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Topical corticosteroids were introduced into medicine about 50 years ago. They represent a significant
milestone in dermatologic therapy. Despite encouragement to report observed adverse drug reactions,
the clinical practice of reporting is poor and incomplete. Likewise, adverse effects and safety of topical
corticosteroids are neglected in the medical literature. The authors provide an updated review of their
adverse-effect profile. Children are more prone to the development of systemic reactions to topically
applied medication because of their higher ratio of total body surface area to body weight. Cutaneous
adverse effects occur regularly with prolonged treatment and are dependent on the chemical nature of the
drug, the vehicle, and the location of its application. The most frequent adverse effects include atrophy,
striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with lower frequency include
hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections. Of
particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher
than generally believed. Systemic reactions such as hyperglycemia, glaucoma, and adrenal insufficiency
have also been reported to follow topical application. The authors provide an updated review of local and
systemic adverse effects upon administration of topical corticosteroids, including the latest FDA report on
the safety of such steroids in children. ( J Am Acad Dermatol 2006;54:1-15.)
Learning objective: At the completion of this learning activity, participants should be familiar with topical
corticosteroids and their proper use.
1
2 Hengge et al J AM ACAD DERMATOL
JANUARY 2006
Pyrexial erythema test are only rarely used. There are no data on interassay
The local reaction to an intracutaneous injection consistency among the individual assays.
of a bacterial pyrogen such as purified lipopolysac-
charide of Salmonella abortus equi is used as an ADVERSE EFFECTS OF TOPICAL
inflammation model for human skin.23 At injection of CORTICOSTEROIDS
a defined quantity of the lipopolysaccharide, the Despite the legal obligation to report to regulatory
local inflammation with and without application of agencies observed adverse drug reactions, the
topical corticosteroid is evaluated at 12 hours. clinical practice of reporting is rather poor and
incomplete. It is estimated that the majority of the
Skin atrophy test moderate to severe side effects will never be re-
The atrophy test is an important addition to ported to regulatory authorities, especially since the
the anti-inflammatory tests, since it can be used drug in question was introduced a long time ago.
to determine those corticosteroids that have only a The available databases (www.fda.gov/cder/drug/
slight antiproliferative effect (atrophogenic poten- default.htm) suggest that only life-threatening side
tial). With the use of the Duhring chamber (a dome- effects were reported or published. Therefore, any
shaped silicone reservoir), the corticosteroid to be summary of adverse events that follow application of
tested is applied to the same skin area for 3 weeks the respective drug is limited.
under occlusion.24 At that point, the resulting atro- During the era when corticosteroids were the
phy and the extent of telangiectasia are evaluated by mainstay of topical therapy for inflammatory dis-
means of a defined score. eases, the unlimited use of these compounds was
recognized to be hazardous. Local as well as systemic
Other tests adverse effects have been documented. Children are
Other test systems include the ammonium hy- more prone to develop systemic reactions to topi-
droxide blister tests,25 the stratum corneum test,24 cally applied medication because of their higher ratio
the skin thickness measurement,26 the acne induc- of total body surface area to body weight (about 2.5-
tion test,27 and the assessment of endogenous cor- to 3-fold that of adults). However, the thicknesses of
tisol production.21,28,29 The psoriasis plaque test, the the stratum corneum and its structural components,
poison ivy test, and the contact eczema inhibition such as keratins and lipids, have been found not to
test are only of historic value.21,30 Others, such as be statistically different from those in adults.33 Under
skin thickness assessment by means of ultrasound31 normal conditions, up to 99% of the applied topical
or early detection of glucocorticoid-specific epider- corticosteroid is removed form the skin by rubbing,
mal alterations with skin surface microscopy,32 also washing off, and exfoliation, and only 1% is
4 Hengge et al J AM ACAD DERMATOL
JANUARY 2006
therapeutically active.34 However, this small percent- of possible adverse effects of topical glucocorticos-
age of percutaneously absorbed corticosteroid can teroids have been reported (Table II). Tachyphylaxis
exert systemic adverse effects, while cutaneous ad- is characterized by decreasing efficacy of cortico-
verse effects may also result from the transient steroids during continued treatment that frequently
presence of topical corticosteroid. necessitates topical corticosteroids of greater po-
Local adverse events of corticosteroid use are far tency. In the experimental setting, tachyphylaxis can
more prevalent than systemic reactions.34,35 A myriad be quantified by means of the vasoconstrictor assay
J AM ACAD DERMATOL Hengge et al 5
VOLUME 54, NUMBER 1
Table V. Reported severe adverse events that follow topical corticosteroid use
Drug Reported adverse effect Reference no.
