An Goossens
Contact Allergy Unit
Department of Dermatology
Katholieke Universiteit
Leuven
B-3000 Leuven, Belgium
Photoallergic contact dermatitis is a classic T-cell-mediated or
delayed-type hypersensitivity reaction of the skin in response to a
photoallergen or photoantigen in a person who has been previously sensitized to
the same chemical or one that cross-reacts with it. The lesions, well demarcated and mostly symmetrical, generally
occur on areas that are exposed to the light.
However, they may be distributed differently depending on the part of
the body exposed or because of transfer from one part of the body to
another. Sometimes the original
application site is not affected while an exposure to the sun produces a
reaction on both exposed and non-exposed areas. As with allergic contact dermatitis, the lesions usually clear
when contact with the photoallergen ceases.
Occasionally, however, the patient may continue to develop lesions in
the presence of sunlight even after removal of the photoallergen and may
present recurrent transient or persistent light reactions (chronic actinic
dermatitis). Although photoallergic
contact dermatitis is considered uncommon, many topical photoallergenic
culprits have been reported in the literature, the most important of which are
sunscreen agents and non-steroidal anti-inflammatory agents.
Key words: allergic photocontact dermatitis, clinical symptoms,
non-steroidal anti-inflammatory agents, sunscreen agents, photoallergens.
Introduction
Both topically applied and systemically administered
substances can produce photoallergic reactions. As systemic reactions have been extensively reviewed in another
article (1), we will focus here on photoallergic reactions induced by the
topical contact of the skin with a chemical in the presence of, or followed by,
exposure to UV or visible light. Some
of the more recently observed photoallergens or those producing peculiar clinical
features will be discussed. However, we
do not intend to provide an exhaustive review here of all the photoallergens
that have been reported.
Mechanisms
Photoallergic contact dermatitis is a classic
T-cell-mediated or delayed-type hyper-sensitivity reaction of the skin in
response to a photoallergen or photoantigen in a subject who has previously
been sensitized to the same or a cross-reacting chemical. The precise mechanism of the formation of a
photoallergen by UV or visible light is poorly understood but two mechanisms
have been proposed (2):
1) A specific chromophore (a molecule able to
absorb light) may be transduced into an excited unstable state. As the molecule reverts to its ground state,
the released energy might lead to conjugation with a carrier.
2) A stable photoproduct is formed that
serves as a hapten that conjugates with a carrier and thereby forms a complete
antigen.
After a complete antigen is formed, the pathogenesis
of a photoallergic contact dermatitis is essentially identical to that of
allergic contact dermatitis: epidermal Langerhans cells process the antigen and
present it - in association with class-II major histocompatibility complexes -
in the draining lymph nodes to antigen-specific T-lymphocytes. Cutaneous lesions will develop when
activated T-cells circulate to the exposed areas of the skin and recognize the
photoallergen (2).
For most of the photoallergens the action spectrum
lies in the UVA range, but some elicit reactions in both the UVA and UVB range
as is the case with diphenhydramine hydrochloride (3, 4) and non-steroidal
anti-inflammatory agents (NSAIDs) (5).
The duration of the response to light irradiation
after stopping the application of a known photoallergen is variable and depends
on the photoallergen. For sunscreens,
for example, it is probably less than 4 days (6). However, NSAIDs such as ketoprofen may cause subjects to react to
sunlight up to several weeks after having stopped its local application (7,
8). This is most probably due to
retention of the molecule for up to at least 17 days (9) in the epidermis.
As with allergic contact dermatitis, avoiding the
photoallergen usually clears the dermatitis.
Occasionally, even after withdrawal of the photoallergen, the patient
may continue to develop dermatitis in the presence of sunlight and may present
recurrent transient, i.e. up to several weeks or months, e.g. with thiourea
derivatives (10) and ketoprofen (8, 11), or persistent light reactions (chronic
actinic dermatitis), such as with ketoprofen (8, 11) and chlorproethazine (12). The formation of endogenous photosensitizers
might perhaps explain this phenomenon (13).
Sometimes contact allergic reactions are aggravated by
light-exposure (photo-aggravation or photo-augmentation). Examples of such allergens are thiourea
(10), NSAIDs (see 14 for a review), including etofenamate (15),
tosylamide/formaldehyde resin (16), and fragrances (17). However, photoaggravation may sometimes be
followed by transient (e.g. 8, 10) or persistent light reactions (8).
