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Photoallergic Contact Dermatitis
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Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of The Dermatologist or HMP Global, their employees, and affiliates.
Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction that occurs following cutaneous exposure to an allergen to which an individual has been previously sensitized. ACD allergens are small molecules that trigger memory T cells to mount an immune response, resulting in an eczematous rash on the exposed skin.1 Photoallergic contact dermatitis (PACD) is a subset of ACD in which an allergen causes a delayed-type hypersensitivity reaction following ultraviolet (UV) exposure. As in ACD, this occurs with subsequent exposure to the allergen in the presence of sunlight, most often the UVA action spectrum.1 This reaction is differentiated from phototoxicity wherein sunlight causes direct cellular damage due to topical or systemic agents. Phototoxicity does not require sensitization.1
The exact mechanism of the photochemical reaction that produces PACD is poorly understood. In general, photo allergen-specific chromophores, or molecules that can absorb light, become excited into an unstable state when irradiated. Energy released as this molecule returns to its ground state may cause covalent binding to carrier proteins and production of a secondary antigen, which then goes on to induce the type IV hypersensitivity reaction. An alternative proposed mechanism suggests exposure to light promotes the formation of a stable hapten that binds with a carrier protein to produce a complete antigen. Once the complete antigen is formed, the mechanism is similar to ACD, with Langerhans cells in the epidermis processing and presenting the antigen to T lymphocytes in lymph nodes. Activated T cells circulate to the skin, whereby they recognize the photo allergen in sunexposed areas and produce a hypersensitivity reaction.2-5
This haptenization and resulting protein modification may in turn cause significant changes to molecular structure and loss of the original biologic function of the molecule.4,5 Further, specific serum components have been implicated as carrier proteins in certain photoallergic reactions, such as in allergy to quinidine sulfate.6
Presentation
PACD presents as an eczematous rash with the same clinical and histopathologic features as ACD. However, the lesions are generally limited to sun-exposed areas that have also been exposed to a photo allergen: the face, neck, upper chest (classically a U- or V-shaped area corresponding to shirt necklines), dorsal hands and forearms, and legs.2,7 Unilateral PACD may be seen if a photo allergen was applied to only 1 body site. Ectopic dermatitis is also possible via transfer by the hands, crossing the legs, or contacting another individual (connubial ACD).2 Realistically, lesions may spread to adjacent nonexposed areas, although the most severe lesions are in areas of sun exposure.
The main differential diagnoses for PACD are airborne ACD and phototoxic reactions. A clue that may point to PACD and away from airborne ACD or alternative diagnoses is relative sparing of the anatomically shadowed areas of the face, such as above and below the eye, the philtrum, the retro-auricular and submandibular regions, and areas covered by hair.2,8 The nose should be affected in PACD as it is a prominent area that absorbs UV radiation, whereas in airborne ACD, the nose may be spared in what is called the “beak sign.”9 Photoallergic reactions peak in severity around 72 hours post UV exposure. Inquiring about direct and indirect exposure to light is important, including tanning beds, direct sun, and through windows in cars and airplanes.7
As in ACD, PACD may present as acute, subacute, or chronic dermatitis.2 Severe pruritus is often associated.7 Rare features of PACD include systemic reactions, such as fever, rigors, diarrhea, and liver dysfunction. Erythema multiforme-like eruption, leukomelanoderma, and lichenoid photosensitive eruption have also been reported. Additionally, urticarial reactions and purpuric lesions have been reported in the case of PACD due to the nonsteroidal anti-inflammatory drugs (NSAID) ketoprofen.2
Diagnostics
A biopsy is often helpful as a preliminary step to rule out noneczematous conditions.8 Biopsies of PACD, as in ACD, show epidermal spongiosis, perivascular lymphohistiocytic infiltrate with eosinophils, dilation of dermal vessels, and papillary edema. In the chronic form of the disease, these findings will be accompanied by dermal thickening and hyperkeratosis.7
The first step in pursuing a workup for PACD is to evaluate the patient for objective photosensitivity. This is done by performing minimal erythema dose (MED) testing. During MED testing, incremental doses of UV radiation are applied to a photo protected area of the skin—usually the buttocks if photopatch testing will also be performed.8 MED refers to the minimum amount of UV exposure that produces appreciable erythema over the testing area 24 hours after irradiation.10 MED testing should be performed with both UVA and UVB, as the patient may be sensitive to a specific action spectrum. UVA is a longer wavelength that penetrates the dermis, whereas UVB is a shorter wavelength that causes damage primarily to the epidermis. A normal MED for UVA is generally thought to be greater than 20 J/cm², with a MED less than 10 J/cm² considered to be abnormal. MED-UVA is on average ~33 J/cm² and a more conservative value of less than ~27 J/cm² may suggest photosensitivity.11 MED for UVA radiation does not vary by skin type. For UVB, factors such as skin pigmentation and thickness produce variations in individuals’ MED11 and, thus, what constitutes an atypical MED-UVB varies based on Fitzpatrick skin type (Table). Certain disease states and medications may also make a patient more photosensitive.
