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16 Chapter 92 :: A bnormal Responses to Ultraviolet

Radiation: Photosensitivity Induced

by Exogenous Agents
:: Henry W. Lim
individuals exposed to adequate doses of the agent
ABNORMAL RESPONSES TO and the activating wavelengths of radiation (Table
ULTRAVIOLET RADIATION 92-1). In contrast, photoallergy is a type IV delayed
AT A GLANCE hypersensitivity response to a molecule that has been
modified by absorption of photons. It has a sensitiza-
tion phase, occurs only in sensitized individuals, and
Section 16

Photosensitivity is broadly divided into

phototoxicity and photoallergy, caused requires only a minimal concentration of the photoal-
by topical or systemic agents that absorb lergen (see Table 92-1).
ultraviolet A (UVA) energy.

Phototoxicity occurs in anyone exposed to

sufficient phototoxic agent and UV radiation
Disorders Due to Ultraviolet Radiation

Over 350 medications in the United States have been

and usually manifests as an exaggerated
reported to cause photosensitivity.1 Only a small num-
sunburn reaction.
ber of them, however, induce reactions frequently or
Photoallergy is an immune reaction to a have been well studied (Tables 92-2, 92-3, 92-4, and
92-5). In evaluations performed at photodermatol-
UVA-modified chemical, commonly topical
ogy centers in New York City, Melbourne, Singapore,
sunscreen agents and antimicrobials in the
and Detroit, photosensitivity induced by a systemic
United States and the United Kingdom
drug was documented in 5% to 15% of the referred
and topical nonsteroidal anti-inflammatory
patients.2–5 In studies performed in the United States,
agents in Europe. It presents as eczematous
United Kingdom, Europe, and Australia, the percent-
eruption on sun-exposed areas.
age of photopatch-tested patients who had clinically
History taking is an important part of the relevant reactions leading to a diagnosis of photoaller-
gic contact dermatitis ranged from 1.4% to 12.0%, with
evaluation; phototesting and photopatch
the value in most series being around 10%.2,5–11
testing are sometimes helpful.

Differential diagnosis includes contact PHOTOTOXICITY

allergic or contact irritant dermatitis,
airborne contact dermatitis, and other

Management consists of identification Several pathways eventuate in the development of

phototoxic tissue damage, and for many phototoxic
and avoidance of the precipitating agent,
agents more than one pathway is responsible.
photoprotection, and symptomatic therapy.
of radiation energy by the photosensitizer (P) at its
Photosensitivity may be caused by exogenous or endog- ground state, formation of an excited (usually triplet)
enous agents. It occurs when a compound, classically state (3P) molecule occurs. The excited state molecule
one with unsaturated double bonds in a six-carbon may then participate in oxygen-dependent processes
ring, absorbs radiation energy in its action spectrum, (i.e., photodynamic processes) via two major pathways,
usually ultraviolet A (UVA) wavelengths. Exogenous type I and type II reactions, both of which result in cyto-
photosensitizers can be agents administered systemi- toxic injury.12
cally or applied topically. Well-characterized examples The type I reaction involves transfer of an electron
of photosensitivity induced by endogenous photosen- or a hydrogen atom to the excited state photosensitizer
sitizers are the cutaneous porphyrias, which are asso- (3P), which results in the formation of free radicals [Eq.
ciated with enzymatic defects in heme biosynthetic (92-1)]. These may then participate in an oxidation–
pathways that result in elevated levels of porphyrins, reduction reaction that results in peroxide formation
known phototoxic agents (see Chapter 132). and subsequent cell damage [Eqs. (92-2) and (92-3)].
Photosensitivity induced by exogenous agents can 3
be divided into phototoxicity and photoallergy. Pho- P + RH → PH ⋅+ R ⋅ ( 92-1)
totoxicity is the result of direct tissue injury caused by PH ⋅ + PH ⋅ → P + PH2 ( 92-2)
1066 the phototoxic agent and radiation. It can occur in all PH2 + O2 → P + H2O2 ( 92-3)
Table 92-1
Characteristics of Phototoxicity and Photoallergy