Moreover, persistent photosensitivity (chronic actinic
dermatitis) may follow chronic contact allergy as is the case with some plants,
e.g., Compositae (sesquiterpene
lactones) (18, 19), fragrances and lichens (20). This may also be the case with colophony (21) and ketoprofen (8,
11).
Cross-reactions between chemically related substances
have been frequently reported: chlorproethazine cross-photoreacts with other
phenothiazines (12). Ketoprofen
cross-photoreacts with oxybenzone, sulisobenzone, fenofibrate, tiaprofenic
acid, piketoprofen (11), and unsubstituted benzophenone (11, 22), for which
Bosca (23) had determined that photoallergy is indeed due to the benzophenone
moiety of the cross-reacting chemicals involved. Pigatto et al. (24) observed cross-reactions between ketoprofen
and naproxen and between ibuprofen and naproxen in particular, as well as
between ketoprofen and ibuproxam and cinnamic aldehyde. They suggested that the ketonic group in the
ketoprofen and cinnamic aldehyde molecules, and also in tiaprofenic acid after
its conversion, could trigger the cross-reactions observed. However, concomitant multiple sensitivities
seem to be frequent in such patients (22) and could well offer a valid
alternative explanation. Moreover,
associated photoallergic reactions between ketoprofen and molecules not having
a benzophenone moiety, such as dibenzoylmethane derivatives,
tetrachloro-salicylanilide and fentichlor (25), have also been reported. We ourselves have observed associated
reactions upon photopatch testing with suprofen and etofenamate (data on file).
Clinical features
The clinical symptoms of photoallergic contact
dermatitis are those of an eczematous reaction with histopathological features
identical to other forms of allergic contact dermatitis. It may be acute, subacute, or chronic. There are, of course, many similarities with
phototoxic reactions, and clinical and histological features may help to
differentiate between them (2).
Photoallergic contact dermatitis generally affects
well-demarcated areas of the light-exposed areas: the face, neck, and V-area of
the upper chest, the backs of the hands and forearms, and sometimes the
legs. A unilateral reaction may occur
upon the application of a photoallergen to a particular body site and
subsequent sun exposure or greater exposure of one body site (13). The photoallergen may be transferred from
one body site to another, for example, to the contra-lateral areas (8), or may
be due to a cross-leg effect or to transfer by the hands (ectopic dermatitis)(le
Coz, personal communication). A particular
distribution of the lesions may occasionally be a connubial photoallergic
contact dermatitis (26, 27).
Furthermore, the original application site may not be
affected while a subsequent sun exposure produces a reaction on exposed as well
as non-exposed areas, as has been reported for ketoprofen (e.g. 8).
Photoallergic contact dermatitis may resemble an
allergic airborne contact dermatitis (28), although a photo-induced dermatitis
tends to spare the anatomically shadowed portions of the body such as the
eyelids, the retro-auricular and submandibular regions, and those covered by
hair. Of course, "airborne"
substances may have allergenic as well as both phototoxic and photoallergenic
properties. Occupation-induced airborne
photoallergic dermatitis has been described for olaquindox (29), which cases
may be followed by transient or persistent light reactions (30), the pesticides
Maneb® and Fenitrothion® (31), as well as mancozeb and
tetrachloroisophtalonitrile (Daconil®) (32).
A reaction to tetrachloro-isophtalonitrile may be followed by a
persistent light reaction (32).
In addition to airborne dermatitis, also the topical
application of contact allergens on exposed areas and chronic actinic
dermatitis must be considered in the differential diagnosis, although the
patients suffering from such diseases are at increased risk of developing
photoallergy (33). Moreover, certain
other skin conditions like rosacea and lupus erythematosus may be
photoaggravated.
Peculiar clinical features may sometimes occur, such
as an erythema-multiforme-like eruption (11, 26, 34), leukomelanoderma ( 35),
and a lichenoid photosensitive eruption (36) as may occur to Parthenium hysterophorus (already known
as a possible cause of chronic actinic dermatitis and photocontact dermatitis). Urticarial reactions and purpuric lesions
(particularly on the lower legs) due to ketoprofen have also been described (Le
Coz, personal communication).
Systemic reactions, including fever, rigors, diarrhea
(37), and even abnormalities of liver function (38) have been reported in
association with photocontact dermatitis.
The photoallergens
Although photoallergic contact dermatitis has been
considered to be uncommon (33), the literature cites several topical substances
that give rise to it. Some substances
may exceptionally have a photoallergenic effect as cadmium in tattoos (39),
cinchocaine (40), certain NSAIDs such as fepradinol (41), flufenamic acid and
etofenamate (42), Zovirax cream (43), and the sunscreen agent octyl triazone
(44), but others do so frequently. De
Groot et al. (45) give a comprehensive list of topical photoallergens in drugs
and cosmetics although not all of the cases reported have been critically
reviewed (46). Some occupational
photoallergens have also been reported (47).
