27 Photopatch Testing

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Contents

27.1 Introduction . . . . 433

27.2 Prevalence and Factors Predisposing to Photoallergy . . . . 433

27.3 Contact Photoallergens . . . . 434

27.3.1 A Historical Perspective . . . . 434

27.3.2 UV Filters . . . . 434

27.3.3 Other Photoallergens . . . . 435

27.4 General Considerations for Photopatch Testing . . . . 435

27.5 Source and Dose of UVA . . . . 435

27.6 Allergen Application and Reading of Reactions . . . . 437

27.7 Interpretation of Results . . . . 438

27.7.1 Photoallergy vs Phototoxicity . . . . 438

27.7.2 The Possibility of Photo-augmentation or Photo-suppression of Simple Allergic and Irritant Reactions . . . . 438

27.8 Summary . . . . 439

References . . . . 439

27.1 Introduction

Photopatch testing (PhPT) is primarily used to diagnose photoallergy to topical agents. Mechanisms of photoallergy are discussed in Chap. 6, and clinical features of photoallergy are covered in Chap. 17. In a research context, PhPT can be used to evaluate the phototoxic potential of substances, but it is not useful for the diagnosis of suspected phototoxic reactions.

Photoallergy is the result of a type-IV hypersensitivity reaction to a photoproduct or photoactivated chemical. It is rare, and is less common than phototoxicity. The allergens responsible have changed over the past four decades; currently, in the Western world, the most frequent culprits are sunscreens, but even these compounds have a low potential for photosensitization [1]. The rarity of photoallergy is one

of the reasons that PhPT has remained, arguably, an imprecise investigation. The interaction of two agents (a topical chemical and ultraviolet) creates a complexity and potential variability that hinders ac- curacy and reproducibility. The subject has suffered from straddling two subspecialities; namely, contact dermatitis and photodermatology, and variations in the methodology of PhPT have hindered the comparison of data from different studies. Nevertheless, PhPT has a vital role in distinguishing patients with photoallergy, airborne allergic contact dermatitis, and photodermatoses.

There are reported to be 49 known PhPT centers in Europe; the 34 who responded to a survey [2] each conducted only an average of 16 photopatch tests per year, and only two centers conducted more than 50.

There is a lack of standardization in the methodology of PhPT, with wide variations in the agents used, test concentrations, and interpretation of reactions.

This is partly because evidence to recommend any particular approach has not been available. Groups from Scandinavia [3, 4], Germany, Austria and Swit- zerland [5], Italy [6], and Britain [7] have made separ- ate and differing attempts at standardization of the technique. Recently, the European Taskforce for Pho- topatch Testing has produced a consensus methodology [2]. This development was long overdue, and is a major step forwards. It ensures an appropriate degree of standardization, while recognizing that some vari- ation between centers will always exist as a necessity, due to regional variations in allergen exposure and logistical factors.

27.2 Prevalence and Factors Predisposing to Photoallergy

Although it has not been investigated, the prevalence of photoallergy in the general population is likely to be extremely small. Patients diagnosed with photoallergy usually have an underlying photodermatosis [1, 8–10]. This may be explained by the original indication for referral to the investigating unit, the frequent

Photopatch Testing

Roy A. Palmer, Ian R. White 27

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use of sunscreens in photosensitive patients, and the application of sunscreens on inflamed skin (thereby, increasing penetration). It is also possible that such patients are intrinsically prone to sensitization, which is suggested in chronic actinic dermatitis (CAD) by the very high prevalence of contact allergy in that condition.

Until 10 years ago, most reports of PhPT series suggested that 7–20% of patients tested had at least one photoallergic reaction [9, 11–13]. Many of these studies used substances that are now either obsolete or likely to give phototoxic reactions that may be misinterpreted as photoallergic. Studies in the past decade using series consisting predominantly of sunscreen allergens have tended to show lower rates of 2.3–10% [1, 8, 14, 15]. The largest of these studies reviewed the results of 2,715 patients who underwent PhPT between 1983 and 1998 [1]. It found that 2.3% of patients had at least one photoallergic reaction; the average number of positive reactions among these photoallergic patients was 1.3.