Phototoxicity Photoallergy
Clinical presentation Exaggerated sunburn reaction: erythema, Eczematous lesions; usually pruritic
edema, vesicles, and bullae; burning,
stinging; frequently resolves with
Histologic features Eosinophilic keratinocytes, epidermal Spongiotic dermatitis, dermal
necrosis, dermal edema, sparse dermal lymphohistiocytic infiltrate
infiltrate of lymphocytes, macrophages,
and neutrophils
Pathophysiology Direct tissue injury Type IV delayed hypersensitivity response

Chapter 92
Occurrence after first exposure Yes No
Onset after exposure Minutes to hours 24 to 48 hours
Dose of agent needed for reaction Large Small
Cross-reactivity with other agents None Common

Abnormal Responses to Ultraviolet Radiation: Exogenous
Topical agent Clinical Photopatch tests
Systemic agent Clinical + phototests Clinical + phototests; possibly photopatch tests

Alternatively, interaction of 3P with ground state formation of hydroperoxides, which initiate lipid and
oxygen could result in the formation of superoxide protein oxidation.
anion (O2−.), which, in turn, can be converted into Phototoxicities induced by porphyrins,12 quino-
highly reactive and cytotoxic hydroxyl radicals (OH·). lones,13 nonsteroidal anti-inflammatory agents, tet-
The type II reaction is also known as an energy trans- racyclines, amitriptyline, imipramine, sulfonylureas,
fer process. Transfer of energy to ground state oxygen hydrochlorothiazide, furosemide, and chlorpromazine14
results in the formation of singlet oxygen (1O2), which are examples of photodynamic phototoxic reactions.
is highly reactive and has a lifetime of 50 ns [Eq. (92-4)]:
P + O2 → P + 1O2 ( 92- 4 ) sure to radiation may result in the generation of stable
photoproducts that are responsible for tissue injury.
Cytotoxic injury occurs upon singlet oxygen-
Phototoxic products have been demonstrated on
induced oxidation of amino acids and unsaturated
irradiation of phenothiazines, chlorpromazine, tetra-
fatty acids; interaction with the latter results in the
cyclines, quinolones, and nonsteroidal anti-inflamma-
tory agents.15

TABLE 92-2 BINDING TO SUBSTRATE. Another mechanism of

Topical Phototoxic and Photosensitizing Agents phototoxicity is radiation-mediated binding of the pho-
tosensitizer to its biologic substrate. A photoaddition
Agent Exposure reaction occurs when the excited state molecule cova-
lently binds to a ground state molecule. An example is
Fluorescein Used topically to visualize the anterior the covalent binding of 8-methoxypsoralen to pyrimi-
surface of the eye dine bases of the DNA molecules, which results in the
Fluorouracila Topical treatment of actinic keratoses formation of a cross-link between the DNA strands.
Furocoumarins Occur naturally in plants (especially
Compositae species), including fruits INFLAMMATORY MEDIATORS. Mediators of
and vegetables (lime, lemon, celery, fig, inflammation and inflammatory cells participate in
parsley, and parsnip); used in topical phototoxic tissue injury. Biologically active products
photochemotherapy of complement activation, mast cell-derived media-
tors, eicosanoids, proteases, and polymorphonuclear
Retinoidsa For treatment of acne and photoaging
leukocytes contribute to the development of photo-
Rose Bengal Used in ophthalmologic examinations toxicity induced by porphyrins, demeclocycline, and
Tar Used as topical therapeutic agent;
found in roofing materials
APOPTOSIS. Photodynamic therapy (PDT) involves
Induces exaggerated UV response due to skin irritancy. the use of a photosensitizer and electromagnetic 1067
16 TABLE 92-3
Systemic Phototoxic Agents

