STUDY
Retrospective Study of PhotoPatch Testing in a Chinese Population During a 7-Year Period Lujuan Gao, MD, Yue Hu, MD, Chunya Ni, MD, Yu Xu, MD, Li Ma, MD, Shuxian Yan, MD, and Xia Dou, MD Background: Photoallergic contact dermatitis (PACD) is of importance in a proportion of photodermatoses and can be evaluated through photopatch testing (PPT). Objectives: The objectives of this study were to evaluate the results of PPT and investigate the prevalence of PACD reactions to different photoallergens in Chinese patients at the Department of Dermatology of Huashan Hospital Fudan University during a 7-year period. Methods: A retrospective PPT study was conducted. During the 7 years, 4957 patients attending for investigation of suspected photodermatoses were tested according to the European consensus methodology with up to 14 allergens prepared according to Chinese National Standards. The reactions were scored using the International Contact Dermatitis Research Group visual scoring system. Results: A total of 3472 PACD reactions in 2454 subjects (49.5%) were recorded. The most common agents were chlorpromazine (44.3%), followed by para-aminobenzoic acid (14.7%), thimerosal (8.9%), and sulfanilamide (6.9%). Allergic contact dermatitis reactions comprised 409 reactions in 399 subjects (8%). Photoinhibition and photoaugmentation of allergic contact dermatitis compromised 3810 reactions in 2412 subjects and 11 reactions in 11 subjects, respectively. Irritant reactions (1928 reactions) were seen in 1140 subjects. Conclusions: The most predominant photoallergens in our region were chlorpromazine, para-aminobenzoic acid, thimerosal, and sulfanilamide, which likely reflected the particular exposures of this Chinese population.
P
hotoallergic contact dermatitis (PACD) describes the delayed, type IV hypersensitivity reaction, which occurs when an exogenous agent (photoallergen) is applied to the skin and subsequently exposed to UV and/or visible radiation.1 The incidence of PACD is unknown, but it is thought to be uncommon with frequencies of 2% to 10% reported among patients referred for investigation of photoexposed-site dermatoses.2Y4 Although PACD is probably an uncommon event, it can cause significant morbidity. The key investigation is photopatch testing (PPT), for which a European consensus methodology has existed for several years.5 However, awareness of the disease among dermatologists is low, and PPT is not widely available. To determine and understand the prevalence of PACD reaction to different photoallergens among patients presenting for investigation of suspected photodermatoses in our region of China, From the Department of Dermatology, Huashan Hospital Fudan University, Shanghai, People’s Republic of China. Address reprint requests to Xia Dou, MD, No. 12th Wulumuqi Middle Road, Jing’an District, Shanghai, 200040, People’s Republic of China. E-mail: [email protected]. L.G. and Y.H. contributed equally to this study. This study was supported by grants NSFC 30901289 from the National Natural Science Foundation of China. The authors have no conflicts to declare. DOI: 10.1097/DER.0000000000000008 * 2014 American Contact Dermatitis Society. All Rights Reserved. 22
we retrospectively evaluated the results of PPTs performed during a 7-year period.
METHODS Patients who underwent PPT for suspected photodermatoses at Huashan Hospital Fudan University (Shanghai, China) from January 1, 2006, to December 31, 2012, were identified from a clinical database. In general, patients did not undergo PPT if they had skin disease activity on the back that was too active to allow PPT, had applied topical corticosteroids to patch-test sites in the 5 days before PPT, had taken immunosuppressive medication or oral corticosteroids, or had medical conditions that could compromise the evaluation of skin responsiveness. Other photodermatoses such as porphyrias and connective tissue diseases were excluded before PPT. Patient demographics and PPT results were abstracted from the clinical database. During the study period, 4957 patients underwent PPTs with up to 14 allergens. The series of photoallergens included 14 substances, which were purchased from China Medicine (Group) Shanghai Chemical Reagent Corporation (Shanghai, China) and Sigma Corporation (NY). The test allergens were prepared according to Chinese National Standards (GB-17149.2-1997; GB-17149.6-1997) and are shown in Table 1 with associated dilution, vehicle, and chemical abstract service (CAS) number. DERMATITIS, Vol 25 ¡ No 1 ¡ January/February, 2014
Copyright © 2014 American Contact Dermatitis Society. Unauthorized reproduction of this article is prohibited.
Gao et al ¡ PhotoPatch Testing in Chinese Population
23
TABLE 1. Test Agents With Concentration and CAS Number Test Agent (Concentration, Vehicle)
as means T SD. To analyze statistically significant associations between categorical variables, the W2 test was used as appropriate.
CAS No.
