrocortisone in the 1950s, the new more effective fluorinated hydrocortisone analogues became available in the 1960s. In the 1970s and ‘80s, superpotent steroids were introduced. These inclusions meant that there was a great range of potency of these drugs. In 1984, Cornell and Stoughton proposed a potency rating of topically applied corticosteroids. This classification was based primarily on the vasoconstrictor assay or skin-blanching effect of corticosteroid preparations1. More recently, the USP has created a classification of potency ranking for these drugs: low, medium, high and very high based upon the consensus of the USP Dermatology Advisory Panel.
A New Generation of Corticosteroids
Over the past several years, a new series of corticosteroids have been introduced. Of this series, we have included seven agents for review. European and North American based clinical trials have demonstrated that the newer corticosteroids with their improved risk-benefit ratio are as efficacious as products currently in use. Although not all claims have been substantiated, it appears that these drugs have fewer side effects. They act primarily on the upper level of the skin where they interact with the inflammatory mediators, while simultaneously sparing the deeper layers. Not only are the reduced side effects desirable, but there is evidence to show that patients are more compliant2.
While longer clinical follow-up is necessary, current research shows:
- that the newer corticosteroids are potent, belonging to the high potency class of products, with one exception, namely fluocortinbutylester, which can be regarded as less potent because it is transformed in the skin into a nonactive fluocortolone 21-acid.
- that systemic side effects are reduced because of rapid biotransformation, even when used in the wet wrap method to treat atopic dermatitis. However, in very young children and in erythrodermic patients, one should beware of potential hypothalamus and pituitary axis (HPA) suppression, even with the new corticosteroids.
- that local safety with short-term use appears satisfactory1. Indeed, the new generation of corticosteroids does not cause as much cutaneous atrophy or systemic absorption as the older corticosteroids do. This is because of their molecular configuration, which displays a rapidly declining concentration gradient in the skin. They act primarily in the top layers where the most important mediators of the inflammatory reaction are. The action in deeper layers is much diminished. With restricted duration of treatment (up to 6 weeks) clinical safety has been claimed. However, skin atrophy and some telangiectasia have been noted.
The new corticosteroids can be classified in several ways. Chemically, they can be divided as follows:
- Asymmetric acetonides: budesonide
- C21-carboxylesters: alclometasone, fluocortinbutylester, and methylprednisolone aceponate.
- C17-prednicarbonates: 17-prednicarbate
- Carbothiates: fluticasone propionate
- Mometasone furoate
Another way to classify these drugs is by chemical stability:
- Some of these drugs can be regarded as pro-drugs, that undergo metabolization and acryl-exchanges, immediately after application to form the active molecule. They include: prednicarbate, methylprenisolone aceponate, alclometasone, and fluocortin butylesters.
The Issue of Side Effects
The object of the changes made in the corticosteroid molecule between the 1950s and the mid-1980s, was to obtain better skin penetration, slower enzyme degradation, and greater affinity for the cytosol receptors1. However, the changes that increased potency, also led to more side effects.
While systemic side effects are of concern, cutaneous side effects are more common and include problems such as striae formation, atrophy, purpura, peri-oral dermatitis, steroid rosacea, hypertrichosis, and steroid acne1.
Side effects are generally related to the duration and potency of the application, the manner of application (i.e., occlusion), the presence of penetration-enhancing substances, and the state of the skin barrier. The anatomic site of application and the patient’s age can also adversely influence the side effect profile1.
Several of the new corticosteroids may only need to be applied once daily, in contrast to the older corticosteroids, for which a twice-daily application was recommended.
The increase in the number of reports of contact allergic reactions, following the introduction of some of these newer corticosteroids, was unexpected.
In order to explain the increased allergenicity of the newer corticosteroids, data from the literature and clinical studies were reviewed and an attempt was made to define some of the more important groups of cross-reacting molecules4.
Group A – hydrocortisone type: no substitution on the D-ring, except a short chain ester on C17 or C21 or a thioester on C21.
Group B – triamcinolone type: C16, C17-cis-ketal or -diol structure.
Group C – betamethasone type: C16-methylsubstitution, no side chain on C17; possible side chain on C21.
Group D – hydrocortisone-17-butyrate type: long chain ester at C17 and/or C21 with or without C16-methylsubstitution.
