Contact hypersensitivity to tixocortol pivalate

Contact hypersensitivity to tixocortol pivalate Michael E. Lutz, MD, Rokea A. el-Azhary, MD, PhD, Lawrence E. Gibson, MD, and Anthony F. Fransway, MD Rochester, Minnesota Background: Tixocortol pivalate is an established marker to topical corticosteroid allergy. The prevalence of tixocortol pivalate hypersensitivity is well established in Europe, where exposure to this corticosteroid as a therapeutic agent varies. In the United States, tixocortol pivalate is not commercially available and the prevalence of hypersensitivity to it is unknown. Objective: We investigated the prevalence of tixocortol pivalate hypersensitivity in our patch-tested population. We further characterized these patients by clinical background, other contact allergens, and the reactivity to other corticosteroids. Methods: Tixocortol pivalate has been incorporated in our standard 1-52 patch test series since November 1992. We reviewed the histories and patch test results in all patients tested with the standard 1-52 series from November 1992 to December 1996. Results: Of 1536 patch-tested patients, 45 had hypersensitivity to tixocortol pivalate. Dermatitis involving the face was the most common (14 patients). Of the 45 patients, 40 had another allergen identified on patch testing. Eighteen patients underwent further patch testing to an extended corticosteroid panel, and 14 had sensitivity to another steroid agent. Conclusion: The 2.9% prevalence of tixocortol pivalate hypersensitivity in our patch test population is within the range reported in Europe. Patients with tixocortol pivalate hypersensitivity tend to have other contact allergens on patch testing. Predisposing factors to tixocortol pivalate hypersensitivity include facial dermatitis and sensitivity to other contact allergens. (J Am Acad Dermatol 1998;38:691-5.)

Corticosteroid contact allergy is a recently recognized problem. Since the 1950s, when Sulzberger and Witten1 noted that topical hydrocortisone was capable of treating various inflammatory skin disorders, topical steroid use has become widespread. During the past decade, the reported cases of corticosteroid contact dermatitis have increased dramatically. Most of the literature and published data on this subject are European in origin. These findings may or may not represent ours in the United States, where topical steroid selection and preparations may vary from those in Europe.2 Tixocortol pivalate, also known as Pivalone, a corticosteroid nasal spray available in some countries in Europe, has been shown to be a useful agent for assessing From the Department of Dermatology, Mayo Clinic and Mayo Foundation. Accepted for publication Jan. 29, 1998. Reprint requests: Rokea A. el-Azhary, MD, Department of Dermatology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/89169

corticosteroid contact dermatitis, particularly for hydrocortisone-type derivatives.3-6 Although tixocortol pivalate is not commercially available in the United States, we have incorporated this agent since November 1992 in our standard 52-agent patch test panel as a screen for corticosteroidinduced contact dermatitis. We sought to identify and further characterize patients who had a positive reaction to tixocortol pivalate in terms of other corticosteroid cross-reactivity and to identify risk factors for corticosteroid allergy. METHODS We reviewed the medical records of all patients who underwent patch testing to our standard 1-52 series (in which allergen No. 52 is tixocortol pivalate 1% in petrolatum) from November 1992 to December 1996. Tixocortol pivalate was obtained from Chemotechnique Diagnostics, Tygelsjo, Sweden. Patients with noted positive reactions to tixocortol pivalate were identified. Systemic drug allergies and atopic background were noted. All positive reactions to patch tests from the standard series and steroid series (if completed) were recorded. Before October 1995, our extended steroid

691

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692 Lutz et al.

Table I. Characteristics of 45 patients with positive sensitivity to tixocortol pivalate Patient No.

