Level of use and safety of botanical products for itching vulvar dermatoses. Are patch tests useful?

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1 Contact Dermatitis Original Article COD Contact Dermatitis Level of use and safety of botanical products for itching vulvar dermatoses. Are patch tests useful? Monica Corazza, Annarosa Virgili, Giulia Toni, Sara Minghetti, Silvia Tiengo and Alessandro Borghi Dipartimento di Scienze Mediche Sezione di Dermatologia e Malattie Infettive, University of Ferrara, Ferrara, Italy doi: /cod Summary Background. Topical remedies based on botanical ingredients are popular. Objectives. To assess: (i) the usage of botanical substances in subjects affected with itching and chronic vulvar complaints; (ii) the incidence of side-effects associated with their use and the frequency of contact allergy; (iii) the diagnostic usefulness of patch testing. Methods. Sixty-six patients were provided with a questionnaire to assess the prevalence and type of topical botanical preparations used and the occurrence of adverse reactions. Patients were patch tested with (i) the Italian baseline series, (ii) a topical medicament series, and (iii) a botanical series. Results. Forty-two patients (63.6%) reported the use of natural topical products on the vulva. Seven (16.7%) noted adverse reactions; 27 showed positive reactions with the baseline series; 14 (21.2%) had at least one relevant reaction, mainly to allergens in topical products and cosmetics; and 2 (3%) showed positive reactions to the botanical series. Of the 7 patients complaining of adverse effects of botanical products, 3 (42.8%) showed relevant sensitization. Conclusions. The use of natural topical products is widespread among women affected with itching vulvar diseases. Contact dermatitis is a possible adverse effect. Botanical series are of questionable usefulness, owing to the wide variety of botanical ingredients. Key words: botanical products; contact dermatitis; patch test; vulvar diseases. In recent years, the demand for topical products containing botanical extracts has increased, owing to their pleasing fragrance, purported therapeutic properties, and the widespread perception that these products are safer than their synthetic counterparts (1 4). A number of active herbal principles are used both in many cosmetic formulations and in curative topical products. Correspondence: Monica Corazza, Dipartimento di Scienze Mediche, Sezione di Dermatologia e Malattie Infettive, Università di Ferrara, via L. Ariosto 35, Ferrara, Italy. Tel: /205825; Fax: / czm@unife.it Conflicts of interest: The authors declare no conflict of interests. Despite the popular belief in their harmlessness, several cases of adverse reactions to plant extracts have been reported, in particular cutaneous side-effects such as allergic contact dermatitis, irritant contact dermatitis, phototoxic reactions, and contact urticaria (5 10). The aim of the present study was to assess the level of use of topical products containing herbal components in patients affected with itching vulvar inflammatory diseases, the reasons behind the choice of these non-conventional treatments, and the perceived safety of such remedies. The frequency of true contact allergy to topical natural products and the diagnostic usefulness of patch testing with both the baseline series and a specifically prepared botanical series were also assessed. Accepted for publication 24 January 2016 Contact Dermatitis, 74,

2 Materials and Methods The study population consisted of all outpatients aged >18 years consecutively presenting with itching vulvar inflammatory diseases in our department between September 2014 and April The patients included in the present observational study had received a clinical and, when available, histological diagnosis by us, and were either receiving treatment at the time of inclusion or had undergone previous treatments for their vulvar dermatoses. The vulvar diseases included were lichen sclerosus, lichen simplex chronicus, lichen planus, plasma cell vulvitis, psoriasis, vulvar itching without identified