In the past, most photoallergic reactions resulted
from the use of deodorant soaps containing halogenated salicylanilides and
related compounds, and later on musk ambrette and 6-methylcoumarin in
fragrances were identified as important photoallergens (46). Nowadays, among the most frequently observed
photoallergens are sunscreens containing benzophenones and dibenzoylmethane
derivatives (33, 48-51). However, in
the south of Europe, but also in northern "sunny" regions, such as in
Scotland (52) and Southern Sweden (53), and even in Belgium (data on file),
photoallergic contact dermatitis due to topical application of the NSAID
ketoprofen is increasingly being reported.
Photocontact dermatitis has also been attributed to suprofen and
benzydamine (see 14 for a review). Most
of these molecules are also phototoxic and contact allergenic, in the latter
case often associated with photo-aggravation (7, 8, 11).
Of course, the differences in composition of the
standard set of photoallergens influence the frequency of the photopatch-test
results obtained (51).
Conclusion
Photoallergic contact dermatitis has been regarded as
rare. Actually, the main photocontact
allergens seem to be sunscreen agents and non-steroidal anti-inflammatory drugs
(ketoprofen in particular). However, in
view of the misleading clinical features observed in some cases, the diversity
of causal substances identified, and the low frequency with which photopatch
testing is carried out in general, the occurrence of photoallergic contact
dermatitis might well be underestimated.
References
1. Ferguson J. Photosensitivity due to drugs.
Photodermatol Photoimmunol Photomed 2002; 18: 262-269.
2. Mang R, Krutmann J. Mechanisms of phototoxic and photoallergic
reactions. In: Rycroft RJG, Menné T,
Frosch PJ, Lepoittevin J-P (eds), Textbook of contact dermatitis, 3rd ed.,
Berlin: Springer, 2001; 134-143.
3. Emmett EA. Diphenhydramine photoallergy.
Arch Dermatol 1974; 110:
249-252.
4. Yamada S, Tanaka M, Kawahara Y, Inada M,
Ohata Y. Photoallergic contact
dermatitis due to diphenhydramine hydrochloride. Contact Dermatitis 1998; 38: 282.
5. Adamski H, Benkalfate L, Delaval Y, Ollivier I, Le Jean S,
Toubel G, Le Hir-Garreau I, Chevrant-Breton.
Photodermatitis from non-steroidal anti-inflammatory
drugs. Contact Dermatitis 1998; 38: 171-174.
6. Buckley D A, Wayte J, O'Sullivan D,
Murphy G M. The duration of response to
UVA irradiation after application of a known photoallergen. Contact Dermatitis 1995; 33: 138-139.
7. Le Coz CJ, El Aboubi S, Lefèbvre C, Heid E, Grosshans E. Photoallergy from
topical ketoprofen: a clinical, allergological and photobiological study. Abstract, Contact Dermatitis 2000; 42 (suppl): 47.
8. Durieu C, Marguery M-C, Giordany-Labadie F, Journe F, Loche F,
Bazex J. Allergies de contact
photoaggravées et photoallergies de contact au kétoprofène: 19 cas. Ann Dermatol Venereol 2001; 128: 1020-1024.
9. Sugiura M, Hayakawa R, Kato Y, Sugiura K, Hashimoto R. 4 cases of
photocontact dermatitis due to ketoprofen.
Contact
Dermatitis 2000; 43: 16-19.
10. Dooms-Goossens
A, Chrispeels MT, De Veylder H, Roelandts R, Willems L, Degreef. Contact and
photocontact sensitivity problems associated with thiourea and its derivatives:
a review of the literature and case reports.
Br J Dermatol 1987; 116:
573-579.
11. Le Coz CJ, El Aboubi S, Lefèbvre C, Heid E,
Grosshans E. Topical ketoprofen induces
persistent and recurrent photosensitivity.
Abstract, Contact Dermatitis 2000; 42
(suppl): 46.
12. Barbaud A, Collet E, Martin S, Granel F,
Trechot P, Lambert D, Schmutz JL.
Contact sensitization to chlorproethazine can induce persistent light
reaction and cross-photoreactions to other phenothiazines. Contact Dermatitis 2001; 44: 373.
13. White I.
Phototoxic and photoallergic reactions.