CPZ (1%, water) PABA (2%, water) TMS (0.1%, petrolatum) Sulfanilamide (5%, water) Thiourea (0.1%, water) Tetrachlorosalicylanilide (0.1%, petrolatum) Cinnamaldehyde (1%, petrolatum) Limonene (2%, petrolatum) Cinnamyl alcohol (1%, petrolatum) Triclosan (2%, petrolatum) Benzophenone (1%, petrolatum) Sandalwood oil (2%, petrolatum) 6-Methyl coumarin (1%, petrolatum) Ketone musk (5%, petrolatum)
50-53-3 150-13-0 54-64-8 63-74-1 62-56-6 1154-59-2 104-55-2 5989-27-5 104-54-1 3380-34-5 119-61-9 11031-45-1 92-48-8 81-14-1
Photopatch testing was conducted according to the European consensus methodology as described previously.5 In brief, the test agents were applied using Finn Chambers on Scanpor (SmartPractice, Phoenix, AZ) in duplicate to the skin of the back and removed at 24 hours. One set was covered with a UV opaque material, and the other was then irradiated with UV-A. The UV-A dose was determined after performing a minimal erythema dose test before or on the day of patch application.6 The UV-A dose series included less than 5, 5, 7.5, and 10 J/cm2. The critical reading was performed before irradiation, immediately after irradiation, and 48 hours after irradiation. Reactions were scored using the International Contact Dermatitis Research Group (ICDRG) visual scoring system.7 All statistical analyses were carried out with SPSS version 18.0 software (SPSS Inc, Chicago, Ill). Continuous variables were shown
RESULTS From January 1, 2006, to December 31, 2012, a total of 4957 patients (3069 female and 1888 male patients) were tested. The skin phototypes included 147 type III and 4810 type IV. The average age was 43.9 T 15.7 years (range, 6Y93 years). The doses of UV-A used for irradiation were 5 J/cm2 in 368 subjects, 7.5 J/cm2 in 1852 subjects, and 10 J/cm2 in 2370 subjects, with the remaining 367 subjects receiving less than 5 J/cm2. A total of 3472 PACD reactions in 2454 subjects (49.5%) were recorded, including 981 male (51.96%) and 1473 female subjects (48%). There was a significant difference in the frequency of positive PACD reaction between male and female (P G 0.05). The number of PACD reactions recorded for each agent, with the corresponding ICDRG grade of the reactions in the irradiated set, is given in Table 2. Of these allergens, chlorpromazine (CPZ), paraaminobenzoic acid (PABA), thimerosal (TMS), and sulfanilamide most frequently elicited PACD reactions. A total of 1768 PACD reactions (44.3%) to CPZ were recorded, which was responsible for 50.9% of the documented PACD reactions (1768 in 3472 reactions). Among these reactions to CPZ, ICDRG grades were recorded ‘‘+++’’ in 2 subjects, ‘‘++’’ in 45 subjects, and ‘‘+’’ in the remaining subjects. For PABA, 546 (14.7%) PACD reactions were recorded, including 3 recorded as ‘‘++,’’ and the rest recorded as ‘‘+.’’ For TMS, 387 PACD reactions (8.9%) comprising 1 ‘‘+++,’’ 2 ‘‘++,’’ and 384 ‘‘+’’ were recorded. Photoallergic contact dermatitis reactions of sulfanilamide occurred in 333 subjects (6.9%). Photoallergic contact dermatitis reactions to thiourea (2%), tetrachlorosalicylanilide (1.9%), triclosan (0.8%), benzophenone (0.6%), and fragrance allergens were relatively infrequent. The fragrance allergens, in decreasing
TABLE 2. PACD Reactions to the Test Agents With ICDRG Grading of Reactions
Test Agents CPZ PABA TMS Sulfanilamide Thiourea Tetrachlorosalicylanilide Cinnamaldehyde Limonene Cinnamyl alcohol Triclosan Benzophenone 6-Methyl coumarin Sandalwood oil Ketone musk
ICDRG Grade of PACD Reaction in Irradiated Set
PACD
Test Performed
n
%
+
++
+++
3993 3718 4331 4836 4359 3717 4929 3564 4922 4905 4446 1471 4317 3767
1768 546 387 333 88 72 77 44 50 39 26 7 23 12
44.3 14.7 8.9 6.9 2.0 1.9 1.6 1.2 1.0 0.8 0.6 0.5 0.5 0.3
1721 543 384 330 88 71 77 43 50 38 26 7 23 11
45 3 2 3
2
1 1 1
1
Copyright © 2014 American Contact Dermatitis Society. Unauthorized reproduction of this article is prohibited.
1
DERMATITIS, Vol 25 ¡ No 1 ¡ January/February, 2014
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TABLE 3. Frequency of PACD Reactions by Age Group to the Test Series and CPZ Alone Subjects With at Least 1 PACD Reaction
PACD Reactions to CPZ
Subject Age, y
Total No. Subjects
n
%
No. Subjects Tested With CPZ
n
%
0Y10 11Y20 21Y30 31Y40 41Y50 51Y60 61Y70 71Y80 81Y90 91Y100 Total
2 191 1116 873 932 1089 528 193 32 1 4957
0 64 451 415 468 629 314 94 18 1 2454
0.0 33.5 40.4 47.5 50.2 57.8 59.5 48.7 56.3 100.0 49.5
1 143 839 685 735 931 460 169 29 1 3993
0 41 298 285 332 486 232 76 17 1 1768
0.0 28.7 35.5 41.6 45.2 52.2 50.4 45.0 58.6 100.0 44.3
order of frequency, were cinnamaldehyde (1.6%), limonene (1.2%), cinnamyl alcohol (1.0%), 6-methylcoumarin (0.5%), sandalwood oil (0.5%), and musk ketone (0.3%). The effect of age on the frequency of PACD reactions of the test set and CPZ was analyzed by grouping subjects into 10-year blocks, as shown in Table 3. Interestingly, the frequency of PACD reactions gradually increased with age, except among subjects 71 years or older. Analysis of PACD reaction rates to CPZ in different age blocks revealed that the top 3 decades were 80s (58.6%), 50s (52.2%), and 60s (50.4%). In comparison to PACD reactions, allergic contact dermatitis (ACD) reactions were much less frequent, with a total of 409 positive reactions recorded in 399 subjects (8%). Four of the 14 test agents did not lead to any ACD reactions, namely, benzophenone, limonene, 6-methyl coumarin, and ketone musk. The frequencies of ACD reactions reported for the remaining 11 agents are given in Table 4. The corresponding ICDRG grade recorded of the ACD reactions were all 1+. Photoaugmentation of ACD reactions was relatively uncommon, with only 11 reactions in 11 subjects. However, photoinhibition of ACD reactions was not uncommon in our study, with 3810 reactions in 2412 subjects. Among these, TMS, CPZ, and PABA were responsible for 1713, 641, and 438 reactions, respectively. A total of 1928 irritant reactions in 1140 subjects were recorded, including 533 immediate postirradiation irritant reactions in 475 subjects.
DISCUSSION Photopatch testing is an essential tool in the diagnosis of PACD. Here we describe the retrospective study of the PPT results at the Department of Dermatology, Huashan Hospital, during a 7-year period. A total of 4957 patients were included, and the skin phototype distribution represented the typical distribution found in China.