cause, and recurrent vulvovaginal candidiasis. Women completed a self-administered questionnaire composed of two sections. The first section included items addressing the following: demographics; the use of topically applied botanical preparations (regular or occasional use; cosmetic and/or therapeutic aim) on the vulva; the reasons for choosing natural products; the characteristics of the treatment employed [formulation; natural active principle(s); perception of efficacy and tolerability]; adverse reactions [skin signs and symptoms; presumed causative compound(s)]. All of the included patients were patch tested with an extended Società Italiana Dermatologia Allergologica Professionale ed Ambientale (SIDAPA) baseline series (Lofarma, Milano, Italy) and two supplementary series: (i) a topical medicament series (FIRMA, Firenze, Italy), and (ii) a botanical series (FIRMA) (Table 1). When possible, the patients own products (ointments, creams, and oils) were also patch tested. Patients were excluded from the study in the presence of: no previous topical treatments for their vulvar disease; pregnancy or breastfeeding; refusal or inability to complete the questionnaire; and light exposure, application of topical corticosteroids to patch test sites or systemic treatment with immunosuppressive drugs during the 2 weeks before enrolment. Patch tests were performed with Finn Chambers (diameter 8 mm; SmartPractice, Phoenix, AZ, USA) on Scanpor tape (Norgesplaster, Vennesla, Norway); allergens were applied on the upper back, and removed after 2 days. The sites were examined on removal and on day (D)3 and D4, according to ICDRG guidelines (11). Reactions were interpreted as relevant on the basis of the identification of the allergen in a topical product or of a highly suggestive history of cutaneous adverse events after contact with topical products containing the allergen. Table 1. Allergens in the supplementary (a) drug series and (b) botanical series, with the concentrations and vehicles used for patch testing Allergen (a) Tetracaine hydrochloride Quinoline mix Clotrimazole Lidocaine Econazole nitrate Tocopherol (vitamin E) (b) Melaleuca alternifolia extract Compositae mix Aloe vera Peppermint oil Arnica montana extract Sesquiterpene lactone mix Achillea millefolium extract Results Concentration and vehicle 2% pet. 6% pet. 10% pet. 20% pet. 5% pet. 5% pet. 5% pet. 0.5% pet. 0. A total of 66 patients (mean age 59.4 ± 14.6 years) were enrolled in the study. The demographic and clinical characteristics of the enrolled population are shown in Table 2. Twenty-four patients (36.4%) denied using herbal remedies on their vulva. Of the 42 users of the natural products (63.6% of the study population), 7 (16.7% of users) reported use on a regular basis, and 35 (83.3%) sporadic use. The motivations for use were found to be as follows: perceived safety of botanical products with respect to synthetic preparations, 27 (64.3% of users); curiosity, 9 (21.4%); and search for an alternative treatment because conventional therapies had failed, 6 (14.3%). No patients reported mistrust of traditional topical products or the exclusive use of natural products. Overall, 71 herbal products for genital use were identified by the patients. The products used that contained botanical compounds were, in decreasing order: cleansers (30; 42.2% of the total); creams (21; 29.6%); vaginal suppositories and vaginal plugs (18; 25.3%); and perfumes and deodorants (2; 2.8%). Creams and vaginal suppositories and plugs were used mainly for therapeutic purposes. The natural active principles present in the used products are shown in Table 3. A total of 27 patients (64.3% of users) considered the botanical products to be well tolerated and efficacious; 7 (16.7%) considered them to be well tolerated, but with doubtful efficacy; 1 (2.4%) considered them to be inefficacious; 7 patients (16.7%) referred to cutaneous and/or mucosal adverse reactions resulting from botanical product application. The reported adverse effects 290 Contact Dermatitis, 74,