27.3 Contact Photoallergens 27.3.1 A Historical Perspective

Only a small number of substances have been responsible for causing the majority of cases of photoallergy. When substances are recognized as photoallergens, they tend to be withdrawn, so the list of currently relevant allergens is constantly changing. The problem of topical photoallergy was first identified in 1961 by Wilkinson in regard to tetrachlorosalicylanilide [16], which belongs to the family of halogenated salicylanilides. These substances, and also the chlorinated phenols (fentichlor and bithionol), were used as antibacterial agents in soaps and other products. They caused an epidemic of photosensitivity until they were removed from the European environ- ment in the 1970s, although extremely rare cases seemed to develop “persistent light reactivity” (see Chap. 17). Wilkinson described the sparing of skin behind the lower part of the ears in photosensitive individuals with facial eczema; his name is now im- mortalized in the term “Wilkinson’s triangle.”

Musk ambrette was used extensively, and in high concentrations (up to 4%), as a fragrance enhancer in toiletries and aftershaves. It was also found in other products, such as soaps, hair sprays, furniture polish, and fruit-flavored edibles, including yoghurts and sweets. In 1978, it was identified as a photoallergen by Larsen [17]; it is also a simple contact allergen. It be- came an increasing menace, typically causing local-

ized eczema corresponding to the application of aftershave, or a more widespread dermatitis, resem- bling chronic actinic dermatitis [18]. Following recommendations from the International Fragrance As- sociation, the concentrations were reduced and the incidence of new cases fell dramatically. It is now pro- hibited from Europe and most other major markets.

However, it is still widely available in some Asian countries and large quantities are exported from China.

In the West, photoallergy is now rare and legisla- tion requires the evaluation of substances before they are marketed. The stringent guidelines for such eval- uations now ensure that it is unlikely for significant photoallergens to become widely available ever again.

27.3.2 UV Filters

Over the last 20 years, there has been a dramatic increase in the use of sunscreens, driven by a desire to avoid skin cancer and photoaging. In addition, ultraviolet (UV) filters are sometimes included in cosmetics to increase the shelf life of the product by preventing photodegradation [19], and to increase the shelf- life of the user by preventing photoaging. As a result, there has been an increase in the incidence of photoallergy to these agents but, again, once the major culprits were identified (for example, isopropyl diben- zoylmethane [20]), they were removed from the mar- ketplace.Although currently, sunscreens are the most frequent photoallergens [8], they, nevertheless, have a low potential for photoallergenicity, and they also have an excuse; their job is to absorb UV radiation.

There has been an increasing recognition of the role of UVA in photoaging and photocarcinogenesis and, therefore, an increasing drive to provide protec- tion against it, in addition to UVB. UV filters can be divided into organic and physical agents. The physical agents zinc oxide and titanium dioxide, when in pigment form, predominantly reflect (but not absorb) UV, so do not undergo photochemical reactions and, therefore, do not cause sensitization. They tend to have a white appearance because they also reflect visible light, which is an undesirable character- istic that has been reduced by the use ofmicrofine titanium dioxide. This substance predominantly absorbs UV and is usually used in high concentrations;

there is no percutaneous absorption so sensitization does not occur [21, 22]. Organic agents absorb ultra violet radiation (UVR) by undergoing a chemical transformation, which gives them the potential to be photoallergenic. They can be grouped as follows:

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쐽 Benzophenones; absorb UVB and some UVA.

쐽 PABA and its esters; mostly absorb UVB. They have become less frequently used.

쐽 Cinnamates; have largely replaced para-ami- nobenzoic acid (PABA) and its esters as UVB absorbers. Ethylhexyl methoxycinnamate (oc- tyl methoxycinnamate) is commonly used, but is a very rare photoallergen.

쐽 Dibenzoylmethanes; mostly absorbs UVA.

쐽 Camphor derivatives.

In the PhPT study of 2,715 patients referred to earlier, 65% of photoallergic reactions were to sunscreens, particularly benzophenone-3 and benzophenone-10 [1]. In addition, 2% of patients had an ordinary contact allergic reaction to the PhPT series, most commonly to UV filters, again, particularly benzophenone-3 and benzophenone-10.

UV filters can cause an acute reaction with clinical features identical to those of an ordinary allergic contact dermatitis. However, because they are usually applied before exposure to sunlight, it is often dif- ficult to make a diagnosis on the basis of the history alone; reactions to them may be misinterpreted as an idiopathic photodermatosis, and people using sunscreens to treat idiopathic photodermatoses may ac- quire an allergy to them that exacerbates the pre-existing condition.