The results revealed 49.5% of subjects had at least 1 PACD reaction, which is much higher than that in the European Multicentre Photopatch Test Study, which reported a frequency of 19.4%,2 but close to that reported in a French multicenter study by Leonard et al, which included 2067 patients and reported a frequency of PACD at 39.7% to 60.0%.8 Chlorpromazine, the agent with the highest rate of positive PACD reaction, was responsible for 50.9% of the positive reactions. It is a phenothiazine derivative used to treat psychotic disorders. Photoallergic contact dermatitis because of this drug has been classically described in health workers and veterinarians who become sensitized by manipulating this drug.9Y12 Sensitized persons taking the drug systemically could develop a generalized PACD.13 Analogs of CPZ are widely used in China. For example, dihydrochlorothiazide is used in a variety of compound preparations of antihypertensive drugs and serves as a diuretic. Promethazine, another phenothiazine that has been removed from the market in France with its analog chlorproethazine,14 is still widely prescribed as an antipruritic and used as an over-thecounter antipruritic cream in China. Phenothiazine therapies
TABLE 4. ACD Reactions to the Test Agents Test Agent Chlorpromazine TMS PABA Cinnamyl alcohol Thiourea Cinnamaldehyde Sulfanilamide Sandalwood oil Tetrachlorosalicylanilide Triclosan
ACD
Test Performed
n
%
3993 4331 3718 4922 4359 4929 4836 4317 3717 4905
352 23 14 6 4 4 3 1 1 1
8.82 0.53 0.38 0.12 0.09 0.08 0.06 0.02 0.03 0.02
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Gao et al ¡ PhotoPatch Testing in Chinese Population
increase with age as the incidences of hypertension, kidney disease, asteatotic eczema, and senile pruritus increase, which might explain the high PACD reaction rate in the elderly to both CPZ and the whole series, as shown in Table 3. We therefore stress the high reactivity to CPZ in our study compared with a previous study.9 Para-aminobenzoic acid, the second commonest agent with a positive rate much higher than benzophenone, was formerly a widely used sunscreen ingredient and a leading cause of sunscreen photoallergy.15 Concerns in the 1980s, regarding the allergic and photoallergic potential to PABA and its derivatives, led to a general reduction in its use. However, PABA is still used in Chinese cosmetic products and can also still be found in some sunscreen products across Europe.16 Photoallergic contact dermatitis reactions to PABA were seen in 14.7% of individuals in this study, a proportion much higher than previous studies.17 New cases of PABA allergy or photoallergy may, therefore, potentially still arise in China, United Kingdom, and elsewhere.16 A recent published case report documented the development of photocontact allergy to PABA, highlighting the need for continued vigilance.16 The PABA molecule bears structural similarities to benzocaine and p-phenylenediamine. Cross-sensitivity among these chemicals is well recognized, and relevant patients should be warned of this possibility.16 Thimerosal is the third most prominent photoallergen; of 4331 subjects, 387 (8.9%) had positive PACD reactions. It is a mercuric derivative of thiosalicylic acid and has been used as a disinfectant (eg, merthiolate) and a preservative in some vaccines, cosmetics, tattoo inks, eye drops, and contact lens solutions.18 Thus, most clinically relevant allergic reactions to TMS occur with cosmetics use or after contact with ophthalmic preparations, which results in periorbital dermatitis.19 Likewise, TMS allergy is most commonly found among women, health care workers, and cooks owing to increased cosmetic use in women and to vaccination of health care workers and cooks.20 Studies have demonstrated that TMS induces cross-sensitivity to piroxicam, a nonsteroidal antiinflammatory drug (NSAID), and that the common active component among these compounds may be thiosalicylate.21 The high prevalence of TMS sensitization in our country is a marker of piroxicam photosensitivity, which should be noted by physicians. Sulfanilamide, another medication tested, is the fourth prominent agent with 6.9% PACD reactions. Sulfonamides, along with other sulfa-derived drugs (antibacterials, hypoglycemics, and diuretics), have been well-known causes of photosensitivity reactions.22 Nevertheless, sulfonamide and other sulfa-derived drugs are still widely used in clinical practice. Sulfasalazine (salazopyrin), for instance, a popular drug used in the treatment of rheumatoid arthritis, chronic inflammatory bowel disease, and other inflammatory disease, has been reported to cause photoallergy eruptions because the loss of the 5-aminosalicylic portion of the molecule releases a 2-pyridylsulfamoyl radical, which is structurally very similar to the sulfanilamide molecule.23Y25 Dapsone (formerly diaminodiphenylsulfone), a sulfone antibacterial known for years for its antilepromatous action and currently prescribed in the treatment
25
of several noninfectious dermatoses, was identified in the 1980s as causing photosensitivity.22,26 The fact that sulfa-derived drugs are used extensively in clinical practice in China emphasizes the necessity of keeping sulfonamide in the test series of the Chinese population. With regard to the age distribution, the rate of positive PACD reaction is most frequent in the sixth and fifth decades of life, which is discordant with the European multicenter photopatch test study.2 Factors that contributed to this distribution may include the following: first, CPZ with its analogs, the most common culprit for positive PACD reactions in our population, is administered in antipruritics, antihypertensives, and diuretics, which are more frequently used in elderly individuals; second, as elderly individuals get retired in their fifth, they have more leisure time to participate in outdoor activities. The incidence of positive ACD reactions was much less frequent compared with PACD reactions, which is in concordance with that reported in Europe,2 but disagrees with other literature.3,4 Photoinhibition of ACD reactions was not uncommon in our study. The phenomenon of photoinhibition is difficult to explain but may be due to inhibition of inflammatory mediation in some individuals2 or may due to the skin-type distribution in our population. During interpretation of the test results, photoinhibition of ACD reaction was designated when reaction was at least 1 grade weaker, or absent, in the irradiated panel, whereas ACD reaction is confirmed when the same delayed crescendo reaction type to the allergen was seen in both irradiated and control panels.3 Thus, delayed crescendo reactions in the control panel alone were classified as photoinhibition of ACD in our study, which may be included in the ACD reaction group in other studies.3 This may explain the low prevalence of ACD reaction and high prevalence of photoinhibition reaction in our study. Contrasting with most published studies on PPT where organic UV absorbers and NSAIDs were reported as the most frequent photoallergens,1,2 in our population, CPZ, PABA, TMS, and sulfanilamide were the most prominent culprits for positive PACD reactions, whereas fragrances were the least prominent agents. This may, to some extent, reflect the particular characteristics of our population. Nevertheless, local patient demographics, geographic differences (prescribing habits), and patterns of exposure to allergens (the substances available and used daily) may affect the spectrum. First, topical NSAIDs are not so frequently used in China and are out of the allergen list in this study, making the evaluation of reactions to this category in Chinese population impossible. However, variations in prescribing habits of particularly the topical NSAIDs and other less reported agents might influence the results. Second, as pharmaceutical and cosmetic industries produce new agents, such as sunscreens, the pattern and incidence of PACD to specific UV filters have changed. For instance, PABA, the most frequently documented photoallergen in the 1960s, was replaced by the benzophenones in the 1980s.1 Other new UV absorbers are being introduced in sunscreen products.1 Unfortunately, no newly
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DERMATITIS, Vol 25 ¡ No 1 ¡ January/February, 2014
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introduced UV absorber listed in the European baseline series was included in our study yet. Third, well-known photoallergens, such as halogenated salicylanilides, and sulfonamides and the major tranquillizers, which have been excluded from use or largely replaced by other substances in cosmetics, pharmaceutical, and industrial products in many countries, are still in use in China and included in this study, which may result in the variation of the PACD reaction frequency. However, as international brand cosmetics and medications are flowing into China’s market, constant awareness of new allergens is needed. Nowadays, only a few hospitals in China are available for PPT. It is rather important that the use of PPT be encouraged, and new studies on the existing agents to keep the PPT panel used up to date. In conclusion, positive PACD reactions are most frequent to CPZ in our population, especially in elderly individuals, followed by PABA, TMS, and sulfanilamide. An update of our baseline allergens is urgently needed, and new allergens such as octocrylene and some regionally prescribed NSAIDs should be added to our test series.