3 Table 2. Demographic and clinical data of the study population Vulvar diseases Previous topical therapies used for anogenital diseases Unspecified number (%) Anaesthetics, Sex hormones, Antibiotics, Antihaemorrhoidal, Antimycotics, Corticosteroids, RVC, n (%) VI, n (%) PCV, Psoriasis, Mean duration of vulvar disease (months), range(sd) LS, LSC, LP, Mean age (years), range (SD) Number of patients (%) 42 (63.6) 13 (19.7) 1 (1.5) 1 (1.5) 1 (1.5) 6 (9.1) 2 (3.0) 50 (75.8) 27 (40.9) 24 (36.4) 21 (31.8) 13 (19.7) 9 (13.6) 7 (10.6) 50.1 [3 240] (56.5) 66 (100) 59.4 [21 86] (14.6) LS, lichen sclerosus; LSC, lichen simplex chronicus; LP, lichen planus; PCV, plasma cell vulvitis; RVC, recurrent vulvovaginal candidiasis; SD, standard deviation; VI, vulvar itching with unidentified cause. As patients could have undergone multiple treatments, the total of treatments was greater than the number of patients enrolled in the study. Table 3. Botanical active principles contained in topical products used by the study subjects Botanical topical products Number (%) Chamomile 22 (25) Aloe vera 12 (13.63) Calendula officinalis 12 (13.63) Arnica montana 8 (9.09) Mallow (Malva sylvestris) 4 (4.54) Tocopherol (vitamin E) 4 (4.54) Centella asiatica 3 (3.40) Propolis 2 (2.27) Almond oil 1 (1.13) Avocado 1 (1.13) Bergamot (Citrus bergamia) 1 (1.13) Cocoa butter 1 (1.13) Coconut oil 1 (1.13) Corn oil 1 (1.13) Echinacea purpurea 1 (1.13) Hypericum perforatum 1 (1.13) Liquorice 1 (1.13) Limonene 1 (1.13) Olive oil 1 (1.13) Rice starch 1 (1.13) Shea butter 1 (1.13) Soy 1 (1.13) Soy-isoflavone 1 (1.13) Tilia (lime) 1 (1.13) Verbena officinalis (dragon s claw) 1 (1.13) Not known/not remembered by patients 4 (4.54) Total 88 (100) were described as worsening of the clinical features of pre-existing dermatitis (2 patients), or worsening and/or occurrence of cutaneous symptoms and/or signs such as itching (7 cases), burning 6, erythema 3, swelling, and vesiculation 1. Some patients reported more than one adverse effect. All 7 patients with adverse effects discontinued the use of botanical products. Overall, 13 patients (19.7%) referred to local adverse effects resulting from application of topical products on the vulva; in addition to the 7 patients with adverse effects caused by botanical products, 10 patients referred to adverse effects of topical drugs. Four patients referred to local reactions to both drugs and botanical products. All of the study patients underwent patch testing with the SIDAPA and the supplementary series. A total of 47 positive reactions were observed in 27 patients (40.9%). Of the 47 positive reactions, 23 were considered to be relevant; 14 patients (21.2%) had at least one relevant reaction. Table 4 shows the positive reactions in detail. The most frequent allergens found to be positive in the SIDAPA series were nickel sulfate (11 reactions), fragrance mix Contact Dermatitis, 74,

4 I(5), Myroxylon pereirae resin (5), methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) (4), and fragrance mix II (3). Concerning the supplementary topical medicament series, three positive reactions were found: two to tetracaine hydrochloride and one to quinoline mix. Three further patients reacted to corticosteroids included in the extended SIDAPA series. Two patients showed positive reactions to the botanical series, namely to Arnica montana and Compositae mix, respectively. All positive reactions to the supplementary series were considered to be relevant. Five patients were tested with their own products. One positive reaction (cream containing vitamin E) was detected, and judged to be relevant. Regarding the occurrence of relevant positive reactions in relation to the vulvar disease duration, we found that the risk of having at least one relevant sensitization among the patients with diseases that had lasted for >24 months was higher than in the patients whose disease had started more recently (odds ratio 5.87, 95%CI: , p = 0.041, Fisher s exact test). Regarding the occurrence of relevant sensitization related to vulvar disease, namely comparing patients affected with vulvar lichen sclerosus (42 subjects) with those affected