I S S U E

25SEPTEMBER

2018

I N T H I S I S S U E

The Last of the Corticosteroid Markers: Hydrocortisone-17-Butyrate and Beyond ......... p1

In the Blink of an Eye: New Directions in Eyelid Dermatitis ............................................. p3

Concentration, Volume, and Dose in PPD Patch Testing ................................................... p5

The Last of the Corticosteroid Markers: Hydrocortisone-17-Butyrate and Beyond

Hydrocortisone-17-butyrate (H-17-B) is a midstrength (methylpred- nisolone aceponate type) corticosteroid (see the September 2017 issue), most often used to treat inflammatory skin diseases and psoriasis. H-17-B, which is a Coopman Group D2 steroid and may be the third most

sensitizing corticosteroid after tixocortol pivalate (see the March 2018 issue) andbudesonide (see the June 2018 issue), is the patch test marker for D2 steroids. Of the 2% of patients who exhibited a corticosteroid allergy in a large Danish study, the overall rate of positive reactions to H-17-B was 1%. In North America, the prevalence of positive reactions to H-17-B has been slightly lower, ranging from about 0.1 to 0.7%. Positive reactions to H-17-B, however, tend to have high clinical relevance—almost 80% in one study from the North American Contact Dermatitis Group (NACDG).

Patients may be exposed to H-17-B in many over-the-counter and prescription pharma-ceuticals. In the work environment, it may be encountered in a variety of medicaments formulated in creams, lotions, ointments, and powders. At home, patients may be exposed to H-17-B in the same formulations used to treat eczema and other localized skin inflammations; in ear, nose, and eye drops; and in rectal suspensions. Skin-to-skin transfer of the allergen can also elicit a dermatitic outbreak (i.e., consort dermatitis) if a spouse, children, or other individuals with whom patients have close contact use such topical preparations.

Corticosteroid hypersensitivity, both in general and specifically to H-17-B, tends to be a treatment-related contact allergy. Factors found to be associated with allergy to H-17-B have included occupational dermatitis, age older than 40 years, and, most significantly,

duration of dermatitis. Like tixocortol pivalate, H-17-B is a popular topical medicament. In contrast to tixocortol, however, which is associated with both atopic dermatitis and leg dermatitis (for example, from its use to treat stasis dermatitis or leg ulcers, particularly in the elderly), no association has been found between sensitization to H-17-B and these conditions.

As with other corticosteroids, diagnosing sensitization to H-17-B can be challenging. Failure of a skin condition to improve or one that worsens when treated with H-17-B can be a symptom of sensitization. Improvement of a patient’s dermatitis when treatment is stopped can also signal an allergy to H-17-B. A rare manifestation of allergic contact dermatitis (ACD) related to H-17-B is a skin eruption that mimics acute generalized exanthematous pustulosis, and ACD involving the face has mimicked papular rosacea in at least one reported case.

Dear Reader,

Hair dye, of course, is a classic source of exposure to para-phenylenediamine(PPD). Now a new cosmetic trend is poised to increase the risk of sensitiza-tion to this highly sensitizing chemical. Read In the Blink of an Eye to discover the novel link between eyelid dermatitis and PPD.

Speaking of PPD, the sensitizing po-tential of PPD has even elicited con-cerns about its safety for use in patch testing—at least at the 1% concentra-tion currently considered by many as standard. But is 1% PPD in petrolatum safe, or is it actively sensitizing pa-tients? And if it is not safe, are there any alternatives? Explore this topic in Concentration, Volume, and Dose in PPD Patch Testing.

This issue concludes our series on patch testing with corticosteroids by focus-ing on hydrocortisone-17-butyrate. The marker for Group D2 corticosteroids, H-17-B can manifest signs of sensitiza-tion similar to those of the other cor-ticosteroids while presenting diagnos-tic challenges of its own.

As always, we remain committed to our mission of helping you provide an accurate diagnosis to your patients. If you have questions, we are just a phone call away!

Kind Regards,

Dr. Curt Hamann President and CEO, SmartPractice

all things contact dermatitis N E W S & N O T E S

™

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For patch testing, some clinicians have recommended using H-17-B in ethanol (allergEAZE NA69), which is thought to enhance penetration of the allergen. The timing of readings is another consideration. Delayed readings (i.e., at day 7) are often recom-mended for corticosteroids, including H-17-B. Reactions to H-17-B, however, can disappear relatively rapidly, a phenomenon that may be related to the metabolism of the allergen in the skin. Therefore, reading H-17-B only at day 7 may be associated with an unacceptably high rate of false-negative reactions. Cli-nicians must remember that patients can have a negative patch test reaction to any corticosteroid, including H-17-B, even when they are truly sensitized; the response reflects the inherent im-munosuppressant property of the drugs.