REFERENCES 1. Foti C, Bonamonte D, Cassano N, et al. Photoallergic contact dermatitis. G Ital Dermatol Venereol 2009;144(5):515Y525. 2. A European multicentre photopatch test study. Br J Dermatol 2012;166(5): 1002Y1009. 3. Bryden AM, Moseley H, Ibbotson SH, et al. Photopatch testing of 1155 patients: results of the U.K. multicentre photopatch study group. Br J Dermatol 2006;155(4):737Y747. 4. Darvay A, White IR, Rycroft RJ, et al. Photoallergic contact dermatitis is uncommon. Br J Dermatol 2001;145(4):597Y601. 5. Bruynzeel DP, Ferguson J, Andersen K, et al. Photopatch testing: a consensus methodology for Europe. J Eur Acad Dermatol Venereol 2004;18(6): 679Y682. 6. British Photodermatology Group. Photopatch testingVmethods and indications. Br J Dermatol 1997;136(3):371Y376. 7. Wahlberg JE. Patchtesting. In: Rycroft R, Menne T, Frosch P, et al, eds. Textbook of Contact Dermatitis. 3rd ed. Berlin: Springer-Verlag and Heidelberg GmbH & Co. K.; 2001:939Y968. 8. Leonard F, Adamski H, Bonnevalle A, et al. The prospective multicenter study on standard photopatch tests by the French Society of Photodermatology from 1991Y2001. Ann Dermatol Venereol 2005;132(4):313Y320. 9. Cardoso JC, Canelas MM, Goncalo M, et al. Photopatch testing with an extended series of photoallergens: a 5-year study. Contact Dermatitis 2009;60(6):325Y329.
10. Katsarou A, Makris M, Zarafonitis G, et al. Photoallergic contact dermatitis: the 15-year experience of a tertiary reference center in a sunny Mediterranean city. Int J Immunopathol Pharmacol 2008;21(3): 725Y727. 11. Emmert B, Schauder S, Palm H, et al. Disabling work-related persistent photosensitivity following photoallergic contact dermatitis from chlorpromazine and olaquindox in a pig breeder. Ann Agric Environ Med 2007;14(2):329Y333. 12. Giomi B, Difonzo EM, Lotti L, et al. Allergic and photoallergic conditions from unusual chlorpromazine exposure: report of three cases. Int J Dermatol 2011;50(10):1276Y1278. 13. Barbaud A, Collet E, Martin S, et al. Contact sensitization to chlorproethazine can induce persistent light reaction and cross-photoreactions to other phenothiazines. Contact Dermatitis 2001;44(6):373. 14. Kerr A, Woods J, Ferguson J. Photocontact allergic and phototoxic studies of chlorproethazine. Photodermatol Photoimmunol Photomed 2008; 24(1):11Y15. 15. Dromgoole SH, Maibach HI. Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria. J Am Acad Dermatol 1990;22(6 Pt 1):1068Y1078. 16. Waters AJ, Sandhu DR, Lowe G, et al. Photocontact allergy to PABA in sunscreens: the need for continued vigilance. Contact Dermatitis 2009; 60(3):172Y173. 17. Victor FC, Cohen DE, Soter NA. A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad Dermatol 2010;62(4):605Y610. 18. Breithaupt A, Jacob SE. Thimerosal and the relevance of patch-test reactions in children. Dermatitis 2008;19(5):275Y277. 19. Herbst RA, Uter W, Pirker C, et al. Allergic and non-allergic periorbital dermatitis: patch test results of the Information Network of the Departments of Dermatology during a 5-year period. Contact Dermatitis 2004;51(1):13Y19. 20. Suneja T, Belsito DV. Thimerosal in the detection of clinically relevant allergic contact reactions. J Am Acad Dermatol 2001;45(1):23Y27. 21. Ikezawa Z, Kitamura K, Osawa J, et al. Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate. J Invest Dermatol 1992;98(6):918Y922. 22. Vassileva SG, Mateev G, Parish LC. Antimicrobial photosensitive reactions. Arch Intern Med 1998;158(18):1993Y2000. 23. Bouyssou-Gauthier ML, Bedane C, Boulinguez S, et al. Photosensitivity with sulfasalazopyridine hypersensitivity syndrome. Dermatology 1999;198(4): 388Y390. 24. Veale DJ, Ho M, Morley KD. Sulphasalazine-induced lupus in psoriatic arthritis. Br J Rheumatol 1995;34(4):383Y384. 25. Yamakado S, Yoshida Y, Yamada T, et al. Pulmonary infiltration and eosinophilia associated with sulfasalazine therapy for ulcerative colitis: a case report and review of literature. Intern Med 1992;31(1):108Y113. 26. Dhanapaul S. DDS-induced photosensitivity with reference to six case reports. Lepr Rev 1989;60(2):147Y150.
