Allergic Contact Dermatitis Due to Topical Application of Corticosteroids: Review and Clinical Implications

Subspecialty Clinics: Dermatology Allergic Contact Dermatitis Due to Topical Application of Corticosteroids: Review and Clinical Implications MICHAEL E.

LUTZ, M.D., AND ROKEA

A. EL-AzHARY, M.D., PH.D.

Allergy due to topically applied corticosteroids is being recognized more frequently. Testing for hypersensitivity to these agents is performed with delayed hypersensitivity patch testing. Cross-reactivity among topically administered corticosteroids is frequent and often can be predicted on the basis of addi-

tional patch testing and an established classification scheme. Herein we review allergy due to topically applied corticosteroids with regard to its prevalence, means of testing, cross-reactivity among the subclasses, risk factors, and relationship to steroids. (Mayo Clin Proc 1997;72:1141-1144)

Since the identification of the anti-inflammatory action of corticosteroids by Hench and associates I at the Mayo Clinic in the late 1940s, numerous medical applications have been discovered for these agents. Successful topical application of hydrocortisone for inflammatory skin conditions was first noted by Sulzberger and Witten in 1952.2 Since then, corticosteroids have become a mainstay of treatment for various inflammatory and autoimmune skin diseases. The side effects of these agents are diverse and often treatment-limiting. The first case of contact dermatitis due to hydrocortisone was reported in 1959.3 Subsequently, allergy due to topically administered corticosteroids has become recognized more frequently. The widespread use and availability of topically applied corticosteroids, particularly for dermatologic disorders, have contributed to the development of hypersensitivity to these agents. In addition, exposure to mucous membranes through the use of inhaled corticosteroid s for asthma, chronic obstructive pulmonary disease, and allergic rhinitis has further contributed to this increased problem of exposure. The clinical dilemma posed by a case of allergy due to topically applied corticosteroids can be challenging. In this review, we attempt to address numerous issues regarding testing and allergenicity of corticosteroids on the basis of our experience and a review of the literature.

REPORT OF CASE A 48-year-old man, a computer programmer, with a l5-year history of hand dermatitis sought medical assessment beFrom the Department of Dermatology, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. R. A. el-Azhary, Department of Dermatology. Mayo Clinic Rochester, 200 First Street SW , Rochester, MN 55905 .

Mayo CUn Pro c 1997;72:1141-1144

cause of a scrotal rash. His previous dermatologic history was remarkable for intermittent use of topically applied corticosteroids for his hand dermatitis and positive results of patch testing to Quaternium-l S, Preservative-free 2.5% hydrocortisone cream with wet dressing was prescribed for the patient's presumed scrotal dermatitis . After the hydrocortisone cream was applied, the scrotal rash flared, and the pruritus worsened. Relief was obtained with triamcinolone cream. Patch testing was performed with the standard allergen panel of 52 agents and the corticosteroid series. The results revealed numerous sensitivities, including sensitivity to tixocortol pivalate, neomycin sulfate, thiuram mix, formaldehyde, Quaternium15, and bacitracin. The results of testing with the corticosteroid panel, including budesonide, triamcinolone, and betamethasone, were negative except for tixocortol pivalate . The patient was instructed to avoid hydrocortisone preparations and the other allergens in the panel. He continued to apply topical triamcinolone cream when his hand dermatitis flared, and this treatment was successful.

PREY ALENCE OF CONTACT ALLERGY TO CORTICOSTEROIDS Most of the reports on allergy due to topically applied corticosteroids have focused on hydrocortisone and its screening agent for patch testing, tixocortol pivalate. Although tixocortol pivalate is not available commercially in the United States, it is a good screening agent for hydrocortisone and its related compounds (F ig. 1).4.7 Worldwide, prevalences of allergy due to tixocortol pivalate have differed, ranging from 4.9% of the patients undergoing patch tests in the United Kingdom" to 0.2% of those in Spain, " Recently, a reported prevalence of 2.3% was reported from a series of patients who underwent patch testing in Van-

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1142 TOPICAL CORTICOSTEROID-INDUCED ALLERGY

