Phototoxic and Photoallergic Skin Reactions

Abstract

Indirect action of sun together with different exogenous agents (systemic medications and topically applied compounds) sometimes may result in phototoxicic and photoallergic reactions. Drug-induced photosensitivity reactions refer to the development of cutaneous disease as a result of the combined effects of a drug and light (mostly spectrum within the UVA and visible light range or UVB range). The aim of the review was to show the prominent features of phototoxic and photoallergic reactions, which occur in sun-exposed areas, including face, neck, hands and forearms. Phototoxic reactions are significantly more common than photoallergic reactions and mostly resemble to exaggerated sunburn. Photoallergic reactions appear only in a minority of individuals and resemble allergic contact dermatitis on sun-exposed areas, although sometimes may extend into covered areas. Generally, the physical examination and a positive patient's history of photosensitivity reactions on substances are of great importance for the diagnostics. The treatment of these reactions includes identification and avoidance of offending agent and application of anti-inflammatory dressings, ointments and corticosteroids.

Full text

Coll. Antropol. 31 (2007) Suppl. 1: 63–67
Professional paper
Phototoxic and Photoallergic Skin Reactions
Liborija Lugovi}, Mirna [itum, Suzana O`ani}-Buli} and Ines Sjerobabski-Masnec
Department of Dermatology and Venereology, University Hospital »Sestre milosrdnice«, Zagreb, Croatia
ABSTRACT
Indirect action of sun together with different exogenous agents (systemic medications and topically applied com-
pounds) sometimes may result in phototoxicic and photoallergic reactions. Drug-induced photosensitivity reactions refer
to the development of cutaneous disease as a result of the combined effects of a drug and light (mostly spectrum within
the UVA and visible light range or UVB range). The aim of the review was to show the prominent features of phototoxic
and photoallergic reactions, which occur in sun-exposed areas, including face, neck, hands and forearms. Phototoxic re-
actions are significantly more common than photoallergic reactions and mosty resemble to exaggerated sunburn. Photo-
allergic reactions appear only in a minority of individuals and resemble allergic contact dermatitis on sun-exposed ar-
eas, although sometimes may extend into covered areas. Generally, the physical examination and a positive patient’s
history of photosensitivity reactions on substances are of great importance for the diagnostics. The treatment of these re-
actions includes identification and avoidance of offending agent and application of anti-inflammatory dressings, oint-
ments and corticosteroids.
Key words: photosensitivity, phototoxic, photoallergic reactions
Introduction
Following sun exposure, because of a direct damage of
skin by UV radiation, cutaneous changes appear in the
form of sunburn or other sun induced dermatoses. Long-
term effects of sun damage include degenerative and ma-
lignant skin disorders, as well as, solar elastosis and skin
tumours. Indirect action of sun together with different
exogenous agents results in phototoxicity and photoaller-
gy1,2. Drug-induced photosensitivity refers to the devel-
opment of cutaneous disease as a result of the combined
effects of a chemical agent and light1. Therefore photo-
activation of the chemical agent may cause photototoxic
and photoallergic cutaneous reactions (table 1). Drug-in-
duced photosensitivity reactions are mostly stimulated
by action spectrum within the UVA (320–400 nm) and
visible light range or sometimes UVB (290–320 nm)
range. Photosensitivity reactions, phototoxic and photo-
allergic, may be result of systemic medications and topi-
cally applied compounds. There are many potential exog-
enous agents causing photosensitivity reactions (table
2)1,2. Although, sometimes the two can not be distin-
guished on the clinical basis, there are a number of dis-
tinguishing characteristics (table 1).
Both phototoxic and photoallergic reactions occur in
sun-exposed areas, including face, neck, hands and fore-
arms, with the exception of hair-bearing scalp, retroau-
ricular and periorbital areas, and submental part of the
chin growth4. A widespread eruption suggests exposure
to a systemic photosensitizer, whereas a localized erup-
tion indicates a reaction to a topical photosensitizer.
Sometimes phototoxic reactions are of a benefit for a pa-
tient, e.g. psoralens and tar containing products which,
after applying to the skin after the UV exposure cause
specific photosensitivity reaction, and by increasing cell
turnover influence the disease course acting as therapeu-
tic agents5.