Age (yr)

Sex

Atopic history

Diagnosis at presentation

Location

No. of other allergens

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

70 64 50 23 44 51 66 44 80 57 29 59 57 49 33 75 25 46 71 41 70 69 37 55 49 41 68 62 64 31 58 59 54 54 55 62 41 28 50 74 68 78 43 60 74

F F M F M F M M F F F M M M F F F M F M F F M M M F F M M F M F F F F F F M M F F F F F M

+ + + + – – – – – – – – – + – – – – – – – – – – – + – – – + – + – – – + – + + – – – + – –

CD Neurodermatitis, CD CD CD CD CD CD CD CD CD CD Neurodermatitis, CD CD CD Neurodermatitis, CD CD CD CD CD CD CD CD CD Erythema multiforme, CD CD Nummular dermatitis, CD CD CD CD CD CD CD CD Dermatomyositis CD CD CD CD Neurodermatitis CD CD CD, neurodermatitis CD Lichen planus CD

Face Shin Genital, perianal Arm, leg Ear Lips Penis Periorbital Hands, face Hands, feet Face Shins Gums Hand Face Face Hands, arms Leg, hand Hands Face Face Generalized Ankle Penis, chest Generalized Generalized Leg Wrist, heel Arms Hands Ear Generalized Generalized Generalized Face, groin Generalized erythroderma Hand Trunk, arms Scalp, neck Generalized Generalized Generalized Face, hand Groin, vagina Hand

2 4 4 1 5 1 7 5 3 6 0 8 5 2 2 12 2 2 9 2 8 3 2 2 3 6 3 4 5 0 5 4 4 0 8 4 0 1 2 2 2 0 4 3 5

CD, Contact dermatitis.

series consisted of seven corticosteroids, namely, hydrocortisone valerate, hydrocortisone (in 2.5dimethyl sulfoxide and ethyl alcohol), hydrocortisone 17-butyrate 1%, triamcinolone 1% (alcohol and petrolatum), fluocinonide 1%, and desonide cream. Since

October 1995, our steroid patch series has been extended to 17 (see “Results”). All patients were seen in the Department of Dermatology at the Mayo Clinic before undergoing patch testing. Patch testing was performed as part of the

Journal of the American Academy of Dermatology Volume 38, Number 5, Part 1

dermatologic work-up for suspected contact dermatitis. All patch testing was done with Finn Chambers left in situ for the standard 48 hours. Patch tests were read at 48, 72, and 96 hours. Positive reactions were recorded as +1 for erythema only, +2 for erythema and induration, +3 for erythema, induration, and vesiculation, and +4 for bullae. A positive patch test reaction included any result +1 or higher at 96 hours. RESULTS

A total of 1536 patients underwent patch testing to the standard series during this period. Of the 1536 patients, 45 had a positive reaction to tixocortol pivalate, for an incidence of 2.9% in our population. Table I summarizes the characteristics of these patients. Twenty-seven women and 18 men were identified; their ages ranged from 23 to 80 years. Thirteen patients reported a systemic drug allergy. Only one of these patients reported a systemic allergic response to prednisone, manifested as a generalized rash and weakness. Twelve patients had an atopic background either by personal or by family history. Most of the patients were referred for patch testing because of a clinical suspicion of contact dermatitis. As shown in Table I, dermatitis involving the face was the most common (14 patients). Two of these patients had ear involvement, and one had oral mucous membrane involvement. Six patients had perineal involvement. Dermatitis occurred on either extremity in 18 other patients and was generalized in nine others. Stasis dermatitis was documented in only four patients, with extremity involvement. Two other patients without a diagnosis of dermatitis were tested. Patient 34 had a diagnosis of dermatomyositis with a recent flare and the question of allergic contact dermatitis. On patch testing, no allergens were identified except tixocortol pivalate. The extended steroid series was not performed. Patient 44 had a vulvar erosive eruption and oral lichen planus. Patch testing was performed because of a suspicion of an allergic component. She was found to have tixocortol pivalate and hydrocortisone acetate allergies. Three other allergens were also identified. Forty of the 45 patients had at least one other positive patch test result. Neomycin and fragrance mix were the most common allergens noted. Fourteen patients reacted to neomycin and 12 to fragrance mix. Other significant allergens included

Lutz et al. 693 Table II. Corticosteroid panel with number of positive steroid contact allergens in patients patch-test positive to tixocortol pivalate

