Allergen Focus Allergic Contact Elise M. Herro, MD, and Sharon E. Jacob, MD

contact urticaria, may be explained, as history (not patch testing) can point to these as the correct diagnosis for the patient. It is important to note that ICD, the most prevalent form of con- tact dermatitis, can at times precede, or be a concomitant diagnosis, with ACD. 4,5 Unlike ACD, ICD is not im- mune-mediated, but occurs secondary to contact with an irritating or abra- sive substance. Contact urticaria (wheal and flare reaction), on the other hand, represents the least prevalent form of . It is important to note that it is an immune-mediated phenomenon whose hallmark is an IgE and mast cell-mediated immediate- type hypersensitivity reaction. We ac- knowledge this form of hypersensitiv- ity due to the severity of the potential deleterious anaphylactic type reactions and direct the reader to key sources.6,7,8 In this section focus, we highlight ACD and explore top relevant aller- gens, regional-based dermatitis presen- tations, topic-based dermatitis presen- llergic Con- with the avoidance regimen, they be- tations and clinical tips and pearls for tact Derma- come at risk for recurrent or sustained diagnosis and treatment. titis (ACD) is dermatitis or progression to a system- A 2,3 an important disease, atized presentation. In fact, education Allergic Contact Cheilitis which notably affects of the patient often begins before the Contact cheilitis is a term used to 14.5 million Ameri- diagnostic patch test is ever placed. This describe inflammation of the , most Sharon E. Jacob, MD cans each year.1 The ensures that the patient has an appro- often caused by either irritant contact economic impact of priate understanding of potential out- cheilitis (ICC) or allergic contact cheili- this disease is high in comes, including his or her central role tis (ACC).9 This inflammation can cause terms of both patient in both the disease and treatment. a variety of signs and symptoms, such as morbidity and loss of During the initial consultation, pa- dryness, scaling, crusting, fissuring, ery- income, school and tients are often taught about the patho- thema, edema and/or , work, not to mention physiology of ACD: its delayed presen- as well as burning or itching.9,10 significant expendi- tation; its relationship with the immune Contact allergy of the , Elise M. Herro, MD tures for visits to health system (sensitization to a chemical and allergic contact (ACS), is less care providers and for then elicitation of a dermatitis with common than contact allergy of skin of medicaments.1 Once patch testing is re-exposure); and its occurrence at any the lips.9 A potential explanation regard- performed and a culprit has been iden- point in time, even to something that ing this phenomenon involves saliva’s tified, education becomes the critical the patient has been using regularly for cleansing effect, washing away antigens intervention to ensure adherence to a short period of time or even inter- that are presented to the mucosa, where an avoidance regimen. With allergen mittently for years. In certain cases, the antigen-presenting cells may also be avoidance, remission of the dermatitis topics of the other key players, such as less prevalent.10 The vascularity of the ensues. If patients are unable to comply irritant contact dermatitis (ICD) and buccal mucosa also aids in the disper-

18 August 2011 | Skin & Aging | www.skinandaging.com Allergen Focus

Table 1. Differential Diagnosis of Allergic Contact Cheilitis9,10,28,29 Diagnosis Clinical Presentation Comments Allergic contact cheilitis Angular cheilitis, dryness, fissuring, edema, crusting; may have effacement of vermillion border Irritant contact cheilitis Angular cheilitis, peri-oral dryness and scaling “ licking” dermatitis, xerostomia (dry mouth) (solar keratosis) Hyperkeratosis, erythema, crusting, erosions; may have ef- Often associated with fair-skinned individuals; facement of vermillion border; background of facial actinic sunburn, phototoxicity, chronic, premalignant damage; lower lip > upper lip Angular cheilitis Seborrheic dermatitis Angular cheilitis Perioral dermatitis Zone