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Home , Fluprednisolone, Hydrocortisone aceponate, Methasone, Tixocortol pivalate

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dermatitis (ICD) and contact urticarial (CU) are also explained. Of note, unlike AND ACD, history rather than patch testing can often lead one to the correct diagno- sis of ICD and CU. CONTACT DERMATITIS ICD, the most prevalent form of con- This article focuses on the epidemiology, pathophysiology, and clinical manifestations of tact dermatitis, can at times precede topical and systemic - induced contact dermatitis. or be a concomitant diagnosis with ACD. 4,5 Unlike ACD, ICD may occur ALINA GOLDENBERG, MD, MAS, AND SHARON E. JACOB, MD on the first exposure to an irritating or abrasive substance. The innate immune system is activated and inflammation ensues. CU (wheal and flare reaction), on the other hand, represents the least prevalent form of the contact dermatitis. It is an immune-mediated phenomenon governed by a hallmark IgE and mast cell-mediated immediate-type hyper- sensitivity reaction. We acknowledge this form of hypersensitivity due to its potentially deadly anaphylactic reactions and direct the reader to key sources.6-8 This article focuses on the role of top- ical and systemic corticosteroids within contact dermatitis and explores the epi- demiology, pathophysiology, and clinical manifestations of such interactions.

HISTORICAL PERSPECTIVE In the early 20th century, the adrenal gland became the focus of medical re- search after the discovery of the lifesav- ing potential of adrenalin. Enthused by the idea of an undiscovered frontier of adrenal gland products, Edward Calvin Kendall worked endlessly to isolate several llergic contact dermatitis (ACD) tained, recurrent, progressive, or even hormones from the adrenals, including affects more than 14.5 million systemic dermatitis.2,3 To ensure patients and . By joining AAmericans each year, notably de- have an appropriate understanding of all forces with the military and Merck phar- fining itself as an important widespread the potential outcomes and their central maceuticals,’ researcher Lewis Sarett pro- disease.1 Due to overwhelming patient role in disease pathology and treatment, duced the first synthesized cortisone from morbidity, loss of school and work time, education of the patient may occur even ox bile at a cost of $200/g.9 Dr. Kendall and significant expenditures for health before the diagnostic patch test is placed. was ultimately co-awarded a Nobel Prize care visits and medicaments, ACD pres- Important aspects of patient counsel- in Physiology or Medicine (c. 1950) for ents with a high economic burden. ing include explaining the nature of their his contribution to cortisone discovery. Fortunately, through keen patient inter- disease, for example, the delayed presen- Topical hydrocortisone became avail- viewing and patch testing, a culprit may tation of ACD [aka the importance of a able in the 1950s. The first reported be identified. Therefore, remission can delayed read at 96 hours]; the relationship dermatologic use came from Drs. Spies occur with implementation of an aller- with the immune system (sensitization to and Stone from Alabama—they success- gen avoidance regimen. a chemical followed by elicitation of der- fully treated chronic hand dermatitis.10 Education becomes the critical bridg- matitis with re-exposure); and, the indif- Nevertheless, the treatments remained ing intervention to ensure treatment ference to time (a substance the patient expensive until the Syntex Company adherence and symptom resolution. Pa- has been using regularly, briefly, or inter- discovered a way to use sarsasapogenin, tients who are unable to comply with mittently can sensitize at any point.) In a plant from Mexican yams, to avoidance regimens are at risk for sus- certain cases, the topics of irritant contact produce a $6/g cortisone.11