Corticosteroid

No. positive steroid contact allergens

Hydrocortisone valerate petrolatum* Hydrocortisone 17-butyrate 1% alcohol*† Hydrocortisone acetate 1% petrolatum Hydrocortisone acetate 0.5% alcohol Hydrocortisone in 2.5-dimethyl sulfoxide and ethyl alcohol* Triamcinolone 1% petrolatum*† Triamcinolone 1% alcohol*† Budesonide 0.1% petrolatum Betamethasone 17-valerate 1% petrolatum Alclometasone 17, 21-dipropionate 1% petrolatum Clobetasol 17-propionate 1% alcohol Dexamethasone 21-phosphate 1% alcohol Amcinonide 1% alcohol Fluocinolone acetonide 1% alcohol Fluocinonide 1% alcohol*† Prednisone 5% petrolatum Halcinonide 1% petrolatum Desonide cream* Betamethasone dipropionate 0.5% alcohol Mometasone furoate 1% alcohol

3 3 5 5 3 3 1 3 0 0 0 0 2 0 1 1 0 1 0 0

*Corticosteroids

used in the extended series before October 1995 and not currently included in the extended series as shown above. †Corticosteroids used in both series.

balsam of Peru, cobalt chloride, nickel, and formaldehyde. Of the 45 patients, 18 underwent further patch testing to an extended corticosteroid panel (Table II). Fourteen of the 18 patients reacted to another corticosteroid preparation. The most common agent was hydrocortisone acetate, to which five patients reacted. Three patients had reactions to hydrocortisone 17-butyrate and three others to hydrocortisone valerate. More potent steroids, including clobetasol 17-propionate, fluocinolone acetonide, betamethasone dipropionate, betamethasone valerate, mometasone furoate, alclometasone 17, 21-dipropionate, dexamethasone 21-phosphate, and halcinonide, did not yield any positive reactions. Four patients showed positive reactions to triamcinolone. All four noticed burning or worsening of dermatitis after using triamcinolone. Two of the four also had a positive reaction to amcinonide. Clinical histories of the 45 patients revealed that

694 Lutz et al. 11 had improvement of the dermatologic condition with topical triamcinolone. Of these 11, four underwent extended steroid patch testing without a reaction to triamcinolone and the other seven were treated with triamcinolone empirically without undergoing further corticosteroid patch testing. DISCUSSION

Our study documents a 2.9% prevalence of tixocortol pivalate sensitivity in our patch test population. Previous studies throughout Europe reported prevalences of 0.2% in Barcelona,7 1.6% in a Belgian series,3 and 4.8% in a series from the United Kingdom5 of positivity to tixocortol pivalate in patients with suspected contact dermatitis. Our prevalence lies within the range reported from Europe.3,5 Our study population had no previous exposure to tixocortol pivalate because it is not commercially available in the United States. Therefore presensitization is not a factor, and cross-reactivity with other corticosteroids must be the mechanism of acquiring this hypersensitivity. Risk factors for hypersensitivity to topical corticosteroids are multiple. Our finding that 89% of patients allergic to tixocortol had reactions to other allergens in the standard series suggests that patients with numerous contact allergens have a higher risk of corticosteroid hypersensitivity. Reitamo et al.8 showed that two groups of patients were at increased risk for corticosteroid hypersensitivity: those with two or more positive patch test reactions to other agents (as in our series) and those with treatment-resistant eczema. Other studies found leg ulcers, stasis dermatitis, perineal dermatitis, and chronic actinic dermatitis to be welldocumented risk factors.9-12 Our study shows that patients with facial dermatitis may also be at higher risk. In addition, perineal dermatitis was common. This may be due to the tendency toward use of hydrocortisone products on the face and inguinal region, with consequent cross-reactivity to tixocortol pivalate. Although stasis dermatitis was documented in only four of our patients, the incidence may actually be higher, particularly in patients with extremity or generalized involvement. Twelve of our patients (30%) had an atopic background. Although this incidence may seem significant, it is probably not higher than that in the normal population. The incidence of atopic