Copyright © 2014 American Contact Dermatitis Society. Unauthorized reproduction of this article is prohibited.
Retrospective Study of PhotoPatch Testing in a Chinese Population During a 7-Year Period Lujuan Gao, MD, Yue Hu, MD, Chunya Ni, MD, Yu Xu, MD, Li Ma, MD, Shuxian Yan, MD, and Xia Dou, MD Background: Photoallergic contact dermatitis (PACD) is of importance in a proportion of photodermatoses and can be evaluated through photopatch testing (PPT). Objectives: The objectives of this study were to evaluate the results of PPT and investigate the prevalence of PACD reactions to different photoallergens in Chinese patients at the Department of Dermatology of Huashan Hospital Fudan University during a 7-year period. Methods: A retrospective PPT study was conducted. During the 7 years, 4957 patients attending for investigation of suspected photodermatoses were tested according to the European consensus methodology with up to 14 allergens prepared according to Chinese National Standards. The reactions were scored using the International Contact Dermatitis Research Group visual scoring system. Results: A total of 3472 PACD reactions in 2454 subjects (49.5%) were recorded. The most common agents were chlorpromazine (44.3%), followed by para-aminobenzoic acid (14.7%), thimerosal (8.9%), and sulfanilamide (6.9%). Allergic contact dermatitis reactions comprised 409 reactions in 399 subjects (8%). Photoinhibition and photoaugmentation of allergic contact dermatitis compromised 3810 reactions in 2412 subjects and 11 reactions in 11 subjects, respectively. Irritant reactions (1928 reactions) were seen in 1140 subjects. Conclusions: The most predominant photoallergens in our region were chlorpromazine, para-aminobenzoic acid, thimerosal, and sulfanilamide, which likely reflected the particular exposures of this Chinese population.
P
hotoallergic contact dermatitis (PACD) describes the delayed, type IV hypersensitivity reaction, which occurs when an exogenous agent (photoallergen) is applied to the skin and subsequently exposed to UV and/or visible radiation.1 The incidence of PACD is unknown, but it is thought to be uncommon with frequencies of 2% to 10% reported among patients referred for investigation of photoexposed-site dermatoses.2Y4 Although PACD is probably an uncommon event, it can cause significant morbidity. The key investigation is photopatch testing (PPT), for which a European consensus methodology has existed for several years.5 However, awareness of the disease among dermatologists is low, and PPT is not widely available. To determine and understand the prevalence of PACD reaction to different photoallergens among patients presenting for investigation of suspected photodermatoses in our region of China, From the Department of Dermatology, Huashan Hospital Fudan University, Shanghai, People’s Republic of China. Address reprint requests to Xia Dou, MD, No. 12th Wulumuqi Middle Road, Jing’an District, Shanghai, 200040, People’s Republic of China. E-mail: [email protected]. L.G. and Y.H. contributed equally to this study. This study was supported by grants NSFC 30901289 from the National Natural Science Foundation of China. The authors have no conflicts to declare. DOI: 10.1097/DER.0000000000000008 * 2014 American Contact Dermatitis Society. All Rights Reserved. 22
we retrospectively evaluated the results of PPTs performed during a 7-year period.
METHODS Patients who underwent PPT for suspected photodermatoses at Huashan Hospital Fudan University (Shanghai, China) from January 1, 2006, to December 31, 2012, were identified from a clinical database. In general, patients did not undergo PPT if they had skin disease activity on the back that was too active to allow PPT, had applied topical corticosteroids to patch-test sites in the 5 days before PPT, had taken immunosuppressive medication or oral corticosteroids, or had medical conditions that could compromise the evaluation of skin responsiveness. Other photodermatoses such as porphyrias and connective tissue diseases were excluded before PPT. Patient demographics and PPT results were abstracted from the clinical database. During the study period, 4957 patients underwent PPTs with up to 14 allergens. The series of photoallergens included 14 substances, which were purchased from China Medicine (Group) Shanghai Chemical Reagent Corporation (Shanghai, China) and Sigma Corporation (NY). The test allergens were prepared according to Chinese National Standards (GB-17149.2-1997; GB-17149.6-1997) and are shown in Table 1 with associated dilution, vehicle, and chemical abstract service (CAS) number. DERMATITIS, Vol 25 ¡ No 1 ¡ January/February, 2014
Copyright © 2014 American Contact Dermatitis Society. Unauthorized reproduction of this article is prohibited.
Gao et al ¡ PhotoPatch Testing in Chinese Population
23
TABLE 1. Test Agents With Concentration and CAS Number Test Agent (Concentration, Vehicle)
as means T SD. To analyze statistically significant associations between categorical variables, the W2 test was used as appropriate.
CAS No.