Budesonide Intraocular pressure changes (up to 30%) 115
Irritation, itching, burning (up to 1%) 116
Contact dermatitis (100 of 7,238) 117
Hydrocortisone Pseudotumor cerebri (benign intracranial hypertension or 118, 119
elevated intracranial pressure)
Cataract 77
Glaucoma 79
Contact dermatitis (74 of 7,238 patients) 114, 117
Triamcinolone acetonide Cushing syndrome 120, 121
Table VI. Topical corticosteroid products licensed Table VII. Reported adverse events in pediatric
for use in pediatric patients in the United States, patients, according to the FDA report
by age limitation Event Frequency (n = 202)*
Age limitation Drug Local irritation 66
[1 y Alclometasone dipropionate Skin depigmentation 30
cream and ointment or discoloration
Prednicarbate emollient cream Striae or skin atrophy 30
[2 y Mometasone furoate Cushing syndrome 6
monohydrate cream Growth retardation 5
[6 y (for up to 4 wk) Fluocinolone acetonide Hyperglycemia (diabetes) 5
topical oil Scarring 5
[3 mo (for up to 4 wk) Fluticasone propionate cream Staphylococcal infection 5
[12 y Betamethasone dipropionate Genital hypertrichosis 4
ointment, cream, gel, lotion Hirsutism 4
and in combination with Rosacea 4
clotrimazole Acne 3
Clobetasone propionate cream, Glaucoma 3
ointment, solution, gel Hypersensitivity reaction 3
Adrenal insufficiency 2
Bruising 2
Fungal infection 2
lead to associated edema and possible hypocalce- Gynecomastia 2
mia. Perioral dermatitis 2
Mental status 2
or mood change
SPECIAL ASPECTS IN PEDIATRIC
PATIENTS *Several other adverse events occurred in fewer than 2 reports
Because the skin of children is particularly sensi- and are not listed here.
tive,104,105 the British National Formulary empha-
sizes that children are particularly susceptible to side
effects. The organization recommends that in gen- children whose data were analyzed for the FDA
eral, topical corticosteroids be avoided in children or, report had a mean age of 7.7 years and a mean time
if necessary, used with great care and for short to onset of lesions of 169.3 days. Most adverse events
periods. A variety of topical corticosteroid products were reported between 1987 and 1997. The censor-
is licensed for use in pediatric patients (Table VI). ing date for analysis was May 2001. Betamethasone-
Recently a postmarketing safety review has been containing products were most frequently impli-
released by the FDA’s Center for Drug Evaluations cated in reports of adverse reactions (79.4%). The
and Research, which assessed the 24 most frequently combination of betamethasone dipropionate and
used topical corticosteroids in pediatric patients clotrimazole cream was used in 52 (25.7%) cases,
aged 0-18 years.106 and triamcinolone acetonide in combination with
In that summary was an assessment of 202 reports nystatin cream was used 18 times. All other analyzed
of adverse events associated with the use of topical topical corticosteroids were used in less than 10
corticosteroids in this patient population.106 The cases. Most frequently, the drug was applied to the
12 Hengge et al J AM ACAD DERMATOL
JANUARY 2006
face and neck (n = 40); buttock, groin, or genitals side effects include the use of lower-potency steroids,
(n = 32); legs or feet (n = 22); arms or hands application only in the morning, and alternate-day
(n = 19); head or scalp (n = 12); trunk (n = 8); treatment (reducing tachyphylaxis and avoidance
entire body (n = 4); or axilla (n = 2). In 79 adverse of occlusion; Table VIII).112 Steroid-induced atrophy
event reports, no localization was stated. may be prevented with the use of topical tretinoin
Of these 202 cases, the frequency of adverse without lessening the steroid anti-inflammatory
events was reported (Table VII). While local irritation effect.37 Topical keratolytics, such as salicylic acid,
and reactions at the sites of application were most may be used simultaneously for thickened plaques,
frequently reported, numerous systemic adverse obviating the need for high-potency steroids and
events were also noticed. Among these systemic facilitating substitution with lower-potency ones. A