Metabolically, H-17-B is first converted to hydrocortisone-21- butyrate and then to hydrocortisone, a Group A steroid. Conse-quently, cross-reactivity between H-17-B and Group A steroids can occur. Patients allergic to H-17-B may need to avoid ste-roids in both Group D2 and Group A. Concomitant reactions between H-17-B and the Group B steroid budesonide have also been reported. Sensitized patients should check all anti- inflammatory preparations (prescription and nonprescription)

for H-17-B as well as for related corticosteroids and should ask their pharmacist if they are

uncertain whether a medication contains the allergen. Patients must inform their health care providers and ask them to use or prescribe products that are free from H-17-B and related corticoste-

roids. Sensitized patients should avoid products that list the following ingredients: h.17b, Laticort, locoid, hb(sub 17), Alfason, Cortisol 17-butyrate, Plancol, and Hydrocortisone butyrate as well as to those listed in Table 1.

Markers for corticosteroids in groups C and D1 are also available: clobetasol-17-propionate for the former and desoximetasone for the latter. Overall, sensitization to these corticosteroids appears to be rare. For example, as of the year 2000 only four cases of ACD to clobetasone butyrate had been reported, and, based on a recent analysis, desoximetasone, at least in a topical spray formulation, appears to have little potential for sensitization (or irritation). Based on NACDG data, the prevalence of positive patch test reactions to clobetasol has ranged from 0.3 to 0.7% while that of desoximetasone has been 0.2% or less.

When H-17-B is combined with the other major markers for cor-ticosteroid allergy, tixocortol pivalate and budesonide, 80% of patients who are allergic will be identified. These three markers are included on T.R.U.E. TEST® to make screening for cortico-steroid allergies easy and are, of course, also available from allergEAZE in petrolatum

The Last of the Corticosteroid Markers…continued

Click here to see the Full Prescribing Information for T.R.U.E. TEST

IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGET.R.U.E. TEST is an epicutaneous patch test indicated for use as an aid in the diagnosis of allergic contact dermatitis in persons 6 years of age and older whose history suggests sensitivity to one or more of the 35 substances included on the T.R.U.E. TEST panels.

CONTRAINDICATIONS• Do not apply to skin of patients with a history of severe allergic reaction (sys-

temic and/or local) to any of the allergen components or inactive substances of T.R.U.E. TEST.

• Do not apply to skin that is injured or inflamed.

WARNINGS AND PRECAUTIONS• Acute allergic reactions, including anaphylaxis, may occur.• Sensitization to one or more of the allergens may occur with initial or repeat

testing.• Extreme positive reactions, excited skin syndrome, tape reactions, irritant

contact dermatitis, persistent reactions, and late reactions at the test site may occur.

ADVERSE REACTIONS• The most common adverse reactions (occurring in more than 1% of the

study population) were burning, tape irritation, persistent reactions, erythema, and hyper/hypo pigmentation.

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formulations. Desoximetasone (NA68) is available in a petrola-tum formulation while Clobetasol-17-propionate is offered in both ethanol (CS998) and petrolatum (CS492, NA20) formula-tions. Corticosteroids and their role in ACD are complicated. So, if you still have questions about which products would best serve the needs of your practice, our friendly sales representatives are available to answer your questions at 1-800-878-3838.

Table 1: Products that May Cause Reactions in Patients Sensitized to H-17-BAmcinonide Hydrocortisone acetateBudesonide Hydrocortisone butyrateCloprednol Hydrocortisone valerateCortifoam cortisol HydroxycorticosteroneCortril Incortin-H Kendall’s compound FDesonide MethylprednisoloneEfcorlin Micronized fluocinonideEfcortelin PrednicarbateElcorbin PrednisoloneFludrocortisone acetate Prednisolone acetateFluocinolone acetonide ProctoscortFluocinonide RectoidFlurandrenolide Steroids: Group B & Group D2Halcinonide TriamcinoloneHydrocortisone

SUGGESTED READINGS

Pratt M, Mufti A, Lipson J, et al. Patch test reactions to corticosteroids: retrospective analysis from the North American Contact Dermatitis Group 2007-2014. Dermatitis 2017;28(1):58-63

Nadkarni A, Saleem MD, Feldman SR. Topical desoximetasone 0.25% spray and its vehicle have little poten-tial for irritation or sensitization. J Drugs Dermatol 2017;16(8):755-758