CPZ (1%, water) PABA (2%, water) TMS (0.1%, petrolatum) Sulfanilamide (5%, water) Thiourea (0.1%, water) Tetrachlorosalicylanilide (0.1%, petrolatum) Cinnamaldehyde (1%, petrolatum) Limonene (2%, petrolatum) Cinnamyl alcohol (1%, petrolatum) Triclosan (2%, petrolatum) Benzophenone (1%, petrolatum) Sandalwood oil (2%, petrolatum) 6-Methyl coumarin (1%, petrolatum) Ketone musk (5%, petrolatum)
50-53-3 150-13-0 54-64-8 63-74-1 62-56-6 1154-59-2 104-55-2 5989-27-5 104-54-1 3380-34-5 119-61-9 11031-45-1 92-48-8 81-14-1
Photopatch testing was conducted according to the European consensus methodology as described previously.5 In brief, the test agents were applied using Finn Chambers on Scanpor (SmartPractice, Phoenix, AZ) in duplicate to the skin of the back and removed at 24 hours. One set was covered with a UV opaque material, and the other was then irradiated with UV-A. The UV-A dose was determined after performing a minimal erythema dose test before or on the day of patch application.6 The UV-A dose series included less than 5, 5, 7.5, and 10 J/cm2. The critical reading was performed before irradiation, immediately after irradiation, and 48 hours after irradiation. Reactions were scored using the International Contact Dermatitis Research Group (ICDRG) visual scoring system.7 All statistical analyses were carried out with SPSS version 18.0 software (SPSS Inc, Chicago, Ill). Continuous variables were shown
RESULTS From January 1, 2006, to December 31, 2012, a total of 4957 patients (3069 female and 1888 male patients) were tested. The skin phototypes included 147 type III and 4810 type IV. The average age was 43.9 T 15.7 years (range, 6Y93 years). The doses of UV-A used for irradiation were 5 J/cm2 in 368 subjects, 7.5 J/cm2 in 1852 subjects, and 10 J/cm2 in 2370 subjects, with the remaining 367 subjects receiving less than 5 J/cm2. A total of 3472 PACD reactions in 2454 subjects (49.5%) were recorded, including 981 male (51.96%) and 1473 female subjects (48%). There was a significant difference in the frequency of positive PACD reaction between male and female (P G 0.05). The number of PACD reactions recorded for each agent, with the corresponding ICDRG grade of the reactions in the irradiated set, is given in Table 2. Of these allergens, chlorpromazine (CPZ), paraaminobenzoic acid (PABA), thimerosal (TMS), and sulfanilamide most frequently elicited PACD reactions. A total of 1768 PACD reactions (44.3%) to CPZ were recorded, which was responsible for 50.9% of the documented PACD reactions (1768 in 3472 reactions). Among these reactions to CPZ, ICDRG grades were recorded ‘‘+++’’ in 2 subjects, ‘‘++’’ in 45 subjects, and ‘‘+’’ in the remaining subjects. For PABA, 546 (14.7%) PACD reactions were recorded, including 3 recorded as ‘‘++,’’ and the rest recorded as ‘‘+.’’ For TMS, 387 PACD reactions (8.9%) comprising 1 ‘‘+++,’’ 2 ‘‘++,’’ and 384 ‘‘+’’ were recorded. Photoallergic contact dermatitis reactions of sulfanilamide occurred in 333 subjects (6.9%). Photoallergic contact dermatitis reactions to thiourea (2%), tetrachlorosalicylanilide (1.9%), triclosan (0.8%), benzophenone (0.6%), and fragrance allergens were relatively infrequent. The fragrance allergens, in decreasing
TABLE 2. PACD Reactions to the Test Agents With ICDRG Grading of Reactions
Test Agents CPZ PABA TMS Sulfanilamide Thiourea Tetrachlorosalicylanilide Cinnamaldehyde Limonene Cinnamyl alcohol Triclosan Benzophenone 6-Methyl coumarin Sandalwood oil Ketone musk
ICDRG Grade of PACD Reaction in Irradiated Set
PACD
Test Performed
n
%
+
++
+++
3993 3718 4331 4836 4359 3717 4929 3564 4922 4905 4446 1471 4317 3767
1768 546 387 333 88 72 77 44 50 39 26 7 23 12
44.3 14.7 8.9 6.9 2.0 1.9 1.6 1.2 1.0 0.8 0.6 0.5 0.5 0.3
1721 543 384 330 88 71 77 43 50 38 26 7 23 11
45 3 2 3
2
1 1 1
1
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TABLE 3. Frequency of PACD Reactions by Age Group to the Test Series and CPZ Alone Subjects With at Least 1 PACD Reaction
PACD Reactions to CPZ
Subject Age, y
Total No. Subjects
n
%
No. Subjects Tested With CPZ
n
%
0Y10 11Y20 21Y30 31Y40 41Y50 51Y60 61Y70 71Y80 81Y90 91Y100 Total
2 191 1116 873 932 1089 528 193 32 1 4957
0 64 451 415 468 629 314 94 18 1 2454
0.0 33.5 40.4 47.5 50.2 57.8 59.5 48.7 56.3 100.0 49.5
1 143 839 685 735 931 460 169 29 1 3993
0 41 298 285 332 486 232 76 17 1 1768
0.0 28.7 35.5 41.6 45.2 52.2 50.4 45.0 58.6 100.0 44.3
order of frequency, were cinnamaldehyde (1.6%), limonene (1.2%), cinnamyl alcohol (1.0%), 6-methylcoumarin (0.5%), sandalwood oil (0.5%), and musk ketone (0.3%). The effect of age on the frequency of PACD reactions of the test set and CPZ was analyzed by grouping subjects into 10-year blocks, as shown in Table 3. Interestingly, the frequency of PACD reactions gradually increased with age, except among subjects 71 years or older. Analysis of PACD reaction rates to CPZ in different age blocks revealed that the top 3 decades were 80s (58.6%), 50s (52.2%), and 60s (50.4%). In comparison to PACD reactions, allergic contact dermatitis (ACD) reactions were much less frequent, with a total of 409 positive reactions recorded in 399 subjects (8%). Four of the 14 test agents did not lead to any ACD reactions, namely, benzophenone, limonene, 6-methyl coumarin, and ketone musk. The frequencies of ACD reactions reported for the remaining 11 agents are given in Table 4. The corresponding ICDRG grade recorded of the ACD reactions were all 1+. Photoaugmentation of ACD reactions was relatively uncommon, with only 11 reactions in 11 subjects. However, photoinhibition of ACD reactions was not uncommon in our study, with 3810 reactions in 2412 subjects. Among these, TMS, CPZ, and PABA were responsible for 1713, 641, and 438 reactions, respectively. A total of 1928 irritant reactions in 1140 subjects were recorded, including 533 immediate postirradiation irritant reactions in 475 subjects.
DISCUSSION Photopatch testing is an essential tool in the diagnosis of PACD. Here we describe the retrospective study of the PPT results at the Department of Dermatology, Huashan Hospital, during a 7-year period. A total of 4957 patients were included, and the skin phototype distribution represented the typical distribution found in China.