27.3.3 Other Photoallergens

Chlorpromazine can induce photoallergic (and phototoxic) reactions in, for example, healthcare workers handling tablets [23]. In the PhPT study of 2,715 patients, 12% of photoallergic responses were to promethazine and 7% to chlorpromazine; the authors recognized that these reactions may have been phototoxic and wrongly diagnosed [1]. Photoallergy due to topical non-steroidal anti-inflammatory drugs (NSAIDs) has been reported many times over the last decade, particularly from mainland Europe, where they are used frequently [24–27]. There is no con- vincing evidence that Compositae, lichens, and wood mixes are significant photoallergens, except, pos- sibly, in extremely rare cases [7, 28]. They can cause airborne allergic contact dermatitis and patients with chronic actinic dermatitis often have positive patch tests to Compositae.

Many other contact photoallergens have been described [29] (Table 1), but most are unconfirmed and some of the reports are probably erroneous, attribut- ing photoallergy to cases of phototoxicity. Cross-reactions between chemically related substances have

been reported [30], such as between ketoprofen with benzophenone-3, which share a benzophenone moie- ty [31].

27.4 General Considerations for Photopatch Testing

The major indication for PhPT is the investigation of eczema affecting UV-exposed sites. Some patients will give a history of using potentially photoallergenic preparations and exacerbations following sun exposure. Individuals having PhPTs should also be phototested and patch-tested with a “standard series” that includes allergens that may mimic photosensitivity (such as Compositae), a “facial series,” and their own skin-care products. Patch tests can be performed at the same time as PhPTs. Although published evidence is lacking, false-negative results may be caused by immunosuppressive therapy (topical and systemic) and antihistamines. Therefore, when possible, these should be stopped prior to PhPT, per- haps 1 week beforehand for topical steroids [7] or 2 weeks for systemic immunosuppressants [2].

As regards to the choice of substances for PhPT, those which frequently cause phototoxic reactions should generally be avoided. There cannot be a “standard light series” for all countries because of geo- graphical variations in exposure. A working party of the British Photodermatology Group suggested a routine list of photoallergens for Britain, and the European Taskforce for Photopatch Testing have recently published their recommendations (Table 2) [2, 7]. These will need to be continually reviewed to reflect research and changes in the use of products.

Very little information exists regarding the optimal concentration of agents for PhPT. Patients’ own products should be tested when appropriate, and other agents listed in Table 2 when indicated, such as thiourea (used as an antioxidant in photocopy paper [32]).

Photoallergy to systemic agents, and the difficulties of using PhPT to diagnose it, is discussed in Chap. 17.

27.5 Source and Dose of UVA

UVA is more relevant than UVB or visible light to photoallergy for reasons discussed in Chap. 17. Fluo- rescent UVA lamps of the kind used for psoralen- UVA (PUVA) therapy are preferred [2], since they are cheap, easily available, and have an output which is broad across the UVA region. Also, their irradiance is relatively high and uniform across a large irradiated site, and the different types of these tubes have simi- lar spectra, allowing comparison between centers.

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Whole-body units can be used with appropriate shielding, or, more conveniently, small-area units (of the kind used for hand/foot PUVA) can be mounted on a wall. The irradiance of the latter varies with the distance from the lamps, so the gap should be main- tained at 15 cm from the front panel; then, a change of

±5 cm causes a change in dose of ±12% [7]. The UVA output may fluctuate over weeks to months, so the apparatus must be regularly calibrated.

The dose of UVA has traditionally been 5–15 J/cm². The dose needs to be low enough not to cause sunburn; in white subjects, the UVA minimum erythema dose (MED) of unacclimatized upper-back skin is about 15–20 J/cm²(95% confidence interval; 8–40 J/

cm²[7]). Also, the dose needs to be low enough not to cause, in association with the topical substance, a clinically irrelevant phototoxic response. The latter have been mostly studied with promethazine. Reac- tions to this are more likely to be phototoxic than photoallergic. With a 5 J/cm²dose, reactions to promethazine only occur in 1.8% of patients, but with a dose of 10 J/cm², they occur in 34–45% [7]. There is no evidence that clinically important reactions are missed by 5-J/cm²and revealed by 10-J/cm²doses.Al- though doses of 1 J/cm²or even lower can elicit pho- toallergic reactions [18, 33], the yield of positive reactions decreases below 5 J/cm² [34]. Therefore, although more research is required, a dose of 5 J/cm² has been recommended and gradually seems to be becoming standard [2, 7, 9, 11, 13, 18, 33]. This may be increased for dark-skinned subjects.

If patients who are very sensitive to UVA are exposed to 5 J/cm²of UVA, they may have severe reactions. Therefore, the dose may be reduced to 2.5 J/cm² (or lower) in patients with suspected chronic actinic dermatitis and/or a history of severe photosensitivity [1]. It is helpful if the results of standard phototests are known before the administration of UVA in the PhPT, because this identifies UVA-sensitive patients.