Mayo Clio Proc, December 1997, Vol 72

o

CH2·S

I

CH 3

II I - C - C-CH I

CH3 C = 0

3

CH 3

····OH

o

o Hydrocortisone

Tixocortol pivalate

Fig. I. Chemical structures of hydrocortisone and tixocortol pivalate. Note that they are similar except for thiol group on C-21 in tixocortol pivalate,

couver.'" In our review of patients who have undergone patch testing at the Mayo Clinic, 2.9% had a positive reaction to tixocortol pivalate." These differences in prevalence of corticosteroid-induced allergy have been explained partly by the pattern of use and testing in various countries. 12 TESTING FOR CONTACT ALLERGY DUE TO TOPICALL Y APPLIED CORTICOSTEROIDS Testing for allergy due to topically applied corticosteroids is a relatively noninvasive procedure that can guide decisions about future therapy. Topical contact allergic reactions are usually mediated by type IV delayed-type hypersensitivity. Testing requires a minimum of 96 hours of patient compliance. For the first 48 hours, various potential antigens in Finn chambers are placed on the patient's upper back area

Fig. 2. Patient with patch tests in place on upper back area.

(Fig. 2). These sites are evaluated for reactions (at 48, 72, and 96 hours). Reactions can vary from subtle erythema to intense vesicobullae. Several studies have shown that tixocortol pivalate is an effective screening agent for sensitivity to topically administered corticosteroids, specifically for hydrocortisone."? This agent, however, cannot be used to screen for all corticosteroids, and other screening corticosteroids are needed. In particular, budesonide is useful for detecting other potential corticosteroid allergens for which tixocortol pivalate will not act as a screening agent." If corticosteroid-induced allergy is suspected, patch testing with a varied corticosteroid panel is useful and essential. Burden and Beck" identified 131 cases of corticosteroid sensitivity, of which 90.8% had a positive reaction to tixocortol pivalate. No satisfactory corticosteroid marker was identified for the 9.2% of cases that had a negative reaction. The importance of positive and negative results of patch tests for corticosteroid sensitivity has been debated. Falsenegative patch test results for topically applied corticosteroids are a problem. The inherent property of corticosteroids to suppress their own allergic reaction is the main problem, especially if the concentration of the corticosteroid used in the patch test is excessively high." Furthermore, studies have shown that when skin barrier function is compromised, sensitivity to topically applied corticosteroids is more likely to be manifested. 15 Another factor contributing to falsenegative patch test results has been the difficulty in finding the ideal vehicle and concentration for each allergen. Provocative use testing or repeated open application testing can also be useful in determining the relevance of an allergen on patch testing. The suspected allergen is placed on the antecubital fossa twice a day for 7 days without

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Mayo Clin Proc, December 1997, Vol 72

occlusion. A positive reaction to the test usually occurs within 96 hours; however, a reaction may be seen up to 7 days later. Similar to patch testing, the limitation of repeated open application testing is the possibility of falsenegative results because the testing is performed on normal skin." The ideal testing protocol continues to be refined. Interpretation of the findings from these studies necessitates experience in making clinical correlations and understanding the limitations of the testing methods.

CROSS·REACTIVITY TO OTHER TOPICALLY APPLIED CORTICOSTEROIDS Tixocortol pivalate is not commercially available in the United States, and hence no presensitization could exist. Cross-reactivity must be the means by which US patients react to the agent. In 1989, an initial classification scheme for cross-reactivity was established by Coopman and colleagues " on the basis of structural variations of the steroid molecule. Four classes were identified (Table 1): group A consists of hydrocortisone, tixocortol pivalate, and related compounds; group B, of triamcinolone acetonide, amcinonide, and acetonide function-related compounds; group C, of betamethasone, dexamethasone, and related compounds; and group D, of esters such as hydrocortisone-17-butyrate and c1obetasone17-butyrate. This classification scheme has proved helpful in assessing potential cross-reactivity; however, some overlap between groups occurs for certain agents, most notably budesonide," one of the commonest corticosteroid allergens." It shares properties with both acetonide compounds in group B and some esters in group D. 13 Another study," however, did not confirm this classification, and continued refinement of the scheme is ongoing . RISK FACTORS Risk factors for allergy due to topically applied corticoste roids are well documented and include venous stasis dermatitis and leg ulcers." :" One theory is that ulceration may allow greater penetration of the allergen. Perhaps stasis leads to a more localized allergen contact time, which further facilitates allergic potential and eventually produces clinical manifestations. Other risk factors are sensitivities to several other topically administered agents and perineal and chronic actinic dermatitis." Studies attempting to determine whether the duration of dermatitis is a risk factor have been inconclusive. According to the study by Wilkinson and English," patients with hand and facial dermatitis seem to have less sensitivity to topically applied hydrocortisone. In their prospective study, no significant difference was found with regard to age, sex, distribution of lesions, presence of atopy, or duration of disease.