If the patient is photosensitive, nonallergic photodermatoses should be considered and photopatch testing may no longer be necessary. However, if the MED is normal and/or PACD is still in question, the clinician can proceed with photopatch testing. As in patch testing for general ACD, photo allergens in a vehicle substance (most often petroleum) are applied to the skin in a small amount by way of plastic or metal chambers with low chemical reactivity. Differing from traditional patch testing, duplicate sets of photo allergens are applied. This is in anticipation of the 24-hour time point when one set of patches is irradiated with UVA light while the other set is kept covered and photo protected.
The light source used in patch testing for PACD is typically UVA only, as most photo allergens are created by light in the UVA action spectrum. However, more reactions are elicited with UVA and UVB testing compared to UVA alone.12 Additionally, some photosensitizers are made allergenic solely by UVB,12 such as sulfanilamide and diphenhydramine.13,14 PACD to sunscreens, specifically those filters that absorb UVB, may be associated with UVB radiation.12 Thus, some photoallergic reactions could be missed with UVA testing alone. However, using UVB is controversial, as the dose required to produce PACD with UVB light often exceeds the MED and, thus, a “reaction” on photo testing may be solely UVB-mediated cutaneous damage.15-17
Knowing a patient’s MED is quite important in the context of PACD patch testing, especially if the clinician plans to irradiate with UVB. If a patient is photosensitive during MED testing, then 2.5 J/ cm² (or lower if needed) of UVA should be administered. Conversely, if the patient is not photosensitive, then typically 5 to 10 J/cm² of UVA is administered.18 Another rule of thumb is to use a dose of UVA that is equal to the MED minus 1 J/cm² if the MED-UVA is less than 10 J/cm². Forty-eight hours after placement, both sets of patches are then removed and read using a standard grading scale.