Generic Name (Common US Generic Name (Common US

Class Trade Names)a Class Trade Names)a
Antifungal Griseofulvin (Fulvicin, Grifulvin V, Immunosuppressant Azathioprine (Azasan, Imuran)
Nonsteroidal anti- Acetic acid derivative
Voriconazole (Vfend)
inflammatory drugs Diclofenac (Arthrotec, Cataflam,
Antimalarials Chloroquine (Aralen)   Voltaren)
Quinineb Alkanone derivative
Nabumetone (Relafen)c
Antimicrobials Sulfonamides
Anthranilic acid derivative
Mefenamic acid (Ponstel)
Demeclocycline (Declomycin)c
Section 16

Cyclooxygenase-2 inhibitor
Doxycycline (Adoxa, Doryx,
Celecoxib (Celebrex)
  Monodox, Periostat, Vibra-Tabs,
Enolic acid derivative
Piroxicam (Feldene)b,c
Minocycline (Arestin, Dynacin,
Propionic acid derivatives
Ibuprofen (Advil, Motrin, Nuprin,

Tetracycline (Helidac, Sumycin)

Trimethoprim (Bactrim, Polytrim,
Disorders Due to Ultraviolet Radiation

Ketoprofen (Orudis, Oruvail)

  Primsol, Septra)
Naproxen (Aleve, Naprelan,
Ciprofloxacin (Cipro)
Oxaprozin (Daypro)
Enoxacin (Penetrex)b
Tiaprofenic acid
Gemifloxacin (Factive)
Salicylic acid derivative
Lomefloxacin (Maxaquin)b,c
Diflunisal (Dolobid)
Moxifloxacin (Avelox)
Nalidixic acid (NegGram)b,c Oncologic drugs Dacarbazine (DTIC-Dome)
Norfloxacin (Chibroxin, Noroxin) Docetaxel (Taxotere)
Ofloxacin (Floxin, Ocuflox) Fluorouracil (Adrucil)
Sparfloxacin (Zagam)c Methotrexate (Rheumatrex)d
Paclitaxel (Taxol)
Cardiac drugs Amiodarone (Cordarone, Pacerone)c
Vinblastine (Velban)
Quinidine (Quinaglute, Quinidex)b
Photodynamic Porfimer (Photofrin)c
Diuretics Furosemide (Lasix)c
therapy agents Verteporfin (Visudyne)c
Bendroflumethiazide (Corzide) Psychotropic drugs Alprazolam (Xanax)
Chlorothiazide (Aldoclor, Diuril)c Chlordiazepoxide (Librax, Librium,
Hydrochlorothiazide (Accuretic,  Limbitrol)
 Aldactazide, Aldoril, Atacand, Clozapine (Fazaclo)
Avalide, Capozide, Diovan, Phenothiazines
Dyazide, Hyzaar, Inderide, Chlorpromazine (Thorazine)c
Lopressor, Lotensin, Maxzide, Perphenazine (Triavil, Trilafon)
Micardis, Microzide, Moduretic, Prochlorperazine (Compazine)c
Prinzide, Teveten HCT, Uniretic, Thioridazine (Mellaril)
Vaseretic, Zestoretic, Ziac)c Trifluoperazine (Stelazine)
Dyes Fluorescein (AK-Fluor, Fluorescite)
Amitriptyline (Elavil, Limbitrol,
Methylene blue
Furocoumarins Psoralens Desipramine (Norpramin)
5-Methoxypsoralenc Imipramine (Tofranil)
Other Dapsone
Flutamide (Eulexin)
Hypoglycemics Sulfonylureas Hypericin (St John’s wort)
Acetohexamide (Dymelor) Pyridoxine (vitamin B6)
Chlorpropamide (Diabinese) Ranitidine (Zantac)
Glipizide (Glucotrol, Metaglip)
Glyburide (DiaBeta, Glucovance,
  Glynase PresTab, Micronase)
Tolazamide (Tolinase)
Tolbutamide (Orinase)c
Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly useful.
Also reported as a systemic photoallergen.
1068 c
Commonly reported.
Induces erythema on previously UV-exposed sites.
TABLE 92-4 TABLE 92-5
Topical Photoallergens Systemic Photoallergens