Tixocortol pivalate (1% petrolatum) was identified as a good screening agent for Group A. Budesonide (1% ethanol) was found to be a marker for the Group B, but also for certain esters, such as hydrocortisone-17-butyrate in Group D. Budesonide is virtually a 1:1 mixture of two diastereomers (R- and S-isomer). The Risomer is the marker for the B Group, the S-isomer for the D Group. There is no marker for the Group C, but it seems that its members cause almost no contact sensitivity and do not crossreact with other groups.
In recent studies5,6 it has been shown that Group D should be divided into two subgroups. Corticosteroids with a methylsubstitution on C16 and halogenation on the B ring can be classified as Group D1. To this group belong not only the older molecules like betamethasone dipropionate, betamethasone-17- valerate, and clobetasol propionate, but also the newer stable corticosteroids: fluticasone propionate and mometasone fuoroate. They rarely cause positive patch test results, and can safely be used even in patients who are allergic to other corticosteroids.
The corticosteroids with a long ester on C17, possibly a side chain on C21, no methyl substitution on C16, and no halogenation on the B ring can be classified in Group D2 . To this group belong hydrocortisone-17-butyrate and hydrocortisone-17- valerate, as well as the “labile” new corticosteroids like prednicarbate and methylprednisolone aceponate. They can cause allergic reactions. Budesonide (S-isomer) is the marker for this Group D2, but they can cross-react with Group A. Fluocortin butylester belongs to Group C.
The following chart lists a number of these new generation steroids.
|Product||Safety||Class||Side Effects||Allergy group|
Stable, asymmetric acetonide. Undergoes rapid biotransformation in the liver with fewer systemic effects.
There may be a problem with contact sensitivity.
This stable drug is a chlorinated topical steroid. It has low penetration with high biliary excretion, and low resorption in the circulation with rapid biotransformation in the liver. Consequently, there is minimal systemic activity. The result: local side effects are rare.
Contact hypersensitivity is very rare.
Labile pro-drug, transformed in the skin into prednisolone.
Contact hypersensitivity is not rare. Can cross-react with group A.
1. Fluocortin butylester
In the skin, biotransformed into the nonactive fluocortolone-21-acid.
Contact hypersensitivity is probably rare.
2. Alclometasone Dipropionate
No longer available in Europe
Contact hypersensitivity is not rare.
3. Methylprednisolone aceponate
Labile pro-drug. Transformed in the skin into methylprednisolone, in the liver into nonactive derivatives.
Fluticasone is a fluorinated topical corticosteroid, which is rapidly metabolized in the liver. This results in a locally potent steroid with a low HPA inhibitory potency.
Contact hypersensitivity is very rare.
Because these agents act via hepatic and extra hepatic biotransformation, they offer a greater systemic safety. However, in very young children, and in erythrodermic patients, one should consider HPA suppression, even with the new corticosteroids.
With restricted duration of treatment (up to 6 weeks), clinical safety has been claimed.
Some of the newer corticosteroids, particularly budesonide and, to a lesser extent, prednicarbate and alclometasone dipropionate, are more prone to cause contact allergic reactions.
Over the past several years, a new series of corticosteroids have been introduced. They act primarily on the upper level of the skin where they interact with the most important inflammatory mediators, while simultaneously sparing the deeper layers. Trials currently underway worldwide are demonstrating that the newer corticosteroids with their improved risk-benefit ratio are as efficacious as products currently in use with better safety. There are also unsubstantiated claims that these drugs have fewer side effects. Fewer side effects are not only desirable from a clinical point of view, but have also been shown to increase patient compliance with therapy2.
- Degreef H, Dooms-Goossens A. The new corticosteroids: are they effective and safe? Dermatol Clin, 11(1):155-60 (1993 Jan).
- Hadzija BW, Ambrose WW. Comparison of cosmetic and physicochemical properties of six topical corticosteroid creams. Cutis, 57(2 Suppl):13-8 (1996 Feb).
- Oranje AP. American Academy of Dermatology, New Orleans (1999 Mar).
- Coopman S, Degreef H, Dooms-Goossens A. Identifications of cross reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol 121(1):27-34 (1989).
- Matura M. Contact Allergy to Locally Applied Corticosteroids [dissertation]. KU Leuven, Belgium (1998 Sep).
- Goossens A, Matura M. Corticosteroids in Occupational Skin Diseases, 3rd edition by Adams R. WB Saunders Company, Philadelphia, USA (1999).