Phototoxic Reactions in the Skin
Phototoxic reactions occur because of the damaging
effects of light-activated cell membrane compounds and
DNA. These reactions are more common in individuals
exposed to sufficient amounts of light and an exogenous
agent, and usually appear as an exaggerated sunburn re-
63
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sponse. Phototoxic reactions result from direct tissue
damage caused by a photo-activated compound. Many
compounds have the potential to cause phototoxicity and
have at least one resonating double bond or an aromatic
ring that can absorb radiation energy. The most common
causative agents are furocoumarins, acridinic dyes or
eosine. Some drugs are more phototoxic, for example,
phenothiazines, tetracycilnes, sulfonamides, amiodaro-
ne, dacarbazine, etc.6,7. Phototoxic dermatitis is inflam-
matory skin reaction caused exclusively by photochemi-
cal reaction (without immunologic mechanisms), leading
to the toxic reaction of various chemicals activated by UV
light and action on cell membrane components, e.g.
DNA2. Most compounds are activated by wavelengths
within the UVA range, although some compounds have
peak absorption within the UVB or visible light range.
The reactive compound absorbs and transmits energy
creating oxygen free radicals, superoxide anions, hydro-
xyl radicals and heat therefore damaging the cells in
phototoxic way metastasis8. The complex mechanism of
cell damage comprises complex of different reactions. In
most instances, photoactivation of a compound results in
the activation of electrons from the stable singlet state to
an excited triplet state. As activated electrons return to a
more stable configuration, they transfer their energy to
oxygen, leading to the formation of reactive oxygen inter-
mediates, such as singlet oxygen, superoxide anions, and
hydrogen peroxide leading to damage of cell membranes
and DNA. This includes the signal transduction path-
ways that result in the production of pro-inflammatory
cytokines and arachidonic acid metabolites, the main
components of inflammatory response, resembling an ex-
aggerated sunburn reaction load2. Another form of drug-
induced phototoxicity is psoralen-induced phototoxicity,
where psoralens intercalate within DNA, forming mono-
functional adducts and, after exposure to UVA radiation,
bifunctional adducts within DNA. It is still not known
how bifunctional adducts cause photosensitivity. As a re-
sult of described reaction on photoexposed body areas
the inflammatory reaction occurs in the form of acute
dermatitis characterized by erythema, oedema, blisters
and secondary hyperpigmentation¹,². Phototoxic respon-
ses often occur within minutes to hours of sun exposure,
appearing earlier than photoallergic reactions. Acute
phototoxicity often begins as an exaggerated sunburn re-
action (erythema and oedema) within minutes to hours
of sun exposure, while in severe cases vesicles and bullae
are also seen. The lesions often heal with secondary
hyperpigmentation, resolving in a matter of weeks to
months. Chronic phototoxicity may appear as an exag-
gerated sunburn reaction or lichenification, caused by re-
peated rubbing and scratching. Thus, distinguishing
phototoxic from photoallergic reactions strictly on physi-
cal appearance of the lesions may be difficult¹. Other less
common skin manifestations of phototoxicity include
pigmentary changes, such as blue-grey pigmentation as-
sociated with several agents, including amiodarone,
chlorpromazine, and some tricyclic antidepressants. Re-
actions to psoralen-containing plants (e.g. phytophoto-
dermatitis) and drugs may also resolve with a brownish
discoloration. Photosensitizing drugs may, as well, cause
a lichen planus–like eruption in sun-exposed areas, such
as reaction to demeclocycline, hydrochlorothiazide, ena-
lapril, quinine, quinidine, chloroquine, and hydroxychlo-
roquine patients10. Sometimes photosensitizing drugs
may also cause pseudoporphyria, with porphyria cutanea
tarda-like changes, characterized by skin fragility and
subepidermal blisters on the dorsal part of hands, e.g. af-
ter exposure to naproxen, nalidixic acid, tetracycline,
sulfonylureas, furosemide, dapsone, amiodarone, etc pa-
tients11,12. Treatment of patient with severe phototoxic
reactions includes management of skin changes in burn
care units, with application of anti-inflammatory dress-
ings, ointments and corticosteroids (e.g. creams, emul-
sions) and the most important identification and avoid-
ance of any offending agent.
L. Lugovi} et al.: Phototoxic and Photoallergic Skin Reactions, Coll. Antropol. 31 (2007) Suppl. 1: 63–67
64
TABLE 1
DISTINGUISHING CHARACTERISTICS OF PHOTOTOXIC AND PHOTOALLERGIC REACTIONS
Feature Phototoxic reaction Photoallergic reaction
Incidence High (more common) Low (less common)
Amount of agent required for
photosensitivity
Large Small
Mechanisms No immune reactions, light-activated
cell membrane compounds and DNA
Immunologically mediated cell-mediated immune
responses (type IV) to a light-activated compound
Onset of reaction after exposure
to agent and light
Minutes to hours 24–72 hours
Distribution Sun-exposed skin only Sun-exposed skin, may spread to unexposed areas
Clinical characteristics Exaggerated sunburn Dermatitis,
photoallergen applied topically
Þeczematous morphology;
photoallergen systemically
Þdrug eruption
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Forms of Phototoxic Reactions
Berloque dermatitis is another form of phototoxic re-
action resulting from the local application of various
cosmetical compounds and UV light (mostly UVA). In
most instances it results from the application of cosme-
tical products (after-shave, soaps, creams, etc.), which
contain phototoxic substances (e.g. oleum bergamote).