Hoffman LK, Kircik L. Efficacy and safety of desoximetasone 0.25% spray in adult atopic dermatitis subjects: pilot study. J Drugs Dermatol 2017;16(9):919-922

Warshaw EM, Maibach HI, Taylor JS, et al. North American Contact Dermatitis Group patch test results: 2011-2012. Dermatitis 2015;26(1):49-59

Wentworth AB, Yiannias JA, Keeling JH, et al. Trends in patch-test results and allergen changes in the stan-dard series: A Mayo Clinic 5-year retrospective review (January 1, 2006, to December 31, 2010). J Am Acad Dermatol 2014;70:269-275

D’Erme MA, Gola M. Allergic contact dermatitis induced by topical hydrocortisone-17-butyrate mimicking papular rosacea (letter). Contact Dermatitis 2012;23(2):95-96

Vind-Kezunovic D, Johansen JD, Carlsen BC. Prevalence of and factors influencing sensitization to corticoste-roids in a Danish patch test population. Contact Dermatitis 2011;64:325-329

Broesby-Olsen S, Clemmensen O, Andersen KE. Allergic contact dermatitis from a topical corticosteroid mimicking acute generalized exanthematous pustulosis. Acta Derm Venereol 2005;85(5):444-445

Isakkson M, Bruze M. Corticosteroids. Dermatitis 2005;16(1):3-5

Isaksson M. Corticosteroids. Dermatologic Therapy 2004;17:314-320

Isaksson M, Andersen KE, Brandao F, et al. Patch testing with corticosteroid mixes in Europe: A multicentre study of the EECDRG. Contact Dermatitis 2000;42(1):27-35

Dooms-Goossens A, Morren M. Results of routine patch testing with corticosteroid series in 20173 patients. Contact Dermatitis 1992;26:182-191

The Last of the Corticosteroid Markers…continued

In the Blink of an Eye: New Directions in Eyelid Dermatitis

In the December 2013 issue of this newsletter, we identified permanent and semi-permanent hair dyes as the primary sources of sensitization to the blue-black aniline dye para-phenylenediamine (PPD) and discussed temporary henna tattoos heavily laced with PPD as a trendy new source of exposure. Now the increasing popularity of yet another new beauty treatment, eyelash dying, threatens to increase the risk of sensitization to this potent allergen or the elicitation of allergic contact dermatitis in previously

sensitized individuals.

A recent survey of beauticians (Ali L, Ghaffar SA. Standard practices and awareness concerning p-phenylenediamine among salons that provide eyelash dyeing services. Contact Dermatitis 2018;78:433-434) calls attention to this new cosmetic trend. Also known

as eyelash tinting, the procedure—and its sister treatment, eyebrow dying—involves mixing the PPD-containing dye with a developer that contains hydrogen peroxide and then applying it to the eyelashes. The survey was

undertaken to determine beauticians’ awareness of the presence of PPD in eyelash dye. Their standard practices revealed troubling results: Most beauticians who responded performed consumer product patch testing before treatment. However, 72% of the beauticians did not know if the eyelash dyes they used contained PPD. Furthermore, only 20% asked their clients if they were allergic to PPD.

Over time, the frequency of positive patch test reactions to PPD has increased, possibly because more people are dyeing their hair and doing so at an earlier age. Eyelash dyeing may add to the problem.

Previous sensitization to PPD can result in severe and persistent allergy to PPD. For example, an otherwise healthy young woman developed edema and redness of both eyelids; erythema of the cheeks,

forehead, and periocular region; severe conjunctival hyperemia; and a mild chemosis with mucous discharge 2 days after having her eyelashes dyed. She had never had her hair

dyed, yet she had a strong positive patch test reaction to PPD, among other allergens.

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In the Blink of an Eye…continued

Moreover, her medical history revealed that she had previously developed an itchy rash after getting a temporary black henna tattoo on vacation. Conclusion? Having been sensitized by the tattoo, the patient was ripe for elicitation of allergic contact dermatitis by the PPD-containing eyelash dye.

Because allergens are easily transferred to the eyes by the hands, other causes of allergic eyelid dermatitis, such as sensitization to gold, fragrance mix, balsam of Peru, nickel, and neomycin, are well established. Other classic causes of eyelid dermatitis include sulfonamide formaldehyde resin in nail polish, acrylates in artifi-cial nails, and rubber in makeup sponges and eyelash curlers. In fact, in some studies, fragrance and moisturizers in cosmetics and beauty products have been identified as the leading sources of eyelid dermatitis. In the case of eyelash dying, products contain-ing potentially allergenic preservatives, fragrances, or emulsifierssuch as cleansing wipes, lotions, and oils are used in pre- and post-dyeing treatment. Moreover, both eyelash dyes and dye developers contain other known sensitizers, such as cetearyl alco-hol, ethylenediamine-tetraacetic acid (EDTA), propylene glycol, resorcinol, m-aminophenol, and p-aminophenol. Additionally, m-aminophenol and toluene-2,5 diamine (TDA) have been report-ed to cause eyebrow allergic contact dermatitis after probable sensitization from PPD in a temporary black henna tattoo.