In these patients, the UVA MED can be determined using the same UVA source as that to be used for PhPT; a suitable dose for PhPT may be 50% of their UVA MED [33]. Such patients have an increased risk of photoexacerbated reactions (irritant and allergic) [2, 35], which are of uncertain relevance and may be falsely interpreted as indicating photoallergy. Ideally, the UVA MED should be tested in all patients prior to PhPT, but this is not essential.

27.6 Allergen Application and Reading of Reactions

Testing should be conducted on skin that has been clinically normal for the preceding two weeks [2]. Pa- tients should be advised of the possible risks of sensitization and strong reactions, preferably with an information sheet. The mid-upper back skin is used, avoiding the paravertebral groove. Two identical sets of allergens are applied as parallel series on either side of the back using conventional patch-test tech- niques. Two days later, both are discarded and the sites are examined for reactions, which are recorded using the standard scoring system. One set of sites is shielded while the other is irradiated with UVA. A reading immediately after irradiation (up to 20 min later) is sometimes performed, and detects immediate phototoxic urticarial reactions that may occur with, for example, benzophenone-3 [36]. In sunny

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Table 1.Examples of topical agents reported to cause (but not necessarily confirmed as causing) photoallergy. Others are listed in Table 2 [1, 29]

Sunscreens Benzophenone-10 Digalloyl trioleate Dimethoxane

2-ethoxyethyl-p-methoxycinnamate Glyceryl p-aminobenzoate 4-isopropyldibenzoylmethane Amyl dimethyl PABA Halogenated antimicrobials

Bis(2-hydroxy-5-chlorophenyl) sulfide (fentichlor) 5-bromo-4′-chlorosalicylanilide

Buclosamide Chlorhexidine Chloro-2-phenylphenol 4,5-Dibromosalicylanilide Hexachlorophene

Tetrachlorosalicylanilide (TCSA)

2,2′-thiobis(4,6-dichlorophenol) (bithionol) Tribromosalicylanilide

Trichlorocarbanilide Triclosan

Fragrance ingredients 6-Methyl coumarin Musk ambrette Musk xylol Others

Brilliant lake red R (DC-R31) Permanent orange (DC-017) Benzocaine

Benzydamine Chlorpromazine Chlorprothixene

NSAIDs, e.g., tiaprofenic acid, ibuproxam Promethazine

Quinine sulfate

Thiourea, dimethylthiourea Zinc pyrithione

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climates, all sites should then be covered with opaque material. Two days later, the sites are examined again.

Some variations on this scheme are used with no published evidence to favor one over the others. In the most common variant, the sites are occluded with allergen for only 1 day (protocol 2 in Table 3). This de- creased occlusion time does not seem to reduce the sensitivity of the test and it does permit, within a

Monday–Friday protocol, a reading 3 days after irradiation. At this time, photoallergic reactions may be more obvious and more easily distinguished from phototoxic reactions by the “crescendo” pattern (see below).A later reading after 1 week has also been pro- posed [37]. The relevance of the result should be determined.

The penetration of PhPT allergens can be increased by “scarifying” the skin or tape-stripping

Table 2.Photopatch testing: choice of photoallergens [2, 7]. This table lists the photoallergens suggested by two working groups for routine inclusion in photopatch series. (BPG, British Photodermatology Group [7], ETPT, European Taskforce for Photopatch Testing [2].) All agents are available through Hermal (Trolab) or Chemotechnique Diagnostics, except those marked with *, which need to be prepared “in-house”

BPG (%) ETPT (%)

Control Petrolatum 100 100

UV filters PABA 5 or 10 10

Ethylhexyl dimethyl PABA 2 or 10 10

Ethylhexyl methoxycinnamate (Parsol MCX^b) 2 or 10 10

Benzophenone-3 (Oxybenzone^a) 2 or 10 10

Butyl methoxydibenzoylmethane (Parsol 1789^b, Avobenzone^a) 2 or 10 10

4-Methylbenzylidene camphor (Mexoryl SD^b) – 10

Benzophenone-4 – 10

Isoamyl p-methoxycinnamate – 10

Phenylbenzimidazole sulfonic acid – 10

NSAIDs Naproxen – 5*

Ibuprofen – 5*

Diclofenac – 1*

Ketoprofen – 2.5*

Other Musk ambrette 1 or 5 –

Patients’ own products As appropriate As appropriate

The first name in the list is the International Nomenclature of Cosmetic Ingredients (INCI) name, which must be used for ingre- dient labeling purposes in Europe.

aInternational Nonproprietary Names (INN names)

bTrade name

Table 3.Commonly used photopatch test protocols Protocol Day

0 1 2 3 4 5 6

1 Application Irradiate with Reading ^a ^a

of allergens 5 J/cm²UVA;

immediate reading

2 Application Irradiate with Reading â â â

of allergens 5 J/cm²UVA;

immediate reading

aDesirable but not essential reading

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[38], or using a prick method [39], but these tech- niques are now rarely used.