The results revealed 49.5% of subjects had at least 1 PACD reaction, which is much higher than that in the European Multicentre Photopatch Test Study, which reported a frequency of 19.4%,2 but close to that reported in a French multicenter study by Leonard et al, which included 2067 patients and reported a frequency of PACD at 39.7% to 60.0%.8 Chlorpromazine, the agent with the highest rate of positive PACD reaction, was responsible for 50.9% of the positive reactions. It is a phenothiazine derivative used to treat psychotic disorders. Photoallergic contact dermatitis because of this drug has been classically described in health workers and veterinarians who become sensitized by manipulating this drug.9Y12 Sensitized persons taking the drug systemically could develop a generalized PACD.13 Analogs of CPZ are widely used in China. For example, dihydrochlorothiazide is used in a variety of compound preparations of antihypertensive drugs and serves as a diuretic. Promethazine, another phenothiazine that has been removed from the market in France with its analog chlorproethazine,14 is still widely prescribed as an antipruritic and used as an over-thecounter antipruritic cream in China. Phenothiazine therapies
TABLE 4. ACD Reactions to the Test Agents Test Agent Chlorpromazine TMS PABA Cinnamyl alcohol Thiourea Cinnamaldehyde Sulfanilamide Sandalwood oil Tetrachlorosalicylanilide Triclosan
ACD
Test Performed
n
%
3993 4331 3718 4922 4359 4929 4836 4317 3717 4905
352 23 14 6 4 4 3 1 1 1
8.82 0.53 0.38 0.12 0.09 0.08 0.06 0.02 0.03 0.02
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Gao et al ¡ PhotoPatch Testing in Chinese Population
increase with age as the incidences of hypertension, kidney disease, asteatotic eczema, and senile pruritus increase, which might explain the high PACD reaction rate in the elderly to both CPZ and the whole series, as shown in Table 3. We therefore stress the high reactivity to CPZ in our study compared with a previous study.9 Para-aminobenzoic acid, the second commonest agent with a positive rate much higher than benzophenone, was formerly a widely used sunscreen ingredient and a leading cause of sunscreen photoallergy.15 Concerns in the 1980s, regarding the allergic and photoallergic potential to PABA and its derivatives, led to a general reduction in its use. However, PABA is still used in Chinese cosmetic products and can also still be found in some sunscreen products across Europe.16 Photoallergic contact dermatitis reactions to PABA were seen in 14.7% of individuals in this study, a proportion much higher than previous studies.17 New cases of PABA allergy or photoallergy may, therefore, potentially still arise in China, United Kingdom, and elsewhere.16 A recent published case report documented the development of photocontact allergy to PABA, highlighting the need for continued vigilance.16 The PABA molecule bears structural similarities to benzocaine and p-phenylenediamine. Cross-sensitivity among these chemicals is well recognized, and relevant patients should be warned of this possibility.16 Thimerosal is the third most prominent photoallergen; of 4331 subjects, 387 (8.9%) had positive PACD reactions. It is a mercuric derivative of thiosalicylic acid and has been used as a disinfectant (eg, merthiolate) and a preservative in some vaccines, cosmetics, tattoo inks, eye drops, and contact lens solutions.18 Thus, most clinically relevant allergic reactions to TMS occur with cosmetics use or after contact with ophthalmic preparations, which results in periorbital dermatitis.19 Likewise, TMS allergy is most commonly found among women, health care workers, and cooks owing to increased cosmetic use in women and to vaccination of health care workers and cooks.20 Studies have demonstrated that TMS induces cross-sensitivity to piroxicam, a nonsteroidal antiinflammatory drug (NSAID), and that the common active component among these compounds may be thiosalicylate.21 The high prevalence of TMS sensitization in our country is a marker of piroxicam photosensitivity, which should be noted by physicians. Sulfanilamide, another medication tested, is the fourth prominent agent with 6.9% PACD reactions. Sulfonamides, along with other sulfa-derived drugs (antibacterials, hypoglycemics, and diuretics), have been well-known causes of photosensitivity reactions.22 Nevertheless, sulfonamide and other sulfa-derived drugs are still widely used in clinical practice. Sulfasalazine (salazopyrin), for instance, a popular drug used in the treatment of rheumatoid arthritis, chronic inflammatory bowel disease, and other inflammatory disease, has been reported to cause photoallergy eruptions because the loss of the 5-aminosalicylic portion of the molecule releases a 2-pyridylsulfamoyl radical, which is structurally very similar to the sulfanilamide molecule.23Y25 Dapsone (formerly diaminodiphenylsulfone), a sulfone antibacterial known for years for its antilepromatous action and currently prescribed in the treatment
25
of several noninfectious dermatoses, was identified in the 1980s as causing photosensitivity.22,26 The fact that sulfa-derived drugs are used extensively in clinical practice in China emphasizes the necessity of keeping sulfonamide in the test series of the Chinese population. With regard to the age distribution, the rate of positive PACD reaction is most frequent in the sixth and fifth decades of life, which is discordant with the European multicenter photopatch test study.2 Factors that contributed to this distribution may include the following: first, CPZ with its analogs, the most common culprit for positive PACD reactions in our population, is administered in antipruritics, antihypertensives, and diuretics, which are more frequently used in elderly individuals; second, as elderly individuals get retired in their fifth, they have more leisure time to participate in outdoor activities. The incidence of positive ACD reactions was much less frequent compared with PACD reactions, which is in concordance with that reported in Europe,2 but disagrees with other literature.3,4 Photoinhibition of ACD reactions was not uncommon in our study. The phenomenon of photoinhibition is difficult to explain but may be due to inhibition of inflammatory mediation in some individuals2 or may due to the skin-type distribution in our population. During interpretation of the test results, photoinhibition of ACD reaction was designated when reaction was at least 1 grade weaker, or absent, in the irradiated panel, whereas ACD reaction is confirmed when the same delayed crescendo reaction type to the allergen was seen in both irradiated and control panels.3 Thus, delayed crescendo reactions in the control panel alone were classified as photoinhibition of ACD in our study, which may be included in the ACD reaction group in other studies.3 This may explain the low prevalence of ACD reaction and high prevalence of photoinhibition reaction in our study. Contrasting with most published studies on PPT where organic UV absorbers and NSAIDs were reported as the most frequent photoallergens,1,2 in our population, CPZ, PABA, TMS, and sulfanilamide were the most prominent culprits for positive PACD reactions, whereas fragrances were the least prominent agents. This may, to some extent, reflect the particular characteristics of our population. Nevertheless, local patient demographics, geographic differences (prescribing habits), and patterns of exposure to allergens (the substances available and used daily) may affect the spectrum. First, topical NSAIDs are not so frequently used in China and are out of the allergen list in this study, making the evaluation of reactions to this category in Chinese population impossible. However, variations in prescribing habits of particularly the topical NSAIDs and other less reported agents might influence the results. Second, as pharmaceutical and cosmetic industries produce new agents, such as sunscreens, the pattern and incidence of PACD to specific UV filters have changed. For instance, PABA, the most frequently documented photoallergen in the 1960s, was replaced by the benzophenones in the 1980s.1 Other new UV absorbers are being introduced in sunscreen products.1 Unfortunately, no newly
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DERMATITIS, Vol 25 ¡ No 1 ¡ January/February, 2014
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introduced UV absorber listed in the European baseline series was included in our study yet. Third, well-known photoallergens, such as halogenated salicylanilides, and sulfonamides and the major tranquillizers, which have been excluded from use or largely replaced by other substances in cosmetics, pharmaceutical, and industrial products in many countries, are still in use in China and included in this study, which may result in the variation of the PACD reaction frequency. However, as international brand cosmetics and medications are flowing into China’s market, constant awareness of new allergens is needed. Nowadays, only a few hospitals in China are available for PPT. It is rather important that the use of PPT be encouraged, and new studies on the existing agents to keep the PPT panel used up to date. In conclusion, positive PACD reactions are most frequent to CPZ in our population, especially in elderly individuals, followed by PABA, TMS, and sulfanilamide. An update of our baseline allergens is urgently needed, and new allergens such as octocrylene and some regionally prescribed NSAIDs should be added to our test series.