of normal skin immediately surrounding vermillion border Oral or lichenoid oral lesions May appear erosive Perlèche (C. albicans) Angular cheilitis/inflammation; usually bilateral; may have Associated with dentures, diabetes, debilitated maceration of commissural epithelium individuals, chronic antibiotic use, HIV patients Infectious cheilitis (Staphylococcal or Streptococcal) Acute, pustular and fissured cheilitis; usually bilateral Sick or malnourished children Secondary syphilis Split papules Herpes simplex Vesicular Aphthous ulcers Region of complete epidermal loss erythematosus Bullous diseases Vesicles and bulla , Nutritional deficiency: Vitamin B2 (riboflavin), iron, Angular stomatitis and/or cheilitis: bilateral or unilateral Eating disorders or a history of total parenteral folate, vitamin B12 with mucosal pallor at commissures, followed by fissuring nutrition (TPN) and ulceration. Atrophy of oral epithelium with depapil- lated; red tongue may be seen. Cheilitis glandularis Swollen, enlarged, everted, exposing superficial Chronic, inflammatory puncta of the salivary ducts along the mucosal disorder of labial salivary glands; lower lip of adult vermilion border. Possible crusting, nodularity may males is usually affected be felt, and viscous fluid may be expressed from the ductal openings. Cheilitis granulomatosa (Miescher, Melkersson- Nontender, swelling and enlargement of one or both lips; Chronic, episodic, inflammatory; lymphatic obstruc- Rosenthal syndrome) may feel soft, firm, or nodular on palpation tion by granulomatous infiltration; upper lip > lower lip. Lingual, palatal, gingival and buccal involve- ment also may occur. Mechanical Dry, chapped, scaling, fissuring; may have maceration of Cold, wind, , ill-fitting dentures, commissural epithelium (jaw protrusion); older age Exfoliative cheilitis Hyperkeratosis and desquamation; may be hemorrhagic Often factitious activity, i.e. repetitive biting, picking (self-induced trauma) Iatrogenic (drugs) Angular cheilitis and scaling of the lips Isotretinoin (Accutane) sal of antigens; however, despite this, the prior to nickel exposure (ear piercing) lergen, and 20% had a relevant PPT to mucosa can become sensitized, with a confers a lower risk of developing nickel only a supplemental allergen, demon- subsequent inflammatory reaction, most allergy than the reverse of first piercing strating the need for testing additional often to dental materials and appliances, then being braced.11 allergens and personal products.9 Like- such as metals, acrylics fillings, crowns The North American Contact Der- wise, two Italian studies, one by Zoli and dentures. Cheilitis and circumoral matitis Group (NACDG) published et al, reported that 18% of 83 patients dermatitis usually accompany primary their results from 2001 to 2004, show- with cheilitis patch tested from 2001 allergic stomatitis, although stomatitis ing that, of 196 patients presenting to 2005 had a PPT to a relevant al- does not necessarily always accompany with cheilitis, ACC was responsible lergen,12 while the other by Schena primary allergic cheilitis.10 Of interest, for 38.3% of these cases.9 Of these, et al found that of 129 patients with early allergen exposure to the oral mu- 16% had a relevant positive patch test cheilitis from 2001 to 2006, 65.1% had cosa may actually be a means to creating (PPT) to both a chemical from the possible or probable relevant reactions, tolerance. For example, it is well docu- NACDG series, as well as either a 42 of which required an extended se- mented that wearing metal dental braces personal product or supplemental al- ries.13 In the United Kingdom, Strauss

August 2011 | Skin & Aging | www.skinandaging.com 19 Allergen Focus