Eyelid dermatitis is a complex area of allergic contact dermatitis, and obtaining an accurate diagnosis can be challenging. Patients are most likely to be women, who are affected far more often than men. The involvement of the eyelids themselves offers some clues to the diagnosis. Bilateral disease may point to allergic con-tact dermatitis, atopic dermatitis, or irritant dermatitis. Unilateral

eyelid dermatitis, however, has been associated with allergic contact derma-titis exclusively. Involvement of all four eyelids may be another major risk factor for allergic contact dermatitis. Nonetheless, eyelid dermatitis is not always restricted to the eyelids. The head and neck may be involved in almost a third of cases, and other parts of the body may be affected in almost half the cases.

The risk of developing eyelid dermatitis is far from restricted to the presence of PPD in the products used to dye eyelashes and eyebrows—or in the many other beauty and hair care products on the market. However, PPD is recognized as a highly sensitizing allergen. In fact, PPD is so sensitizing that concerns about its use even in patch testing have recently emerged, as explored in the next article, Concentration, Volume, and Dose in PPD Patch Testing.

SUGGESTED READINGS

Romita P, Foti C, Mascia P, et al. Eyebrow allergic contact dermatitis caused by m-aminophenol and toluene-2,5 diamine secondary to a temporary black henna tattoo. Contact Dermtitis 2018;79:51-52

Lareb A, Ghaffar SA. Standard practices and awareness concerning p-phenylenediamine among salons that provide eyelash dyeing services (letter). Contact Dermatitis 2018;78:433-434

Crouse L, Ziemer C, Lugo-Somolinos A. Trends in eyelid dermatitis (letter). Contact Dermatitis 2018;29(2):96-97

Sumanth Mukkanna K, Stone NM, Ingram JR. Para-phenylenediamine allergy: current perspectives on diagnosis and management. Journal of Asthma and Allergy 2017;10:9-15

Vogel TA, Conraads PJ, Schuttelaar ML. Allergic contact dermatitis presenting as severe and persistent blepharoconjunctivitis and centrofacial oedema after dyeing of eyelashes. Contact Dermatitis 2014;71:303-317

Rietschel RL, Warshaw EM, Sasseville D, et al. Common contact allergens associated with eyelid dermatitis: data from the North American Contact Dermatitis Group 2003-2004 study period. Dermatitis 2007;18(2):78-81

Guin JD. Eyelid dermatitis: a report of 215 patients. Contact Dermatitis 2004;50(2):87-90

Cooper SM, Shaw S. Eyelid dermatitis: an evaluation of 232 patch test patients over 5 years. Contact Dermatitis 2000:42;291-293

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Concentration, Volume, and Dose in PPD Patch Testing

In 1961, the Consumer Product Safety Commission identified the blue-black aniline dye p-phenylenediamine (PPD) as one of five “strong sensitizers” in the United States. Historically, the primary route of sensitization to this allergen has been through

hair dyes. However, exposure from temporary henna tattoos for-mulated with high levels of PPD led the American Contact Derma-titis Society to name PPD as the 2006 Contact Allergen of the Year. Moreover, given the many other potential sources of exposure to PPD and its derivatives and considering global median prevalenc-es of sensitization to PPD (ranging from 2% to > 6%), the allergen was, until recently, included in all major baseline series.

That is, until concerns about the risks of active sensitization from patch testing with 1% PPD in petrolatum (pet) led the German Contact Dermatitis Research Group [Deutsche Kontaktallergie-Gruppe (DKG)] to remove this allergen from their baseline series in 2005. Backed by a study by Hillen et al., the DKG found that patch testing with this formulation elicited late reactions (on Day 7 or beyond) in 1.5% of patients tested. They interpreted the finding to mean that patch testing with a 1% concentration of PPD might be actively sensitizing patients. In a subsequent study, the DKG found that using a 0.35% concentration of PPD for patch testing was both safe and effective. Based on this and other studies, the Information Network of Departments of Dermatology and the DKG recommended replacing PPD 1% with PPD 0.3% pet in the German baseline series.