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ACD AND TOPICAL CORTICOSTEROIDS lowing it to easily slip through the cell RE-CLASSIFICATION OF CORTICOSTEROIDS Epidemiology membrane. At this stage, it is too small Topical corticosteroids have tradi- As corticosteroids became the pri- to induce an immune response. How- tionally been classified by their mo- mary treatments for cutaneous inflam- ever, within the aqueous cell environ- lecular configuration. In 1989, Coop- matory conditions, including ACD, so ment, is degraded into a ste- man et al28 defined 4 classes of topical did the cases of corticosteroid-induced roid glyoxal via the loss of C21, which, titled A (hydrocortisone type), ACD begin to emerge with the first 2 when combined with serum or skin B ( acetonide type), C cases reported in 1959.12,13 However, it proteins, becomes an allergen and can ( type), and D (clo- was not until the 1990s that the North induce hypersensitivity.18 This degrada- betasone or hydrocortisone esterified American Contact Dermatitis Group tion is facilitated better in an alkaline types). This classification expanded to added the class A and B corticosteroids environment which is found in areas include subdivided classes of D1 (beta- to their North American Standard Se- more prone to sweat (axilla, perineum), dipropionate type) and D2 ries of patch tests. Corticosteroids were and in diseased skin such as that affect- ( aceponate type).29 ultimately deemed as “Allergen of the ed by atopic dermatitis, venous stasis, or This subdivision was clinically signifi- Year” in 2005.14 bacterial infections.19 cant because the D2 group was found The current reported prevalence of As discussed earlier, ACD comprises a to be highly cross-reactive with group topical corticosteroid-induced ACD delayed-type IV allergic reaction. How- A and .30 ranges from 0.2% to 6%.15 A Danish ever, the specific role of T cells contin- In 2011, a new simplified classifica- retrospective study of 3594 patch-test- ues to be investigated. Generally, cyto- tion was developed by Baeck et al.31 ed patients found that the overall fre- toxic CD8 T cells are found in severe This system includes 3 separate groups quency of any topical corticosteroid bullous reactions such as toxic epider- subdivided on the basis of allergic po- allergy to be 2%, specifically 0.8% had mal necrolysis, whereas CD4 T helper tential. Group 1 includes nonmethyl- -21-pivalate specific allergy, cells are present in nonbullous reactions, ated compounds including those in 1% had budesonide specific allergy, and with the Th1 and Th17 cells predomi- Group A, D2, and budesonide—these 1% had hydrocortisone-17-butyrate.16 A nating in allergic pathogenesis20 and are responsible for the majority of al- Mayo Clinic-based retrospective study Th2 response reported occurring only lergic reactions; Group 2 contains ha- of 1188 patch-tested adults found that on exception.21 logenated molecules with C16/C17 10.7% of participants had a prevalent However, there is mounting evi- cis ketal/diol structure and include positive reaction to at least 1 topical dence that CD8 T cells play a promi- the previously designated Group B corticosteroid, and 4.7% had a preva- nent role in ACD.22,23 Baeck et al24 structures; and Group 3 includes ha- lence of reactions to multiple.15 analyzed the T cell recruitment and logenated and C16-methylated mol- The prevalence results are variable cytokine production profile in 27 ecules previously found in groups C because of differences in patch test ap- patients with positive patch tests to and D1, these have the least allergic plication and interpretation. Generally, corticosteroids as compared to non- potential (Table)31,32 tixocortol-21-pivalate (tixocortol piva- sensitized controls. They found that a late) is used as the primary screening CD3+ T cell response predominated PRACTICALS OF PATCH TESTING agent for groupA corticosteroids, which with a Th2 cytokine profile (interleu- Patch testing is often necessary includes hydrocortisone and . kin [IL]-4, IL-5). Interestingly, a CD8 to identify the relevant allergen(s) Shaw and Maibach17 assessed the clinical T cell predominance was absent in the responsible for the patients’ ACD. relevance of positive patch test reactions corticosteroid-sensitive patients. Thus, Screening patch test trays are avail- to tixocortol via the repeated open ap- the T cell mechanisms behind cortico- able to isolate the most common plication test (ROAT). Their results steroid-induced ACD need continued chemicals and offer the provider clues showed that 75% of patch-test positive research to be fully elucidated. for potential sources. The American patients had concurrent positive ROAT Contact Dermatitis Society (ACDS) to hydrocortisone cream, and 38% had ACD AND NON-CUTANEOUS CORTICOSTEROIDS North American Standard Series in- positive ROAT to hydrocortisone oint- Rarely, immediate-type hypersensi- cludes allergens from several different ment. The difference in ROAT positiv- tivity reactions can occur after topical, categories.33 Supplemental trays (such ity was attributed to the vehicles’ differ- oral, or parental administration of cor- as hairdressing, dental materials, cos- ing transepidermal penetrations. ticosteroids.25 The first such reactions metics, and fragrance/flavors) are also were reported in the 1950s by Kendall26 available for purchase.34,35 Pathophysiology in patients receiving numerous cor- Furthermore, some personal prod- The allergenic potential of cortico- ticosteroid injections. The incidence ucts can be tested “as is”, for example steroids is multifactorial. The factors of anaphylaxis following intravenous the European Cosmetics Toiletry and that make corticosteroids preferred corticosteroids in children has been Perfumery Association advises hair treatments for acute inflammation also reported at 0.5%.27 These reactions are dye manufactures to instruct consum- serve to enhance their allergenicity. As mediated by an acute IgE-mediated ers to perform a self-allergy test prior a steroid, cortisol is extremely lipophil- hypersensitivity, rather than the T cell to product use; however, instructions ic and has a low molecular weight al- dominant delayed response. often vary even among products from

® 40 February 2016 | The Dermatologist | www.the-dermatologist.com ALLERGEN FOCUS