with other diseases (24, of whom 13 were affected with lichen simplex chronicus), we did not find any difference (odds ratio 1.04, 95%CI: , p = 0.9, Fisher s exact test). Discussion The findings of the present study highlight the popularity of topical preparations containing botanical extracts among women affected with itching chronic vulvar diseases, as >60% of the patients questioned used natural topical products on their vulva. This percentage was higher than those found in previous observational studies (12 14). Cleansers were the most widely used topical herbal preparations, although creams and vaginal suppositories and plugs were also popular. The perception that herbal remedies are safer than synthetic alternatives was found to be the main reason for choosing natural products for the care of inflammatory vulvar disorders. This suggests that natural products are considered to be particularly suitable for this sensitive site. Indeed, the barrier function of vulvar skin is substantially weaker than that at other anatomical sites, and vulvar skin has been shown to react more intensely to irritants than other skin areas (15). Moreover, as compared with other areas, vulvar skin is exposed to many irritants, including occlusion, friction, sweating, vaginal secretions, and urine, which increase the susceptibility of the skin to contact dermatitis (16, 17). In subjects with chronic inflammatory diseases, the underlying conditions further enhance the degree of irritation. In addition, in the post-menopausal population, owing to the drop in oestrogen leading to tissue atrophy and decreased elasticity, the vulvar tissue becomes increasingly sensitive to injury (18). In the study population, the most widely used medicinal plants were chamomile, Aloe vera, and Calendula officinalis, but the list of botanical active principles is quite long (Table 3). Botanical compounds were judged to be both efficacious and well tolerated by the great majority of patients using these products. However, in spite of this belief, 16.7% of users referred one or more adverse mucosal and/or cutaneous reactions to herbal products. This percentage was higher than previously observed (12 14). The reported adverse effects were described mainly as the occurrence or worsening of distressing symptoms, mainly itching and burning. Erythema, swelling and vesiculation were also reported. Adverse effects led to herbal product discontinuation in all cases. In our study population, 41% of patients had one or more positive patch test reactions, which is generally in keeping with previous studies on vulvar contact dermatitis (15, 16, 19 21). However, only approximately half of the positive reactions were recognized as being clinically relevant. In the literature, the percentages of relevant reactions in patients with vulvar disorders range from 26% to 73% (22 24). Thus, our percentage was a little lower than those previously reported. Notably, we found that the risk of having at least one relevant sensitization was directly related to disease duration, but not to the underlying inflammatory disease. It can be supposed that disease duration can determine either progressive barrier function impairment at the vulvar level or protracted application of topical products, increasing the risk of contact dermatitis, or both. As reported by previous studies, nickel sulfate was found to be the most frequently positive allergen in this study, even though most of these positive reactions were considered not to be relevant (19, 24). With respect to the frequency of sensitization to the allergens typically found in cosmetics and topical medicaments and included in the SIDAPA series, such as fragrance mix, MCI/MI, M. pereirae, formaldehyde, paraben mix, hydroxyisohexyl 3-cyclohexene carboxaldehyde, colophonium, and lanolin alcohols, 25% of patients showed relevant positive sensitization. Sensitization to topical anaesthetics was found in 3% of our patients, in disagreement with data from the literature indicating that these molecules are the most frequent culprits in allergic contact dermatitis of the vulva (15, 17, 21, 25, 26). Sensitization to topical corticosteroids occurred in 4.5% of our patients, in line with previous reports (15, 19), even though, in other 292 Contact Dermatitis, 74,