TOPICAL CORTICOSTEROID-INDUCED ALLERGY

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Table 1.-Initial Classification of Allergy Due to Topically Applied Corticosteroids Group

Agent

A

Hydrocortisone , hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, meprednisone Triamcinolone acetonide, triamcinolone alcohol, amcinonide, budesonide , desonide, fluocinonide , fluocinolone acetonide, halcinonide Betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone Hydrocortisone-I7-butyrate, hydrocortisone-17valerate, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-I?-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprenidene acetate

B

C D

Data from Coopman and associates ."

CROSS·REACTIVITY TO STEROIDS AND SYSTEMIC CORTICOSTEROIDS Schoenmakers and coworkers" documented coreacnvity with hydrocortisone and ll-deoxycortisol in 11 of 18 patients. Five of the 11 patients also had a reaction to 17ahydroxyprogesterone. Of these five, two had clinical symptoms of autoimmune progesterone dermatitis . When hydrocortisone is administered systemically to patients with sites of allergic contact dermatitis induced by hydrocortisone or hydrocortisone-positive patch sites, the sites flare.25.26 Inhalation of corticosteroids and diagnostic intradermal testing with corticosteroids have also been associated with flareUpS.27.28 Evidence shows that topical contact hypersensitivity probably is not related to immediate sensitivity to hydrocortisone. In one study, no immediate reactions to hydrocortisone on prick testing were observed in nine patients who had positive reactions to hydrocortisone on intradermal testing and to tixocortol pivalate on patch testing. " Anaphylactoid reactions to glucocorticoids administered intra-arterially or intravenously have been documented in patients whose reactions to these agents were negative on patch testing. 26.29 With regard to endogenous steroids in patients with sensitivity to topically applied corticosteroids, Belsito" noted that clinicians should be alert to the possibility of dermatitis related to stress reaction or menstruation, conditions in which endogenous steroids may provoke or exacerbate dermatitis. No evidence exists that patients with allergy due to topically administered corticosteroids will have development of Addison's disease from circulating anti-adrenal antibodies. When cortisol and cosyntropin (Cortrosyn) stimulation tests were performed randomly in such patients, results were normaJ.25.28 Conversely, no evidence exists that pa-

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1144 TOPICAL CORTICOSTEROID-INDUCED ALLERGY

tients with Addison's disease have an increased risk of corticosteroid-induced allergy.

CONCLUSION Corticosteroid-induced allergy is fairly common and has been detected in approximately 3% of patients who have had patch tests at the Mayo Clinic. This frequency is similar to that of other well-known topical allergens such as formaldehyde (2.9%) and parabens (2.5%).7 The recognition of this entity necessitates heightened clinical awareness and evaluation of existing risk factors such as stasis dermatitis and leg ulcers. Adequate testing to document this hypersensitivity is available, and further testing with use of a corticosteroid panel can guide physicians in the selection of appropriate topically administered corticosteroids for future therapy. Interpretation of the test results necessitates acknowledgment of the limitations of the tests. Although cross-reactivity can exist, certain corticosteroids can be used and are well tolerated. Systemic use of corticosteroids is not contraindicated in regard to anaphylactic reactions, but flare-ups in skin eruptions may be noted. Detailed information on this topic is available."

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11. 12. 13.

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15.

16. 17.

18. 19.