Table 2. Top Allergens and Sources9,10 Category Allergens Sources Flavorings/ Myroxylon Pereirae Dental cement liquids Fragrances (Balsam of Peru)*14 Cinnamic aldehyde Toothpaste32-34 Fragrance Mix12,14,15 Cinnamic aldehyde* Toothpastes, mouthwashes, chewing gum, dental impression com- Cinnamic alcohol* pounds, cosmetics, perfumes, flavorings a-amylcinnamic alcohol* Eugenol* Isoeugenol* Geraniol Hydroxycitronellal Oak moss absolute Essential Oils Toothpastes and mouthwashes Clove Oil (Eugenol35,36 is main constituent)* Zinc oxide cement, impression pastes, chewing gum37 Cinnamon oil (cassia oil)* Toothpaste,38 bubble gum, lipstick Tea tree oil --- Anise oil --- Menthol39 Toothpastes, mouthwashes, cough drops, chewing gum, food, candy, cigarettes, liqueurs, mixed drinks Metals Mercury** Dental amalgam fillings Sodium gold thiosulfate --- Nickel sulfate21 Dentures, nickel-plated dental instruments,40 bobby pins,41 jewelry, makeup or lipstick containers14 Potassium dichromate21 Dentures Cobalt chloride Pins used with dentures Acrylic resins42 2-hydroxyethyl methacrylate43 Acrylic (artificial nails) Hydroquinone^ Acrylic dentures Benzoyl peroxide^ Acrylic dentures Preservatives/ Parabens Toothpastes and mouthwashes# Antiseptics Dichlorophene Toothpastes and mouthwashes Formaldehyde Thermodent, root canal therapy, nail hardener Iodoform Ribbon packing gauze44 Methyldibromoglutaronitrile/ phenoxyethanol45 Personal hygiene products and cosmetics Gallates46 Octyl gallate Food, cosmetics Propyl gallate Food, cosmetics Lauryl gallate Food (margarine),47 cosmetics Dodecyl gallate Food, cosmetics Propylene glycol Pharmaceuticals, foods (‘‘moist’’ cakes), cosmetics (lipsticks), and personal care products Foods Catechol (related to poison ivy oleoresin) Mango Limonene@ Orange peel Antibacterials Neomycin sulfate Creams, ointments Bacitracin Creams, ointments UV-adsorber Benzophenone- 3 Lipsticks, sunscreen, dental composite materials Formaldehyde resin Tosylamide formaldehyde resin Nail polish Stabilizers Ethylenediamine hydrochloride Mycolog cream Vehicle/Emollients Lanolin alcohol Ointments, lipsticks Propolis Propolis Lip salves, lozenges Corticosteroids Budesonide Creams and ointments Rubber accelerators Mercaptobenzothiazole Rubber pencil eraser, rubber bands, rubber tips of toothbrushes *May cross-react with balsam of Peru **May produce urticaria, ectopic, or generalized dermatitis ^Additives in acrylic denture material #May not be listed on the ingredient list of dentrifices @Essential oil

20 August 2011 | Skin & Aging | www.skinandaging.com Allergen Focus and Orton analyzed patch test data for lergy to dental materials, particularly available, which isolate the most com- patients presenting with cheilitis from those containing metals such as mer- mon chemicals and offer the provider 1982 to 2001 and found a relevant or cury, gold, nickel and chromium.20,21,22 clues for potential sources. The North possibly relevant PPT in 22%.14 These Therefore, if LP lesions are in proxim- American Standard Series includes al- same authors also demonstrated the ity to such materials, one’s index of lergens from several different catego- importance of testing personal prod- suspicion should be raised.10 In addi- ries;48 however, supplemental trays are ucts, given that 18% of patients with tion, perlèche-like symptoms may oc- also available, such as stomatitis/cheili- ACC reacted solely to their prod- cur in previously sensitized individuals tis/perlèche,10 dental materials, cosmet- ucts. Several relevant sources of reac- who contact nickel or rubber objects ics, fragrance/flavors, and specifically, tions were identified, with lipsticks or at the corners of their mouth. Erosions balsam of Peru at some institutions.49 balms and cosmetics being the most resembling aphthous ulcers can also be The idea behind using supplemen- common.9,12,15,16 Given the prevalence formed from oral contact with nickel tal allergens as well is that by includ- of cosmetic sources, it follows that objects23 and have been reported in pa- ing constituents and cross-reactors of females account for the great major- tients with allergies to balsam of Peru.24 the allergen in question, the chance of ity of patch tested patients presenting Sensitivity to constituents of balsam of demonstrating a relevant positive reac- with cheilitis,9,12-17 and that they are Peru in soft drinks, liquors and sauces tion is greater.50 likely to seek medical attention at an (seasoning) has also been considered as Along these same lines, cosmetic prod- earlier date when compared to their a cause of recurrent