Chemical Name Generic Name

Group Trade Namea Property (US Trade Namea)
Sunscreens (see Benzophenones Antifungal Griseofulvin (Fulvicin, Grifulvin V,
Chapter 223) Benzophenone-3 (oxybenzone)b   Gris-PEG)
Benzophenone-4 (sulisobenzone)
PABA derivatives Antimalarial Quinine
Ethylhexyl dimethyl PABA (padimate O)b Antimicrobials Quinolone
PABAb Enoxacin (Penetrex)
Ethylhexyl methoxycinnamate (octinoxate) Cardiac medication Quinidine (Quinaglute, Quinidex)
Cinoxate (cinoxate)
Nonsteroidal anti- Ketoprofen (Orudis, Oruvail)

Chapter 92
inflammatory drugs Piroxicam (Feldene)
Butyl methoxydibenzoylmethane
  (avobenzone, Parsol 1789)b Vitamin Pyridoxine hydrochloride
Octocrylene (octocrylene)   (vitamin B6)
Octyl triazone
Phenylbenzimidazole sulfonic acid Although it is the policy not to use trade names in this book, excep-

  (ensulizole) tions are made in cases in which we consider this information highly

Abnormal Responses to Ultraviolet Radiation: Exogenous

Fragrances 6-Methylcoumarinb
Musk ambretteb
Sandalwood oil
Anti-infective Surface disinfectants: halogenated radiation in the presence of oxygen to treat prema-
agents salicylanilides lignant and malignant skin conditions. In addition to
Dibromosalicylanilide (dibromsalan, DBS)b
generating reactive oxygen species, which results in
Tetrochlorosalicylanilide (Irgasan BS200)b
Tribromosalicylanilide (tribromsalan, TBS)b
cytotoxicity, PDT also is a potent inducer of apoptosis.12
Skin cleansers
Chlorhexidine (Hibiclens)
Hexachlorophene (pHisoHex)
Bithionol (thiobis-dichlorophenol)b ACUTE PHOTOTOXICITY. (See Table 92-1.) Acute
Dichlorophene (G4, Korium, Teniatol) phototoxicity occurs within hours of exposure to the
Dimethylol dimethyl hydantoin phototoxic agent and UV radiation. Symptoms are
Fenticlor (bis-hydroxy-chlorophenyl sulfide)b drug-dose and UV-dose dependent—usually asymp-
Personal care products
tomatic, but at sufficient doses, the patient complains
Triclosan (Irgasan DP300, Microban,
Lexol 300)
of a burning and stinging sensation on exposed areas,
Topical antifungals such as forehead, nose, V area of the neck, and dorsa
Buclosamide (Jadit, of the hands (Fig. 92-1). Erythema and edema may
butylchlorosalicylamide) appear within hours of exposure; in severe cases, vesi-
Multifungin (bromochlorosalicylanilide, cles and bullae may develop accompanied by pruritus.
 BCSA) Protected areas, such as nasolabial folds, postauricu-
Others Antibiotic for cattle lar and submental areas, and areas covered by cloth-
Olaquindoxb ing, are spared. A notable exception to these kinetics
Nonsteroidal anti-inflammatory agents is psoralen-induced phototoxicity, in which often the
(topical) acute response first appears after 24 hours, and peaks
Etofenamate at 48–72 hours, which is the rationale for administer-
ing psoralen plus UVA (PUVA) photochemotherapy
Flufenamic acid
Ketoprofenb doses 48–72 hours apart. The phototoxic response
Phenothiazines resolves with a varying degree of hyperpigmentation,
Chlorpromazine (Thorazine)b which may last for months. At lower drug/UV doses,
Promethazine (Phenergan)b gradual tanning only, without preceding sunburn-like
Miscellaneous reaction, can be seen.
Acyclovir cream (Zovirax)
Clioquinol (Vioform,
PHOTO-ONYCHOLYSIS. Separation of the distal
Cadmium sulfide
nail from the nail bed, usually painful, is a manifesta-
Cinchocaine (Dibucaine) tion of acute phototoxicity, with the nail plate serving
Thiourea (thiocarbamide, sulfourea) as a lens to focus UV energy on the nail bed. It has been
reported with doxycycline and other tetracyclines, flu-
PABA = para-aminobenzoic acid.
oroquinolones, psoralens, benoxaprofen, clorazepate
Although it is the policy not to use trade names in this book, exceptions
are made in cases in which we consider this information highly useful.
dipotassium, olanzapine, aripiprazole, indapamide,
Commonly reported to be photoallergens. and quinine (Fig. 92-2).17 1069
Section 16