One challenge regarding photopatch testing is considerable variability between clinicians, clinics, and location. Methodology may differ regarding irradiation wavelengths, UVA dosage, and time between readings. Some attempts at standardization have been made, most recently with pan-European consensus methodology published by the European Society of Contact Dermatitis.19 In this protocol, agents are applied for 24 or 48 hours and subsequently irradiated with 5 J/cm² with PUVA tube lights. Readings then occur at 24, 48, and, if possible, 72 hours.19 The final reading occurs for both sets of patches 96 hours after placement.7,8
Photoallergens
Sunscreens are among the most common photosensitizing agents, specifically organic UV filters otherwise known as chemical sunscreens. Organic UV filters were first introduced in the 1930s and marketed as “tanning” products to protect from UVB radiation. The original filters included salicylates, para-amino benzoic acid (PABA), and phenylbenzimidazole sulfonic acid.20 As the harmful effects of UVA became known, UVA filters were developed, such as benzophenones and dibenzoylmethanes. Since then, with growing evidence of photocarcinogenesis and demand for cosmetically elegant sunscreens, there has been a continued drive to develop more organic UV filters. Reports of PACD tend to emerge after a lag time during which a new filter has been on the market.8 One of the first reports of PACD was to PABA, which has since been removed from the market due to safety concerns.21 Similarly, isopropyl dibenzoylmethane is banned in the United States and Europe.8
In the most recent North American Contact Dermatitis Group (NACDG) report of photopatch testing results from 1999 to 2009, sunscreens produced the majority of photocontact reactions, most commonly benzophenones followed by avobenzone.22 Benzophenones are also the most commonly reported cause of ACD due to sunscreen.23 Benzophenones are common in many other personal care products, including shampoos, conditioners, styling products, and hand sanitizers.24 Interestingly, PACD to benzophenones used in printing ink on magazine covers has been reported.25 There have been no reports of PACD or ACD to physical sunscreen filters (zinc oxide or titanium dioxide), making these a safe alternative for individuals with PACD due to sunscreens.26
Topical NSAIDs are another common cause of PACD. These medications are typically used for musculoskeletal relief due to their anti-inflammatory and analgesic properties. Although it is a less commonly used NSAID, ketoprofen is a frequent cause of PACD. Ketoprofen contaminates clothing or shoes, which may contribute to persistent dermatitis,27 and may not elicit a reaction at the original application site but rather produce a reaction on both exposed and nonexposed areas with subsequent sun exposure.2 In the United States, diclofenac is the only topical NSAID available over the counter. There have been multiple reported cases of PACD due to diclofenac.28-30 Ketoprofen also cross-reacts with benzophenone-like UV filters (oxybenzone, octocrylene), as well as fenofibrate,31,32 offering a potential explanation for a patient with a nonclinically relevant photopatch reaction to ketoprofen.
Photoallergy to antimicrobials, mainly fentichlor, made up 25% of photopatch reactions in the NACDG data from 1999 to 2009, although none of these reactions were considered clinically relevant.22 It remains in the standard series of photopatch test allergens due to its potent photosensitizing properties.33 Fragrance and plant derivatives also represent other photosensitizing agents. Musk ambrette is the most common cause of fragrance associated PACD.22 Due to safety concerns, there has been decreased use of musk ambrette in products that contact the skin since the late 1990s.34 Photoallergy resulting from systemic absorption is a debated topic, but it is thought to be rare if it does occur.7,8
Treatment
Once PACD is confirmed via photopatch testing, the mainstay of treatment revolves around allergen avoidance. This is usually accomplished via use of a “safe list” provided to the patient detailing products free of their allergens. Other than avoidance, the firstline treatment is topical steroids. Calcineurin-inhibitors may be used if steroid-sparing agents are required or preferred. Persistent, generalized symptoms may require systemic therapy with prednisone.35 Oral antihistamines and cool compresses may relieve itch.
For patients with photoallergy to sunscreen, it is important to find a safe alternative. This could either be a chemical sunscreen that does not contain the specific UV filter to which the patient is allergic or a mineral-based sunscreen containing zinc oxide or titanium dioxide, which have never been reported to cause PACD.35
Conclusion
Although rare, PACD is an important consideration when patients present with photoaggravated dermatoses or a characteristic rash distribution. With the continued development of organic UV filters, new causes of PACD will assuredly emerge. Patients with photodermatoses report significant emotional distress and other hardships living with such diseases, making a diagnosis of PACD invaluable to these individuals.
Caroline Brumley is a medical student at the University of Minnesota and a patch test research fellow at the Park Nicollet Contact Dermatitis Clinic in Minneapolis, MN. Dr Hylwa is a faculty physician in the department of dermatology at Hennepin Healthcare and Park Nicollet Contact Dermatitis Clinic and an assistant professor at the University of Minnesota in Minneapolis, MN.
Disclosure: The authors report no relevant financial relationships.
References
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