aphthous ulcers.25,26 ucts themselves can also be tested “as is.” male counterparts based on duration In fact, ACD to allergens within tooth- Dental products, however, may require of symptoms.12,15 pastes, mouthwashes, teeth whiteners, preparation prior to testing.10 In summa- Additional relevant sources of aller- chewing gum, food, acrylic resin liquid tion, these chemicals and products may gens in ACC include jewelry, medica- and dentures have all been reported.27 overcome a threshold for reactivity. ments (corticosteroids and antibacte- rial creams), oral hygiene products, Top Allergens Pearls of Treatment: Every Dose Counts sunscreens, flavorings in foods and nail Results from patch testing patients As alluded to in the preface, one varnish.9,12,15,16 Freeman and Stephens with cheilitis have been published in- may be exposed to and subsequently also brought attention to the fact that ternationally, listing several allergens as sensitized to a contact allergen, such nickel (in the mouthpiece of a flute) top culprits9,10,12-17 (See Table 2). The as fragrance, for days to years before could be a potential source.16,18 NACDG reported fragrance mix as their demonstrating the clinical picture of most common allergen, followed by My- ACD. With each exposure, there is an Differential Diagnosis roxylon pereirae (balsam of Peru), nickel increasing risk of reaching a point at ACC may be difficult to distinguish sulfate, sodium gold thiosulfate and neo- which the immune system meets its clinically from many other potential mycin sulfate.9 Fragrance mix was also metaphorical “threshold” and subse- diagnoses (See Table 1); therefore, a listed as the most frequent contact aller- quent exposures at this point can lead thorough history is necessary.10 Not gen by groups in the United Kingdom,14 to elicitation of a cutaneous response, only should an allergen exposure his- Italy12 and Singapore.15 such as cheilitis.4,51 Just as repeated tory be obtained, but questions per- Nickel sulfate was ranked as the third contact over time led to this immune taining to ICC, such as lip licking, most common allergen by the NACDG,9 response, repeated avoidance of the should be asked as well, as some stud- and, notably, as the most common allergen majority of exposures over time will ies showed ICC as the most common by both Italian groups.12,13 The primary be required to induce remission. cause of cheilitis.9,13,16 Conditions sources identified were jewelry and lip Avoidance of specific allergens in per- such as atopic or seborrheic dermatitis cosmetics, which highlights the impor- sonal care products can prove to be a te- also should be considered. Depend- tance of ectopic nickel allergic reactions, dious task; however, there are programs ing on the clinical presentation, bac- already known in relation to eyelid der- available to aid in this endeavor. Both terial, fungal or viral cultures can be matitis,9 and generates awareness of the the Contact Allergen Management Pro- performed, and potential nutritional possibility of trace amounts of nickel as a gram (CAMP), a service offered through deficiency can be addressed. If ACC is pollutant in cosmetic products.12,30 More- the American Contact Dermatitis Soci- still suspected, patch testing is the gold over, nickel may also be present in makeup ety (ACDS),52 and the Contact Allergen standard for diagnosing allergic con- or lipstick containers,9 as well as dietary Replacement Database (CARD), de- tact dermatitis or cheilitis.4,19 sources, such as cocoa, dark chocolate, veloped by Mayo Clinic,53 allow for a Perioral dermatitis may have features spinach, oysters and red wine.31 provider to enter a patient’s known con- similar to ACC, but often has a zone tact allergens and produce a “shopping of normal skin immediately surround- Practicals of Patch Testing list” of products void of those particular ing the vermillion border compared to As mentioned above, patch testing chemicals. The programs also have the allergic cheilitis, where the vermillion is often necessary to distinguish ACC ability to exclude cross-reactors. is often involved and effaced.10 Oral from other causes of cheilitis, and to Some sources, however, require avoid- lichen planus (LP) or lichenoid oral identify the relevant allergen(s) re- ance creativity and finding alternatives. lesions may be caused by contact al- sponsible. Screening patch test trays are In cheilitis patients, ingestible sources,