In: Rycroft RJG, Menné T, Frosch PJ, Lepoittevin J-P (eds). Textbook of contact dermatitis. 3rd ed.,
Berlin: Springer, 2001; 367-379.
14. Ophaswonge S, Maibach H. Topical nonsteroidal antiinflammatory drugs:
allergic and photoallergic contact dermatitis and phototoxicity. Contact Dermatitis 1993; 29: 57-64.
15. Sánchez-Pérez J, Sanz Sánchez T, García-Diez A. Combined contact and
photocontact allergic dermatitis to etofenamate in Flogoprofen gel. Am J Contact Dermatitis 2001; 12: 215-216.
16. Vilaplana J, Romaguera C. Contact dermatitis from
tosylamide/formaldehyde resin with
photosensitivity. Contact
Dermatitis 2000; 42: 311-312.
17. Tani A, Hozumi H, Miyoshi H, Kanzaki
T. A case of photoallergic contact
dermatitis to fragrances in aftershave cream.
Environ Dermatol 1999; 6:
105-109.
18. Ross JS, Du Peloux Menagé H, Hawk LM, White
IR. Sesquiterpene lactone contact
sensitivity: clinical patterns of cmpositae dermatitis and relationship to
chronic actinic dermatitis? Contact
Dermatitis 1993; 29: 84-87.
19. Kuno Y, Kawabe Y, Sakakibara S. Allergic contact dermatitis associated with
photosensitivity, from alantolactone in a chrysanthemum farmer. Contact Dermatitis 1999; 40: 224-225.
20. Lim HW, Morison WL, Kamide R, Buchness MR,
Harris R, Soter NA. Chronic actinic
dermatitis: an analysis of 51 patients evaluated in the United States and
Japan. Arch Dermatol 1994; 130: 1284-1289.
21. Kuno Y, Kato M. Photosensitivity from colophony in a case of chronic actinic
dermatitis associated with contact allergy from colophony. Acta Derm Venereol 2001; 81: 442-443.
22. Le Coz CJ, Bottlaender A, Scrivener J-N,
Santinelli F, Cribier BJ, Heid E, Grosshans EM. Photocontact dermatitis from ketoprofen and tiaprofenic acid:
cross-reactivity study in 12
consecutive patients. Contact Dermatitis 1998; 38:
245-252.
23. Bosca F, Miranda MA, Carganico G, Mauleon
D. Photochemical
and photobiological properties of ketoprofen associated with the benzophenone
chromophore. Photo-chemistry and
Photobiology 1994; 60: 96-101.
24. Pigatto P, Bigardi A, Legori A, Valsecchi
R, Picardo M. Cross-reactions in patch
and photopatch testing with ketoprofen, thiaprofenic acid, and cinnamic
aldehyde. Am J Contact Dermatitis 1996;
7: 220-223.
25. Martin S, Barbaud A, Pénétrat S, Tréchot P,
Schmutz JL. Existence of photoallergy
between ketoprofen and molecules without any benzophenone moiety. Abstract.
Contact Dermatitis 2002; 4 (suppl), 55.
26. Mastrolonardo M, Loconsole F, Rantuccio
F. Conjugal allergic contact dermatitis
from ketoprofen. Contact Dermatitis
1994; 30: 110.
27. Mirande-Romero A, González-López A,
Esquivas JI, Bajo C, García-Muñoz M.
Ketoprofen-induced connubial photodermatitis. Contact Dermatitis 1997; 37:
242.
28. Dooms-Goossens AE, Debusschere KM, Gevers
DM, Dupré KM, Degreef HJ, Loncke JP, Snauwaert JE. Contact dermatitis caused by airborne
agents. J Am Acad Dermatol 1986; 15: 1-10.
29. Francalanci S, Gola M, Giorginai S,
Mucinelli A, Sertoli A. Occupational photocontact dermatitis from Olaquindox. Contact Dermatitis 1986; 15: 112-114.
30. Schauder S, Schröder W, Geier J. Olaquindox-induced airborne photoallergic
dermatitis followed by transient or persistent light reactions in 15 pig
breeders. Contact Dermatitis 1996; 35: 344-354.
31. Nakamura M, Arima Y, Nobuhara S, Miyachi
Y. Airborne photocontact dermatitis due
to the pesticides maneb and fenitrothion.
Contact
Dermatitis 1999; 40: 222-223.
32. Matsushita
S, Kanekura T, Saruwatari K, Kanzaki T.
Photoallergic contact dermatitis due to Daconil®. Contact Dermatitis 1996; 35: 115-116.