PPD is an allergen of global importance, and it makes sense for manufacturers of contact allergens to offer PPD at the lower rec-ommended concentration. However, the regulatory process that governs the production and licensing of allergens is extremely time consuming. In 2018, more than a decade after the DKG re-leased its findings, a 0.3% PPD formulation has yet to be licensed in Germany (or anywhere else). The lack of a commercially avail-able 0.3% PPD formulation has effectively eliminated patch test-ing with this important allergen in Germany. A recent article [An-dersen F, Hamann C, Andersen K, et al. Different concentrations and volumes of p-phenylenediamine in pet. (equivalent doses) are associated with similar patch test outcomes: a pilot study. Contact Dermatitis 2018;78:335-340], however, suggests an alternative solu-tion to this dilemma based on using a precise definition of dose.

Dose is often conflated with concentration (percentage) of an allergen. However, dose is a function of the concentration and the amount of allergen dispensed in a patch test chamber of a given size. This distinction is important because dose per unit area is the critical factor underlying both sensitization and elicitation of contact allergy. In mathematical terms, the concept of dose per unit area implies that different volumes of the same concentration of PPD can deliver the same dose per unit area.

Andersen and coworkers demonstrated the validity of this con-cept by patch testing 17 subjects with a known sensitivity to PPD with two precisely measured volumes and concentrations of PPD:

6 mg of PPD 1% and 20 mg of PPD 0.3%. The investigators used the full diameter of the Finn Chamber® (9.5 mm), not just the 8-mm diameter of the inner chamber depres-sion, to account for spreading of the allergen to the edges of the chamber (resulting in an effective area of 71 mm). The frequency of reactions was recorded for both formulations of PPD. Based on the following equation for calculating dose, the two test volumes effectively produced the same dose per unit area.

Amount of allergen dispensed (mg x allergen concentration (%)/patch test chamber area (cm2) = dose (mg)/unit area (cm2).

Overall, 13 of the 17 subjects had a positive reaction to at least one of the allergen formulations. Two subjects had a positive reaction to one formulation each. The overall agreement between the two formulations was 88.2% (95% confidence interval: 63.6 –98.5%).

What is the implication of the finding that the two different volumes and concentrations of PPD, which delivered the same dose per unit area, elicited similar outcomes? Certainly, as a short-term solution to the absence of a licensed PPD 0.3% formulation in Germany, patch testing could be conducted with a smaller amount (6 µl) of the currently available concentration of 1% pet rather than with the amount widely accepted as standard (20 µl).

In general terms, however, the finding underscores the importance of discussing patch test allergens in terms of dose/unit area. And although other allergens were not tested, this finding may well be generalizable. It may then be reasonable to modify the dose of highly sensitizing allergens when desired allergen concentrations are unavailable. Furthermore, the amount of allergen dispensed can vary widely depending on the experience of the person pushing the plunger of an allergen syringe. To reduce the dose of allergen as described in this article, a calibrated micropipette must be used. But for clinicians striving for greater precision in dispensing allergens at the standard doses of 20 µl, TruVol® precision allergen dispenser can eliminate concerns about unwanted variation. A quick phone call (1-800-878-3838) can help you find out how to take this step toward standardizing your patch test practice.

SUGGESTED READINGS

Pollitzer PM, Kameros AJ. Hazardous substances and articles: administration and enforcement regulations: notice of proposed rulemaking: revisions to supplemental definition of ‘strong’ sentistizer. Consumer Prod-uct Safety Commission, 16 CFR Part 1500, 2013. Available at https://www.cpsc.gov/s3fs-public/pdfs/foia_strongsensitizer.pdf (last accessed 11 June 2018).

DeLeo VA. P-phenylenediamine. Dermatitis 2006;17:53-55

Thyssen JP, White JNL. Epidemiological data on consumer allergy to p-phenylenediamine. Contact Derma-titis 2008;59:327-343

Hillen U, Jappe U, Frosch PJ, et al. Late reactions to the patch-test preparations para-phenylenediamine and epoxy resin: a prospective multicenter investigation of the German Contact Dermatitis Research Group. Br J Dermatol 2006;154:665-670

Geier J, Ballmer-Weber BK, Dickel H, et al. Monitoring contact sensitization to p-phenylenediamine (PPD) by patch testing with PPD 0.3% in petrolatum. Contact Dermatitis 2013;69:26-31

Johansen JD, Aalto-Korte K, Agner T, et al. European Society of Contact Dermatitis guideline for diagnostic patch testing—recommendations on best practice. Contact Dermatitis 2015;73:195-221

Bruze M, Frick-Engfeldt M, Gruvberger B, et al. Variation in the amount of petrolatum preparation applied at patch testing. Contact Dermatitis 2007;56:38-42

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