Described phototoxic reaction appears on photoexposed
body parts in the form of erythema, oedema, vesicles and
bullae with long lasting residual hyperpigmentations.
The most common sites are the face, neck and neckline.
Treatment includes complete avoidance of cosmetical
compounds containing photosensitising substances. The
resulting hyperpigmentation can be treated with 5% to
10% monobenzil esther of hydrokinone or with 0.15%
A-vitamin acid patients2. Phytophotodermatitis is a form
of photoreaction resulting in toxic dermatitis after the
contact with plants on photo exposed body areas after
sun exposure2,9. Furocoumarins from plants together
with UVA induce acute bullous reaction with erythema
and postinflammatory hyperpigmentations. The treat-
ment comprises of local application of different antibac-
terial and corticosteroid creams and lotions. Photo-ony-
cholysis may also be a manifestation of phototoxicity,
mostly induced by the use of systemic medications, in-
L. Lugovi} et al.: Phototoxic and Photoallergic Skin Reactions, Coll. Antropol. 31 (2007) Suppl. 1: 63–67
65
TABLE 2
COMMON PHOTOSENSITIZING MEDICATIONS
Class Medication Phototoxic
Reaction
Photoallergic
Reaction
Antibiotics
Tetracyclines (doxycycline, tetracycline) Yes No
Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) Yes No
Sulfonamides Yes No
Nonsteroidal
anti-inflammatory
drugs (NSAIDs)
Ibuprofen Yes No
Ketoprofen Yes Yes
Diuretics Furosemide Yes No
Hydrochlorothiazide Yes Yes
Retinoids Isotretinoin Yes No
Acitretin Yes No
Hypoglycemics Sulfonylureas (glipizide, glyburide) No Yes
PDT Pro-photosensitizers
5-aminolevulinic acid Yes No
Methyl-5-aminolevulinic acid Yes No
Verteporfin Yes No
Photofrin Yes No
Neuroleptic drugs
Phenothiazines (chlorpromazine, fluphenazine, perazine,
perphenazine, thioridazine) Ye s Yes
Thioxanthenes (chlorprothixene, thiothixene) Yes No
Antifungals Itraconazole Yes Yes
Voriconazole Yes No
Sunscreens
Para-aminobenzoic acid (PABA) No Yes
Cinnamates No Yes
Benzophenones No Yes
Salicylates No Yes
Fragrances Musk ambrette No Yes
6-Methylcoumarin No Yes
Other drugs
Para-aminobenzoic acid (PABA) Yes Yes
5-FU Yes Yes
Amiodarone Yes No
Diltiazem Yes No
Quinidine Yes Yes
Coal tar Yes No
Dapsone No Yes
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cluding tetracycline, psoralens, chloramphenicol, fluoro-
quinolones, oral contraceptives, quinine, and mercapto-
purine.
Photoallergic Reactions in The Skin
Photoallergic reactions are less prevalent and develop
only in a minority of individuals exposed to the combina-
tion a compound (mostly systemic drugs) and UV light.
Photoallergic reactions can be caused either by topical or
systemic administered substance. The amount of drug
required for photoallergic reactions is considerably smal-
ler than that required for phototoxic reactions. Photo-
allergic reactions resemble allergic contact dermatitis,
with a distribution limited to sun-exposed areas, al-
though they may sometimes extend into covered areas of
skin3,7. Described reactions are cell-mediated immune re-
sponses to a light-activated compound and typically de-
velops in sensitized individuals 24–48 hours after expo-
sure. The antigen is a light-activated drug transformed
to a metabolite that binds to protein carriers in the skin
forming a complete antigen. The reaction then proceeds
exactly as other cell-mediated immune responses do.