31,32 Disclosure: Dr. Jacob has Table. CORTICOSTEROID CLASSIFICATIONS BASED ON ALLERGENCITY served as a consultant for Group 1 Group 2 Group 3 Johnson & Johnson. (Previously A, D2, and (Previously B) (C, D1) Disclosure: Dr. Goldenberg Budesonide) reports no relevant financial Budesonide Alclomethasone dipropionate relationships. Sharon E. Jacob, MD, Beclomethasone dipropionate Section Editor References 1. Bickers DR, Lim HW, Mar- acetate Betamethasone golis D, et al. The burden of skin diseases: 2004 a joint acetate acetonide Betamethasone 17-valerate project of the American Academy of Dermatology Association and the Society for Investigative Derma- Hydrocortisone Betamethasone dipropionate tology. J Am Acad Dermatol. 2006;55(3):490-500. 2. Hsu JW, Matiz C, Jacob SE. Nickel allergy: lo- Betamethasone sodium phosphate calized, id, and systemic manifestations in children. propionate Pediatr Dermatol. 2011;28(3):276-80. 3. Salam TN, Fowler JF Jr. Balsam-related sys- Hydrocortisone 17-butyrate Clobetasol butyrate temic contact dermatitis. J Am Acad Dermatol. 2001;45(3):377-381. Hydrocortisone 21-butyrate Triamcinolone hexacetonide 4. Nijhawan RI, Matiz C, Jacob SE. Contact der- Hydrocortisone hemisuccinate matitis: from basics to allergodromes. Pediatr Ann. 2009;38(2):99-108. acetate Dexamethasone sodium 5. Militello G, Jacob SE, Crawford GH. Allergic phosphate contact dermatitis in children. Curr Opin Pediatr. 2006;18(4):385-390. Methylprednisolone aceponate valerate 6. Valks R, Conde-Salazar L, Cuevas M. Allergic Methylprednisolone acetate Diflucortolone diacetate contact urticaria from natural rubber latex in healthcare and non-healthcare workers. Contact Methylprednisolone hemisuccinate Flumethasone pivalate Dermatitis. 2004;50(4):222-224. 7. Walsh ML, Smith VH, King CM. Type 1 and propionate type IV hypersensitivity to nickel. Australas J Der- Prednisolone pivalate furoate matol. 2010;51(4):285-1286. 8. Gimenez-Arnau A, Maurer M, De La Cuadra J, Prednisolone succinate Maibach H. Immediate contact skin reactions, an update of Contact Urticaria, Contact Urticaria Syn- Prednisone drome and Protein Contact Dermatitis-- “A Never Ending Story.” Eur J Dermatol. 2010;20(5):552-562. 9. Rasmussen N. Steroids in arms science, govern- Triamcinolone ment, industry, and the hormones of the adrenal cortex in the United States, 1930-1950. Med Hist. 2002;46(3):299-324. the same company, and it is unclear ing alternatives and being aware of 10. Spies TD, Stone RE. Effect of local application how many consumers of the intended indirect exposures. of synthetic cortisone acetate on lesions of iritis audience actually follow through with There are programs available to aid in and uveitis, of allergic contact dermatitis, and of 36 psoriasis. South Med J. 1950;43:871-874. the process. the avoidance endeavor. The Contact Al- 11. The decade of the sex hormones. American lergen Management Program, a service Chemical Society website. http://acswebcontent. PEARLS OF TREATMENT: EVERY DOSE offered through ACDS, and the Contact acs.org/landmarks/marker/decade.html. Accessed COUNTS IN AVOIDANCE Allergen Replacement Database, de- January 26, 2016. A person may be exposed to, and veloped by Mayo Clinic, can assist with 12. Kooij R. Hypersensitivity to hydrocortisone. 37,38 Br J Dermatol. 1959;71:392-394. subsequently sensitized to a particular identifying allergen-free products. 13. Burckhardt W. Contact eczema caused by hy- allergen for days to years before actu- Both programs allow the provider to per- drocortisone. Hautarzt. 1959;10:42-43. ally developing ACD. Exposures can sonalize “shopping lists” of products void 14. Isaksson M, Bruze M. Corticosteroids. Derma- be additive, eventually causing one’s of specific dermatitis-inducing chemi- titis. 2005;16(1):3-5. immune system to become trained to cals, as well as any cross-reactors. n 15. Davis MD, el-Azhary RA, Farmer SA. Results of patch testing to a corticosteroid series: a retrospec- identify a chemical, at which time a tive review of 1188 patients during 6 years at Mayo cutaneous response would be elicited Dr. Goldenberg is a resident at the University Clinic. J Am Acad Dermatol. 2007;56(6):921-927. upon exposure.4 From a pathophysi- of California San Diego in 16. Vind-Kezunovic D, Johansen JD, Carlsen BC. ologic standpoint it is logical that the La Jolla, CA. Prevalence of and factors influencing sensitization repeated contact over time which Dr. Jacob is the Section to corticosteroids in a Danish patch test popula- tion. Contact Dermatitis. 2011;64(6):325-329. lead to immune stimulation and hy- Editor of Allergen Focus, and 17. Shaw DW, Maibach HI. Clinical relevance of tix- persensitivity, conversely translates to professor and director of the ocortol pivalate-positive patch tests and questionable repeated avoidance over time induc- Contact Dermatitis Clinic at bioequivalence of different hydrocortisone prepara- tions. Contact Dermatitis. 2013;68(6):369-375. ing remission. Avoidance creativity, Alina Goldenberg, MD, Loma Linda University in however, may be necessary by utiliz- MAS Loma Linda, CA. Additional references at www.the-dermatologist.com.

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