Journal of the American Academy of Dermatology May 1998

dermatitis in our patch test population was 29% (unpublished observation). Wilkinson and English12 demonstrated that there was no significant difference in the sex distribution or incidence of atopy between a group sensitive to hydrocortisone and a control group that was not. Thirteen of our patients reported a systemic drug allergy. This occurrence may suggest that patients with systemic drug allergy are at an increased risk of corticosteroid sensitivity. One patient reported an allergy to oral prednisone, manifested as an exacerbation of dermatitis, weakness, and fatigue. On the extended steroid series, he had numerous steroid sensitivities, including hydrocortisone acetate, triamcinolone, and amcinonide. In the extended steroid patch test series, hydrocortisone showed the highest number of positive reactions. This finding is not surprising with the established cross-reactivity between tixocortol and hydrocortisone.13 Although hydrocortisone 17butyrate and valerate belong to group D of the Lepoittevin classification,13 cross-reactivity with tixocortol from group A may still occur. This may support the findings of Wilkinson, Hollis, and Beck14,15 that C6 or C9 substitution may be more important than C17 or C21 in determining crossreactivity patterns. The two patients with amcinonide positivity also had positive reactions to triamcinolone, which confirmed previous cross-reactivity patterns.13 Further studies in a large number of patients are needed to clarify cross-reactivity patterns. Patch testing to the corticosteroid panel can often provide useful information for treatment in the difficult dermatologic population of patients with corticosteroid sensitivity. Thus patients without reactions to triamcinolone were successfully treated with this agent. Furthermore, seven others who did not undergo patch testing to a corticosteroid panel were empirically treated with triamcinolone for their dermatologic condition and did well. It is important to note that patch testing to corticosteroids can be difficult. False-negative reactions can occur, and different vehicles may alter the patch test results. In summary, tixocortol pivalate hypersensitivity in our patch test population apparently is not uncommon. Chronic dermatitis, facial involvement, or positive reaction to other patch test allergens is frequent in this subset of patients. Atopy

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does not appear to be a predisposing factor. Positivity to tixocortol pivalate does not preclude the use of other corticosteroids. Testing a comprehensive corticosteroid panel on patients can be useful in guiding future topical corticosteroid therapy. REFERENCES 1. Sulzberger MB, Witten VH. Effect of topically applied compound F in selected dermatoses. J Invest Dermatol 1952;19:101-2. 2. Dooms-Goossens A, Meinardi MM, Bos JD, Degreef H. Contact allergy to corticosteroids: the results of a twocentre study. Br J Dermatol 1994;130:42-7. 3. Dooms-Goossens AE, Degreef HJ, Marien KJ, Coopman SA. Contact allergy to corticosteroids: A frequently missed diagnosis? J Am Acad Dermatol 1989;21:538-43. 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;25:132-3. 5. Wilkinson SM, Cartwright PH, English JS. Hydrocortisone: an important cutaneous allergen. Lancet 1991;337:761-2. 6. Burden AD, Beck MH. Contact hypersensitivity to topical corticosteroids. Br J Dermatol 1992;127:497-500.

O

7. 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. 8. Reitamo S, Lauerma AI, Stubb S, Kayhko K, Visa K, Forstrom L. Delayed hypersensitivity to topical corticosteroids. J Am Acad Dermatol 1986;14:582-9. 9. Alani MD, Alani SD. Allergic contact dermatitis to corticosteroids. Ann Allergy 1972;30:181-5. 10. Guin JD. Contact sensitivity to topical corticosteroids. J Am Acad Dermatol 1984;10:773-82. 11. Wilkinson M, Cartwright P, English JS. The significance of tixocortol-pivalate-positive patch tests in leg ulcer patients. Contact Dermatitis 1990;23:120-1. 12. Wilkinson SM, English JS. Hydrocortisone sensitivity: clinical features of fifty-nine cases. J Am Acad Dermatol 1992;27:683-7. 13. Lepoittevin JP, Drieghe J, Dooms-Goossens A. Studies in patients with corticosteroid contact allergy: understanding cross-reactivity among different steroids. Arch Dermatol 1995;131:31-7. 14. Wilkinson M, Hollis S, Beck M. Reactions to other corticosteroids in patients with positive patch test reactions to budesonide. J Am Acad Dermatol 1995;33:963-8. 15. Wilkinson SM, Hollis S, Beck MH. Reactions to other corticosteroids in patients with allergic contact dermatitis from hydrocortisone. Br J Dermatol 1995;132:76671.

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