33. Darvay A, White IR, Rycroft RJG, Jones AB,
Hawk JLM, McFadden JP. Photoallergic
contact dermatitis is uncommon. Br J
Dermatol 2001: 145: 597-601.
34. Zhang X-M, Nakagawa M, Kawai K, Kawai
K. Erythema-multiforme-like eruption
following photoallergic contact dermatitis from oxybenzone. Contact Dermatitis 1998; 38: 43-44.
35. Nabeya RT, Kojima T, Fujita M. Photocontact dermatitis from ketoprofen with
an unusual clinical feature. Contact
Dermatitis 1995; 32: 52-53.
36. Verma KK, Sirka CS, Ramam M, Sharma
VK. Parthenium
dermatitis presenting as photosensitive lichenoid eruption. Contact Dermatitis 2002; 46: 286-289.
37. de
Groot AC, Van Der Walle HB, Jagtman BA.
Contact allergy to 4-isopropyl- dibenzoylmethane and
3-(4'-methylbenzilidene) camphor in the sunscreen Eusolex 8021. Contact Dermatitis 1987; 16: 249-254.
38. Parry EJ, Bilsland D, Morley WN. Photocontact allergy to
4-tert.butyl-4'-methoxy-dibenzoylmethane (Parsol 1789). Contact Dermatitis 1995; 32: 251-256.
39. Yazdian-Tehrani H, Shibu MM,Carver NC. Reaction in a red tattoo in the absence of
mercury. Br J
Plast Surg 2001; 54: 555-556.
40. Urrutia I, Jáuregui I, Gamboa P, González
G, Antépara I. Photocontact dermatitis
from cinchocaine (dibucaine). Contact
Dermatitis 1997; 39: 139-140.
41. Rodríguez Granados T, Piñeiro G, de la
Torre C, Cruces Prado MJ. Photoallergic
contact dermatitis from fepradinol.
Contact Dermatitis 1998; 39:
194-195.
42. Montoro J, Rodriguez-Serna M, Liñana JJ,
Ferré MA, Sanchez-Motilla JM. Photoallergic
contact dermatitis due to flufenamic acid and etofenamate. Contact Dermatitis 1997; 37: 139-140.
43. Rodriguez-Serna M, Velasco M, Miquel J, De
La Cuadra, Aliaga A. Photoallergic contact dermatitis from Zovirax cream. Contact Dermatitis 1999; 41: 54-55.
44. Sommer S, Wilkinson SM, English JSC,
Ferguson J. Photallergic contact
dermatitis from the sunscreen octyl triazone.
Contact Dermatitis 2002; 46:
304-305.
45. de Groot AC, Weyland JW, Nater JP. Unwanted effects of cosmetics and drugs used
dermatology. 3rd.ed. Amsterdam:
Elsevier, 1994: 136-154.
46. White IR.
Photopatch testing. Chapter
27. In: Rycroft RJG, Menné T, Frosch
PJ, Lepoittevin J-P (eds). Textbook of
contact dermatitis, 3rd ed., Berlin:
Springer, 2001: 527-537.
47. DeLeo V.
Occupational phototoxicity and photoallergy. In:
Kanerva L, Elsner P, Wahlberg JE, Maibach HI (eds). Handbook of Occupational Dermatology. Berlin: Springer, 2000: 314-324.
48. Gonçalo M, Ruas E, Figueiredo A, Gonçalo
S. Contact and photocontact sensitivity
to sunscreens. Contact Dermatitis 1995;
33: 278-280.
49. Schauder S, Ippen H. Contact and photocontact sensitivity to
sunscreens. Review of a 15-year
experience and of the literature.
Contact Dermatitis 1997; 37:
221-232.
50. Berne B, Ros A-M. 7 years experience of photopatch testing with
sunscreen allergens in Sweden. Contact
Dermatitis 1998; 38: 61-64.
51. Bakkum RSLA, Heule F. Results of photopatch testing in Rotterdam
during a 10-year period. Br J Dermatol
2002; 146: 275-279.
52. Horn HM, Humphreys F, Aldridge RD. Contact dermatitis and prolonged
photo-sensitivity induced by ketoprofen and associated with sensitivity to
benzophenone-3. Contact Dermatitis 1998; 38: 353-354.
53. Hindsén
M, Bruze M, Zimerson E. Fotoallergi mot ketoprofen i södra Sverige. Abstract of paper
presented at the Svenska Läkaresällskapets Riksstämma (27-29 November,
2002). Program Sammanfattningar, p.149.