Figure 92-3  Minocycline-induced blue–gray pigmenta-

tion on cheeks and upper lip.

scars, although similar pigmentation on forearms and

Disorders Due to Ultraviolet Radiation

shins can also occur. Chronic exposure to diltiazem, a

benzothiazepine calcium channel blocker, has resulted
Figure 92-1  Amiodarone-induced phototoxicity. Note in photodistributed, reticulated, slate-gray pigmenta-
the erythema and slate-gray pigmentation (nose, fore- tion. Slate-gray pigmentation seen in argyria involves
head) on the sun-exposed area. the nail lunulae, mucous membranes, and sclerae. A
photochemical reaction, in which silver granules are
deposited in the dermis, results in these pigmentary
SLATE-GRAY PIGMENTATION. Asymptomatic alterations.
blue–gray pigmentation on sun-exposed areas has
been associated with exposure to several agents.18,19 LICHENOID ERUPTION. Lichenoid eruption has
One percent to ten percent of patients taking amioda- been reported as a form of phototoxicity, but is con-
rone develop this side effect (Fig. 92-1). Chlorproma- troversial.
zine and clozapine can induce a similar change. The
tricyclic antidepressants imipramine and, less com- PSEUDOPORPHYRIA. The development of por-
monly, desipramine have also been reported to cause phyria cutanea tarda-like cutaneous changes of skin
slate-gray pigmentation. A drug metabolite–melanin fragility, vesicles, and subepidermal blisters is asso-
complex has been postulated to be the cause of this ciated with several phototoxic agents (Fig. 92-4).
alteration. Minocycline can induce blue–gray pigmen- Although histologic and immunofluorescence findings
tation on the face (Fig. 92-3), frequently on sites of acne are similar to those of porphyria cutanea tarda, the por-
phyrin profile is normal or in the upper range of nor-
mal in these patients. Naproxen is the most commonly
reported causative agent. Other drugs incriminated
include amiodarone, β-lactam antibiotics, celecoxib,
ciprofloxacin, cyclosporine, diflunisal, etretinate, furo-
semide, imatinib, nabumetone, nalidixic acid, narrow-
band UVB, oral contraceptives, oxaprozin, ketoprofen,
mefenamic acid, the tetracyclines, tiaprofenic acid,
torsemide, and voriconazole.20,21


This has been uniquely described with voriconazole, a
broad spectrum antifungal agent. Immunosuppressed
patients receiving voriconazole for >12 weeks can
develop photosensitivity, pseudoporphyria, photoag-
ing, lentigines, premature dermatoheliosis; in addition,
squamous cell carcinoma and melanoma have been
described in this group of patients who were on vori-
conazole for >12 months.21


angiectasia on sun-exposed areas has been reported
1070 Figure 92-2  Distal onycholysis in a patient receiving pso- with calcium channel blockers, including nifedip-
ralen plus ultraviolet A therapy. ine, amlodipine, felodipine, and diltiazem, with the

Chapter 92
Figure 92-4  Pseudoporphyria. Note subtle erosions on
dorsum of hand and at the base of the index finger, and
crusting on the knuckle.