changes, striae cutis distensae, Cushing syndrome, recent study of 18 children has confirmed that
growth retardation, hyperglycemia, hirsutism, glau- weaker concentrations of topical corticosteroids
coma, and adrenal insufficiency were most sig- under occlusion had comparable high efficacy but
nificant. The most severe outcome of topical were associated with a lower risk of HPA axis sup-
corticosteroid treatment in this survey consisted of pression.94,96 Systemic toxicity after topical adminis-
hospitalization (n = 14), disability (n = 5), life- tration seems to be more frequent in patients with
threatening illness (n = 1), and death (n = 1). The renal and hepatic disease.88,91 On the other hand,
authors concluded that long-term application of laboratory studies often revealed adrenal suppres-
topical corticosteroids in high-risk settings (eg, ap- sion in the absence of clinical signs. The frequency
plication to gluteal folds, genitals, and groin areas and severity of local adverse events must be kept in
in young patients) should be limited. In addition, mind.
topical corticosteroids should not be continued
when the dermatoses failed to improve.
CONCLUSIONS
For many patients, the intermittent use of topical
Prescription of topical corticosteroids corticosteroids is highly effective, bears little risk,
A recent study indicated that pediatricians fre- and is relatively inexpensive.35 However, when the
quently prescribed combination products (eg, cor- inflammatory disease remains recalcitrant or affects
ticosteroid and antibiotic),107 while they only particularly sensitive areas, the repeated use of
infrequently prescribed single-agent high-potency potent such steroids is not desirable for extended
topical corticosteroids. In particular, fixed combina- periods. In addition, patients may have genuine
tions of betamethasone and clotrimazole were fre- concerns about these agents that lead to noncom-
quently prescribed.108 As expected, pediatricians pliance, even where treatment with them is appro-
preferred low-potency (56.3%) over high-potency priate. Thus a significant proportion of patients does
(5%) or medium-potency derivatives (28.7%).107,109 not receive adequate treatment.15,16 Patient educa-
In addition, these combination products tend to be tion by the physician is important to dispel fears and
used for diaper rash and are therefore occluded by ensure the safe use of topical corticosteroids.
the diaper. This study highlighted the importance of The ideal, skin-selective corticosteroid will be
monotherapy and the thoughtful use of preparations difficult to develop because the intracellular recep-
in small children and babies. tors that are responsible for corticosteroid efficacy
are also responsible for the various manifestations of
Prevention of adverse effects adverse events.2,113 Selective glucocorticoid receptor
Guidelines and suggestions regarding the use of agonists capitalize on the recent finding that con-
topical corticosteroids have been provided to pre- ventional glucocorticoids affect gene expression by
vent their misuse.110,111 Possible measures to prevent means of 2 distinct mechanisms. Seventy percent of
J AM ACAD DERMATOL Hengge et al 13
VOLUME 54, NUMBER 1
the therapeutic effects are mediated by transrepres- 21. Niedner R. Human models. In: Maibach HI, Surber C, editors.
sion, while an equal proportion of glucocorticoid TCS. Basel: Karger; 1992. pp. 17-25.
22. Sukanto H, Nater JP, Bleumink E. Suppression of ultraviolet
adverse effects are mediated by transactivation.
erythema by topical corticosteroids. Dermatologica 1980;
Selective novel glucocorticoid receptor ligands that 161:84-8.
demonstrate relative dissociation between transre- 23. Stengel R, Stricker R, Schopf E. Anti-inflammatory effect and
pression and transactivation have recently been tachyphylaxis of systemic and combined systemic-topical
developed and await clinical tests.122 treatment with corticosteroids in the pyrexal erythema test.
Z Hautkr 1984;59:1620-2.
24. Frosch PJ, Behrenbeck EM, Frosch K, Macher E. The Duhring
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