August 2011 | Skin & Aging | www.skinandaging.com 21 Allergen Focus such as chewing gum, cough drops, and (TOACS). Acta Derm Venereol. 2002;82(5):359-364. tests. Contact Dermatitis. 1975;1(2):70-76. liqueurs in menthol-allergic patients, 12. Zoli V, Silvani S, Vincenzi C, Tosti A. Al- 34. Kirton V, Wilkinson W. Sensitivity to cinnamic lergic contact cheilitis. Contact Dermatitis. aldehyde in aº toothpaste: 2. further studies. Con- margarine in gallate-allergic patients, 2006;54(5):296-297. tact Dermatitis. 1975;1(2):77-80. and peanut butter in nickel-allergic pa- 13. Schena D, Fantuzzi F, Girolomoni G. Contact 35. Goransson K, Karltorp N, Ask H, Smedberg O. tients,54 should be given consideration. allergy in chronic eczematous lip dermatitis. Eur J Some cases of eugenol sensitivity. Svensk Tandlak Educating patients to increase their Dermatol. 2008;18(6): 688-692 Tikski. 1967;60(10):545-549. awareness of sources of allergens and 14. Strauss RM, Orton DI. Allergic contact cheili- 36. Koch G, Magnusson B, Nyquist G. Contact tis in the United Kingdom: retrospective study. Am allergy to medicaments and materials used in den- having the patient inform their health J Contact Dermat. 2003;14(2):75-77. tistry: II. Sensitivity to eugenol and colophony. and dental professionals of their contact 15. Lim SW, Goh CL. Epidemiology of ec- Odont Revy. 1971;22(3):275-289. allergens is also important. n zematous cheilitis at a tertiary dermatological 37. Beswick S, Ramsay H, tan B. Contact Der- referral centre in Singapore. Contact Dermatitis. matitis from flavourings in chewing gum. Contact Dr. Jacob, the Section Editor of Allergen Fo- 2000;43(6):322-326. Dermatitis. 1999;40(1):49-50. 16. Freeman S, Stephens R. Cheilitis: analysis of 75 38. Fisher AA. Allergic contact stomatitis. Cutis. cus, directs the contact dermatitis clinic at Rady cases referred to a contact dermatitis clinic. Am J 1975;15:149. Children’s Hospital – University of California Contact Dermat. 1999;10(4):198-200. 39. Papa CM, Shelley WB. Menthol hypersensitiv- in San Diego, CA. She is also Associate Clinical 17. Kanthraj GR, Shenoi SD, Srinivas CR. Patch ity; diagnostic basophil response in a patient with Professor of Pediatrics and Medicine (Dermatol- testing in contact cheilitis. Contact Dermatitis. chronic urticaria, flushing, and headaches. JAMA. ogy) at the University of California, San Diego. 1999;40(5):285. 1964;189:546-548. 18. Jacob SE, Herro EM. School Issued Musical 40. Fisher AA, Shapiro A. Allergic eczematous Instruments: Significant Source of Nickel. Derma- contact dermatitis due to metallic nickel. JAMA. Dr. Herro is the Contact Dermatitis Fellow at titis. 2010; 21(6):332-333. 1956;161(8);717-721. Rady Children’s Hospital – UCSD 2010-2011. 19. Jacob SE, Steele T, Brod B, Crawford GH. Dis- 41. Wilson H_T. Nickel dermatitis. Br J Dermatol. pelling the Myths Behind Pediatric Patch Testing— 1955;67(8-9):291-298. Disclosure: Dr. Jacob is the principal investiga- Experience from Our Tertiary Care Patch Testing 42. Crissey JT. Stomatitis, dermatitis and denture tor for Smartchoice USA PREA-2 trial. Centers. Pediatr Dermatol. 2008 ;25(3):296-300. materials. Arch Dermatol. 1965;92(1):45-48. 20. Frykholm KO, Frithiof A, Fernstrom AI, et al. 43. Goon A, Isaksson M, Zimerson E, et al. References Allergy to copper derived from dental alloys as a Contact allergy to (meth)acrylates in the dental 1. Bickers DR, Lim HW, Margolis D, et al. The possible cause of oral lesions of lichen planus. Acta series in Southern Sweden. Contact Dermatitis. burden of skin diseases: 2004 a joint project of the Derm Venereol. 1969;49(3):268. 2006;55(4):219-226. American Academy of Dermatology and the So- 21.Koch P, Bahmer F. Oral lesions and symptoms 44. Maurice PD, Hopper C, Punnia-Moorthy A, ciety for Investigative Dermatology. 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