Specifically, Langerhans cells (LCs) and other antigen-
presenting cells take up the photoallergen and migrate to
regional lymph nodes where present it to T cells, which
express antigen-specific receptors. Then T cells become
activated, proliferate, and return to the site of photo-
allergen deposition, leading to an inflammatory skin
response2. Generally, when the photoallergen is applied
topically there is usually an eczematous response, but if
the photoallergen is administered systemically, the result
is a skin drug reaction. The reaction usually manifests as
a pruritic eczematous eruption with erythema and vesi-
cles in the acute phase, while more chronic exposure re-
sults in erythema, lichenification and scaling. Hyper-
pigmentation does not occur in photoallergic reactions.
Photoallergic reactions are significantly less common
than phototoxic reactions, still with unknown frequency.
Men are more likely to have photoallergic reactions than
women. Generally, drug-induced photosensitivity reac-
tions can occur in persons of any age2. The carcinogenic
potential due to prolonged exposure to photosensitizing
drugs has been suggested.
Diagnostics
The physical examination and a positive patient’s his-
tory of photosensitivity reactions on medications or sub-
stances locally applied to the skin are of great importance
(e.g. sunscreens, fragrances, antibacterial soaps, etc.). In
the diagnosis of photoallergic contact dermatitis, photo-
patch testing is an important tool, performed by applying
suspected photoallergens to the back in 2 sets (one set is
removed after 24 hours and irradiated, and both sets of
patch tests are evaluated for a positive reaction (mani-
fested with erythema, oedema, and/or vesicles after 48
hours)14,15. A positive reaction at the non-irradiated site
with a stronger one at the irradiated site should be inter-
preted as both allergic dermatitis and photoallergic con-
tact dermatitis reaction to the same compound2,14. Pho-
totesting with UVA, UVB, and in some instances, visible
light is helpful in diagnosing photosensitivity disorders
and performed by exposing small areas of skin on the
back or inner aspect of the forearms with gradually in-
creasing doses of light. Histopathologic analysis of photo-
toxic reactions shows epidermal spongiosis and dermal
oedema, with mixed infiltrate of lymphocytes, macropha-
ges, and neutrophils. In acute phototoxic reactions, ne-
crotic keratinocytes are observed. Blue-grey pigmenta-
tion is characterized by phototoxic reactions results from
increased melanin in the dermis or deposition of the drug
or its metabolites in the skin2. Photoallergic reactions
histologically resemble contact dermatitis, with epider-
mal spongiosis and dermal lymphocytic infiltrate, ne-
crotic keratinocytes, which is suggestive of photoallergy.
Therapy
Treatment of photodermatoses includes identification
and avoidance of the causative agent, symptomatic mea-
sures, topical corticosteroids, cool dressings, and sys-
temic corticosteroids in the severe cases. If sunscreens
are not the causative agents, patients are encouraged to
use the sunscreens with UVA protection. SPF is not a re-
liable indicator of protection against drug-induced photo-
sensitivity and refers to the degree of protection against
primarily UVB range.
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L. Lugovi}
Clinical Department of Dermatovenerology, University Hospital »Sestre milosrdnice«, Vinogradska cesta 29,
10000 Zagreb, Croatia
e-mail: liborija@yahoo.com
FOTOKSI^NE I FOTOALERGIJSKE KO@NE REAKCIJE
SA@ETAK
Indirektno djelovanje sunca zajedno sa razli~itim egzogenim tvarima (sistemski lijekovi i lokalno aplicirane tvari)
ponekad mogu dovesti do fototoksi~nih i fotoalergijskih reakcija. Fotopreosjetivost potaknuta lijekom odnosi se na raz-
voj ko`ne bolesti kao rezultat kombiniranog djelovanja lijeka i svjetla (ve}inom unutar UVA spektra i vidljivog svjetla ili
UVB). Cilj ove studije bio je prikazati istaknute karakteristike fototoksi~nih i fotoalergijskih reakcija koje se odvijaju na
fotoeksponiranim predjelima, uklju~uju}i lice, vrat, {ake i podlaktice. Fototoksi~ne reakcije su zna~ajno u~estalije od
fotoalergijskih reakcija i ve}inom sli~e te{kim opekotinama. Fotoalergijske reakcije se javljaju samo u malog broja ljudi i
sli~e alergijskom kontaktnom dermatitisu na fotoeksponiranim predjelima, iako se ponekad mogu {iriti na neizlo`ene
dijelove. Op}enito su od velikog zna~enja za dijagnozu bolesnika s reakcijom preosjetljivosti na razli~ite tvari fizikalni
pregled i pozitivna anamneza. Lije~enje ovih reakcija uklju~uje prepoznavanje i izbjegavanja takvih tvari te primjenu
antiupalnih krema, masti i kortikosteroida.
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