5 Table 4. Positive reactions to the allergens of the SIDAPA series, integrative topical medicament series and integrative botanical series in the study population Patient no. Allergens of the SIDAPA series Allergens of the topical medicament series Allergens of the botanical series 4 Fragrance mix II 14% (R) 5 Myroxylon pereirae resin (R) 12 Nickel sulfate 5% 17 Nickel sulfate 5% 19 Nickel sulfate 5%, Myroxylon pereirae resin (R) 25 Nickel sulfate 5% 26 Nickel sulfate 5%, Myroxylon pereirae resin (R) 30 Fragrance mix II 14% 33 Fragrance mix I 8% (R), MCI/MI 0.01% (R) 38 Cocamidopropyl betaine 1% (R) Arnica montana 0.5% (R) 40 Myroxylon pereirae resin (R), MCI/MI 0.01% (R), Compositae mix 6% (R) methyldibromo glutaronitrile 0.3% 41 Nickel sulfate 5% 46 Quinoline mix 6% (R) 48 Tetracaine hydrochloride 2% (R) 49 Potassium dichromate 0.5%, MCI/MI 0.01% 50 Cocamidopropyl betaine 1% (R), fragrance mix I 8% (R) 51 Potassium dichromate 0.5% 53 Nickel sulfate 5% 54 Myroxylon pereirae resin, MCI/MI 0.01%, methyldibromo glutaronitrile 0.3% 56 Budesonide 0.01% (R), corticosteroid mix 2.1% (R), Quaternium-15 1% (R) 57 Nickel sulfate 5% 58 Hydrocortisone 21 acetate 1% (R) 60 Formaldehyde 1% (R), nickel sulfate 5% (R), cobalt chloride 1% 61 Fragrance mix I 8%, nickel sulfate 5% 62 Fragrance mix I 8% 63 Fragrance mix I 8%, fragrance mix II 14% (R), hydroxyisohexyl 3-cyclohexene carboxaldehyde 5% 65 Nickel sulfate 5%, cobalt chloride 1% Tetracaine hydrochloride 2% (R) MCI/MI, methylchloroisothiazolinone/methylisothiazolinone (3:1 mixture); R, relevant positivity. The reported numbers correspond to the consecutive ones given to the patients at enrolment. series, positive patch test rates as high as 10% have been reported (25). It is of interest that, among the 7 patients reporting cutaneous side-effects of botanical products, 4 (57.1%) showed at least one positive reaction, of whom 3 (42.8%) showed relevant sensitization. When the patients were tested with the botanical series as well, only two relevant positive reactions (28.7%) were found. Thus, a considerable proportion of the patients referring to cutaneous side-effects of natural products were not sensitized to natural active principles. This result may be explained in several ways. First, cosmetic ingredients, such as fragrances and preservatives, may be the main responsible allergens rather than plant ingredients as such (23). On the other hand, some of the cutaneous side-effects reported by our patients may not really be allergic dermatitis, but irritant dermatitis or worsening of the pre-existing inflammatory disorder resulting from contact with the natural products (15). Finally, it could be supposed that, as only a limited number of standardized botanical allergens are commercially available, they cannot be representative of the wide variety of botanical ingredients found in natural cosmetics. Moreover, as botanical extracts may greatly vary in composition, owing to origin and extraction, preservation and storage procedures, the commercial botanical allergens might be not representative of the actual sensitizing molecules. As a consequence, numerous cases of contact allergy may go unrecognized. The results reported herein should be viewed in the light of the limitations of the study. Both skin symptoms and causal relationships between exposure to herbal preparations and adverse skin reactions were retrospectively self-reported, and not corroborated by clinical Contact Dermatitis, 74,