27.7 Interpretation of Results

If there is a reaction to the UVA alone, then the pa- tient is UVA-sensitive and the PhPT results should usually be disregarded; if necessary, the test may be repeated with a lower dose of UVA.

Assuming this has not occurred, there are seven possible reactions to PhPT:

쐽 Negative

쐽 Photoallergic

쐽 Phototoxic

쐽 Irritant (unlikely to be clinically relevant):

쐽 Photo-augmented irritant (unlikely to be clinically relevant)

쐽 Photo-suppressed irritant

(unlikely to be clinically relevant)

쐽 Allergic:

쐽 Photo-augmented allergic

쐽 Photo-suppressed allergic

No reaction at the unirradiated site but a reaction at the irradiated site signifies photoallergy. Equal reactions at both sites are interpreted as “ordinary” allergy. Allergic and photoallergic reactions, when strongly positive, are usually easy to interpret. How- ever, diagnostic difficulties arise with weaker reactions and two particular issues have to be considered.

27.7.1 Photoallergy vs Phototoxicity

The tendency of the agent in question to give phototoxic reactions at the concentration and UVA dose being used should be known. Weak reactions tend to be phototoxic and strong ones photoallergic. A peak of the reaction within the first 24 h (“decrescendo”) tends to indicate phototoxicity, whereas a reaction that becomes stronger after 24 h (“crescendo”) tends to indicate photoallergy [5, 40]. However, these crite- ria often fail to distinguish the nature of reactions.

When they were used in an analysis of 1,500 patients with 2,859 positive reactions, 28% of reactions were phototoxic, 4% were photoallergic, and 27% of reactions had a reaction pattern that did not fit into the typical patterns of either phototoxicity or photoallergy [40]. In addition, 29% were classified as allergic reactions (erythematous or palpable immediately after removal of the patches; the possibility of subse- quent exacerbation or suppression of these reactions

by UV was not examined) and 12% as immediate, short-lived, non-specific reactions. The agents mak- ing up the 27% of reactions not fitting the typical patterns of either phototoxicity or photoallergy were, particularly, NSAIDs, phenothiazines, and disinfec- tants, and were thought to mostly have phototoxic mechanisms.

One method to distinguish photoallergy from phototoxicity is to carry out a serial dilution of the suspected photoallergen and also vary the dose of irradiation, for example, using a series from 10–50% of the UVA MED [7]. A positive response at a very low concentration and/or a very low UV dose points to photoallergy rather than phototoxicity. It is helpful to test controls negatively to exclude phototoxicity. His- tology may be helpful to distinguish phototoxic reactions from photoallergic ones.

27.7.2 The Possibility

of Photo-augmentation or Photo-suppression of Simple Allergic and Irritant Reactions

It is well known that UV has a profound suppressive effect on the sensitization phase of contact hypersen- sitivity (in one model, 93% suppression from one exposure to a dose of UV equal to double the minimum erythema dose [41]). However, in this context, we are concerned with the effect of one exposure to UVA on the elicitation phase and, here, the picture is more complicated. Murine studies show that UV may actu- ally augment the elicitation phase [42–44], and this also seems to occur in a considerable proportion of people [45–47]. The effect may be age-dependent, with older individuals being less likely to undergo photo-suppression [46]. Photo-augmentation of irritant reactions has also been shown to occur [47].

Therefore, reactions where both sites are positive but the irradiated site is only slightly stronger should be interpreted with caution. It is, of course, possible that such reactions indicate that contact allergy is co- existing with photoallergy, but this may be rare in comparison to the phenomenon of photo-augmentation of simple contact reactions. Furthermore, weak- ly positive reactions at an irradiated site with negative reactions at the unirradiated site could be due to photo-augmentation of an otherwise subclinical contact allergy.

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27.8 Summary

So, from all of the above discussion, there are four factors that can lead to a false diagnosis of photoallergy: (1) phototoxicity; (2) photo-augmentation of irritant responses; (3) photo-augmentation of allergic responses; and (4) technical error. With these issues in mind, the results of PhPT can be interpreted.

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