REFERENCES 1. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17 -hydroxy-lldehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949;24:181-197 2. Sulzberger MB, Witten VH. The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 1952;19:101-102 3. Burckhardt W. Knotaktekzem durch hydrocortison. Hautarzt 1959;10:42-43 4. Wilkinson SM, English JS. Hydrocortisone sensitivity: a prospective study of the value of tixocortol pivalate and hydrocortisone acetate as patch test markers. Contact Dermatitis 1991;25:132-133 5. Lauerma AI, Tarvainen K, Forstrom L, Reitamo S. Contact hypersensitivity to hydrocortisone-free-alcohol in patients with allergic patch test reactions to tixocortol pivalate. Contact Dermatitis 1993;28:10-14 6. Wilkinson SM, Cartwright PH, English JS. Hydrocortisone: an important cutaneous allergen. Lancet 1991;337:761-762 7. Dooms-Goossens AE, DegreefHJ, Marien KJ, Coopman SA. Contact allergy to corticosteroids: a frequently missed diagnosis? JAm Acad Dermatol 1989;21:538-543 8. Burden AD, Beck MH. Contact hypersensitivity to topical corticosteroids. Br J Dermato1 1992;127:497-500 9. Dooms-Goossens A, Andersen KE, Burrows D, Camarasa JG, Ducombs G, Frosch PJ, et al. A survey of the results of patch tests with tixocortol pivalate. Contact Dermatitis 1989;20:158 10. Morton CE, Dohil MA. A survey of patch test results with tixocortal pivalate in Vancouver. Am J Contact Dermat 1995;6:17-18

20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

Lutz ME, el-Azhary RA, Gibson LE, Fransway AF. Tixocortol piva1ate hypersensitivity. J Am Acad Dermatol [in press] Dooms-Goossens A, Meinardi MM, Bos JS, Degreef H. Contact allergy to corticosteroids: the results of a two-centre study. Br J Dermatol 1994;130:42-47 Lepoittevin JP, Drieghe J, Dooms-Goossens A. Studies in patients with corticosteroid contact allergy: understanding cross-reactivity among different steroids. Arch Dermatol 1995;131:31-37 Lauerma AI. Screening for corticosteroid contact sensitivity: comparison of tixocorto1 pivalate, hydrocortisone-17-butyrate and hydrocortisone. Contact Dermatitis 1991;24:123130 Wilkinson SM, Heagerty AH, English JS. A prospective study into the value of patch and intradermal tests in identifying topical corticosteroid allergy. Br J Dermatol 1992; 127:22-25 Hannuksela M, Salo H. The repeated open application test (ROAT). Contact Dermatitis 1986;14:221-227 Coopman S, Degreef H, Dooms-Goossens A. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol 1989;121:2734 Wilkinson SM, Hollis S, Beck MH. Reactions to other corticosteroids in patients with allergic contact dermatitis from hydrocortisone. Br J Dermatol 1995;132:766-771 Dooms-Goossens A, Morren M. Results of routine patch testing with corticosteroid series in 2073 patients. Contact Dermatitis 1992;26:182-191 Wilkinson M, Hollis S, Beck M. Reactions to other corticosteroids in patients with positive patch test reactions to budesonide. JAm Acad Dermatol 1995;33:963-968 A1ani MD, Alani SD. Allergic contact dermatitis to corticosteroids. Ann Allergy 1972;30:181-185 Guin JD. Contact sensitivity to topical corticosteroids. JAm Acad Dermato1 1984;10:773-782 Wilkinson SM, English JS. Hydrocortisone sensitivity: clinical features of fifty-nine cases. J Am Acad Dermato1 1992; 27:683-687 Schoenmakers A, Vermorken A, Degreef H, DoomsGoossens A. Corticosteroid or steroid allergy? Contact Dermatitis 1992;26:159-162 Lauerma AI, Reitamo S, Maibach HI. Systemic hydrocortisone/cortisol induces allergic skin reactions in presensitized subjects. JAm Acad Dermatol 1991;24:182-185 Sasaki E. Corticosteroid sensitivity and cross-sensitivity: a review of 18 cases 1967-1988. Contact Dermatitis 1990; 23:306-315 Lauerma AH, Kiistala R, Makinen-Kiljunen S, Haahtela T, Lauerma AH. Allergic skin reaction after inhalation of budesonide [letter]. Clin Exp Allergy 1993;23:232-233 Wilkinson SM, Smith AG, English JS. Erythroderma following the intradermal injection of the corticosteroid budesonide. Contact Dermatitis 1992;27:121-122 Kounis NG. Untoward reactions to corticosteroids: intolerance to hydrocortisone. Ann Allergy 1976;36:203-206 Belsito DV. Allergic contact dermatitis to topical glucocorticosteroids. Cutis 1993;52:291-294 Maibach HI, Surber C, editors. Topical Corticosteroids. Basel: Karger; 1992

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