6 assessment by a dermatologist. Because of the retrospective design of our analysis, we could not consider the clinical pattern of the skin reactions. As the natural products and herbal compounds used by the study patients were also self-reported, a memory bias in collecting data cannot be excluded. Possible risk factors for contact dermatitis, such as atopic background and previous, documented skin sensitization, were not investigated in our population. In spite of these limitations, this is the first study to specifically address both the level of use of topical products containing herbal components in the care of inflammatory vulvar diseases and the frequency of sensitization to such compounds. On the basis of our findings, there is widespread use of natural products among subjects affected with itching vulvar complaints. Despite their presumed harmlessness, natural products can cause contact dermatitis and adverse skin reactions at the vulvar level. Our results also suggest that the botanical integrative series may be of questionable diagnostic usefulness, as it scarcely improves the diagnostic accuracy of patch testing with standard series. Acknowledgements The authors would like to thank Ms Silvia Giari and Chiara Casaro for data management and technical assistance. References 1 Bedi M K, Shenefelt P D. Herbal therapy in dermatology. Arch Dermatol 2002: 138: Reuter J, Merfort I, Schempp C M. Botanicals in dermatology: an evidence-based review. Am J Clin Dermatol 2010: 11: Aburjai T, Natsheh F D. Plants used in cosmetics.phytother Res 2003: 17: Baumann L. Botanical ingredients in cosmeceuticals.j Drugs Dermatol 2007: 6: Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000: 143: Bruynzeel D P, Van Ketel W G, Young E et al. Contact sensitization by alternative medical medications containing plant extracts. The Dutch Contact Dermatoses Group. Contact Dermatitis 1992: 27: Aberer W. Contact allergy and medicinal herbs. J Dtsch Dermatol Ges 2008: 6: Niggemann B, Grüber C. Side-effects of complementary and alternative medicine. Allergy 2003: 58: Thomson K F, Wilkinson S M. Allergic contact dermatitis to plant extracts in patients with cosmetic dermatitis. Br J Dermatol 2000: 142: Simpson E L, Law S V, Storrs F J. Prevalence of botanical extract allergy in patients with contact dermatitis. Dermatitis 2004: 15: Wilkinson D S, Fregert S, Magnussen B et al. Terminology of contact dermatitis. Acta Derm Venereol 1970: 50: Corazza M, Borghi A, Lauriola M M, Virgili A. Use of topical herbal remedies and cosmetics: a questionnaire-based investigation in dermatology out-patients. J Eur Acad Dermatol Venereol 2009: 23: Corazza M, Borghi A, Gallo R et al. Topical botanically derived products: use, skin reactions, and usefulness of patch tests. A multicentre Italian study. Contact Dermatitis 2014: 70: Ventura M T, Viola M, Calogiuri G et al. Hypersensitivity reactions to complementary and alternative medicine products. Curr Pharm Desi 2006: 12: Margesson L J. Contact dermatitis of the vulva. Dermatol Ther 2004: 17: Al-Niaimi F, Felton S, Williams J. Patch testing for vulval symptoms: our experience with 282 patients. Clin Exp Dermatol 2014: 39: Bauer A, Rödiger C, Greif C et al. Vulvar dermatoses irritant and allergic contact dermatitis of the vulva. Dermatology 2005: 210: Summers P R, Hunn J. Unique dermatologic aspects of the postmenopausal vulva. Clin Obstet Gynecol 2007: 50: Marren P, Wojnarowska F, Powell S. Allergic contact dermatitis and vulvar dermatoses. Br J Dermatol 1992: 126: Utaş S, Ferahbaş A, Yildiz S. Patients with vulval pruritus: patch test results. Contact Dermatitis 2008: 58: Lewis F M, Shah M, Gawkrodger D J. Contact sensitivity in pruritus vulvae: patch test results and clinical outcome. Am J Contact Dermat 1997: 8: Nunns D, Ferguson J, Beck M, Mandal D. Is patch testing necessary in vulval vestibulitis?contact Dermatitis 1997: 37: Haverhoek E, Reid C, Gordon L et al. Prospective study of patch testing in patients with vulval pruritus. Australas J Dermatol 2008: 49: Lucke T W, Fleming C J, McHenry P, Lever R. Patch testing in vulvar dermatoses: how relevant is nickel? Contact Dermatitis 1998: 38: Warshaw E M, Furda L M, Maibach H I et al. Anogenital dermatitis in patients referred for patch testing. Retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group, Arch Dermatol 2008: 144: Warshaw E M, Schram S E, Belsito D V et al. Patch-test reactions to topical anesthetics: retrospective analysis of cross-sectional data, 2001 to Dermatitis 2008: 19: Contact Dermatitis, 74,