REFERENCES 1. Foti C, Bonamonte D, Cassano N, et al. Photoallergic contact dermatitis. G Ital Dermatol Venereol 2009;144(5):515Y525. 2. A European multicentre photopatch test study. Br J Dermatol 2012;166(5): 1002Y1009. 3. Bryden AM, Moseley H, Ibbotson SH, et al. Photopatch testing of 1155 patients: results of the U.K. multicentre photopatch study group. Br J Dermatol 2006;155(4):737Y747. 4. Darvay A, White IR, Rycroft RJ, et al. Photoallergic contact dermatitis is uncommon. Br J Dermatol 2001;145(4):597Y601. 5. Bruynzeel DP, Ferguson J, Andersen K, et al. Photopatch testing: a consensus methodology for Europe. J Eur Acad Dermatol Venereol 2004;18(6): 679Y682. 6. British Photodermatology Group. Photopatch testingVmethods and indications. Br J Dermatol 1997;136(3):371Y376. 7. Wahlberg JE. Patchtesting. In: Rycroft R, Menne T, Frosch P, et al, eds. Textbook of Contact Dermatitis. 3rd ed. Berlin: Springer-Verlag and Heidelberg GmbH & Co. K.; 2001:939Y968. 8. Leonard F, Adamski H, Bonnevalle A, et al. The prospective multicenter study on standard photopatch tests by the French Society of Photodermatology from 1991Y2001. Ann Dermatol Venereol 2005;132(4):313Y320. 9. Cardoso JC, Canelas MM, Goncalo M, et al. Photopatch testing with an extended series of photoallergens: a 5-year study. Contact Dermatitis 2009;60(6):325Y329.
10. Katsarou A, Makris M, Zarafonitis G, et al. Photoallergic contact dermatitis: the 15-year experience of a tertiary reference center in a sunny Mediterranean city. Int J Immunopathol Pharmacol 2008;21(3): 725Y727. 11. Emmert B, Schauder S, Palm H, et al. Disabling work-related persistent photosensitivity following photoallergic contact dermatitis from chlorpromazine and olaquindox in a pig breeder. Ann Agric Environ Med 2007;14(2):329Y333. 12. Giomi B, Difonzo EM, Lotti L, et al. Allergic and photoallergic conditions from unusual chlorpromazine exposure: report of three cases. Int J Dermatol 2011;50(10):1276Y1278. 13. Barbaud A, Collet E, Martin S, et al. Contact sensitization to chlorproethazine can induce persistent light reaction and cross-photoreactions to other phenothiazines. Contact Dermatitis 2001;44(6):373. 14. Kerr A, Woods J, Ferguson J. Photocontact allergic and phototoxic studies of chlorproethazine. Photodermatol Photoimmunol Photomed 2008; 24(1):11Y15. 15. Dromgoole SH, Maibach HI. Sunscreening agent intolerance: contact and photocontact sensitization and contact urticaria. J Am Acad Dermatol 1990;22(6 Pt 1):1068Y1078. 16. Waters AJ, Sandhu DR, Lowe G, et al. Photocontact allergy to PABA in sunscreens: the need for continued vigilance. Contact Dermatitis 2009; 60(3):172Y173. 17. Victor FC, Cohen DE, Soter NA. A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad Dermatol 2010;62(4):605Y610. 18. Breithaupt A, Jacob SE. Thimerosal and the relevance of patch-test reactions in children. Dermatitis 2008;19(5):275Y277. 19. Herbst RA, Uter W, Pirker C, et al. Allergic and non-allergic periorbital dermatitis: patch test results of the Information Network of the Departments of Dermatology during a 5-year period. Contact Dermatitis 2004;51(1):13Y19. 20. Suneja T, Belsito DV. Thimerosal in the detection of clinically relevant allergic contact reactions. J Am Acad Dermatol 2001;45(1):23Y27. 21. Ikezawa Z, Kitamura K, Osawa J, et al. Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate. J Invest Dermatol 1992;98(6):918Y922. 22. Vassileva SG, Mateev G, Parish LC. Antimicrobial photosensitive reactions. Arch Intern Med 1998;158(18):1993Y2000. 23. Bouyssou-Gauthier ML, Bedane C, Boulinguez S, et al. Photosensitivity with sulfasalazopyridine hypersensitivity syndrome. Dermatology 1999;198(4): 388Y390. 24. Veale DJ, Ho M, Morley KD. Sulphasalazine-induced lupus in psoriatic arthritis. Br J Rheumatol 1995;34(4):383Y384. 25. Yamakado S, Yoshida Y, Yamada T, et al. Pulmonary infiltration and eosinophilia associated with sulfasalazine therapy for ulcerative colitis: a case report and review of literature. Intern Med 1992;31(1):108Y113. 26. Dhanapaul S. DDS-induced photosensitivity with reference to six case reports. Lepr Rev 1989;60(2):147Y150.
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