antibiotic cefotaxime, and with antidepressant ven-

Abnormal Responses to Ultraviolet Radiation: Exogenous

lafaxine. In some of these patients, provocation with
UVA resulted in the development of telangiectasia.22
Figure 92-5  Chronic actinic dermatitis. Note the lichenifi-
PERSISTENCE OF PHOTOSENSITIVITY AND cation and hyperpigmentation on sun-exposed areas, and
TITIS. Although phototoxicity usually resolves after
discontinuation of the causative agent, there are reports
of persistence of photosensitivity for many years after
the cessation of exposure, which results in the develop-
SYSTEMIC AGENTS. Table 92-3 lists the major sys-
temic phototoxic agents.24–28 They commonly produce
ment of chronic actinic dermatitis (Fig. 92-5). The con-
an exaggerated sunburn reaction but, like most photo-
dition presents with pruritus and lichenification and
toxins, may also induce an eczematous photoallergic
excoriation on sun-exposed sites; it has been reported
response in a small percentage of users, especially after
with thiazides, quinidine, quinine, and amiodarone.23
topical exposure. As a rule, the action spectra are in
the UVA range; notable exceptions are the porphyrins,
CHRONIC EFFECTS. Cutaneous effects of long- fluorescein, and other dyes, whose action spectra are in
term, repeated phototoxic tissue injury are best exem-
the visible light range.
plified by the manifestations in patients who have
received long-term PUVA photochemotherapy, which
is known to affect DNA. These effects include prema- HISTOPATHOLOGY
ture aging of the skin, lentigines, squamous cell and
basal cell carcinomas, and melanoma. These are dis- Acute phototoxicity is characterized by individual
cussed in greater detail in Chapter 238. necrotic keratinocytes and, in severe cases, epider-
mal necrosis (see Table 92-1). There may be epidermal
PHOTOTOXIC AGENTS spongiosis, dermal edema, and a mild infiltrate con-
sisting of neutrophils, lymphocytes, and macrophages.
TOPICAL AGENTS. Table 92-2 lists the major topi- Slate-gray pigmentation is associated with increased
cal phototoxic and photosensitizing agents. It should dermal melanin and dermal deposits of the drug or its
be noted that fluorouracil and retinoids induce exag- metabolite.18,19 Histologic features of lichenoid erup-
gerated UV response due to their irritant effect on the tions are similar to those of idiopathic lichen planus;
skin. Therapeutic or occupational exposures to these however, there may be a greater degree of spongiosis
agents are the common route of contact. and dermal eosinophilic and plasma cell infiltrates,
and a larger number of necrotic keratinocytes and
Furocoumarins. Topical exposures to furocouma- cytoid bodies. In pseudoporphyria, as in porphyria
rins may occur in individuals in certain occupations cutanea tarda, there is dermal–epidermal separation at
(bartenders, salad chefs, gardeners) and in patients the lamina lucida and deposits of immunoglobulins at
receiving topical photochemotherapy with psoralens. the dermal–epidermal junction and surrounding blood
vessel walls.20,21
Tar. Crude coal tar, although no longer commonly
used in dermatologic therapy, is well documented to
produce a burning and stinging sensation on expo- MANAGEMENT
sure to UVA (“tar smarts”). In addition to phototox-
icity, occupational exposure to tar is associated with Identification and avoidance of the causative phototoxic 1071
increased risk of nonmelanoma skin cancers. agent are the most important steps in management.
16 Beyond this or if the agent cannot be removed, sun
avoidance is essential. Because the action spectrum
cant postinflammatory hyperpigmentation. Lichenoid
eruption has also been reported.
for most agents is in the UVA range, high sun protec- Currently, in the United States, United Kingdom,
tion factor, broad-spectrum sunscreens containing and France, UV filters in sunscreen products (espe-
efficient UVA filters should be used (see Chapter 223). cially benzophenone-3) and antimicrobial agents are
Acute phototoxicity can be managed with topical cor- the most common cause of photoallergy, whereas
ticosteroids and compresses; systemic corticosteroids NSAIDs are the leading topical photoallergens in Eur
should be reserved for only the most severely affected ope.10,11,30–32 Although there have been reports of sys-
patients. Management of patients with slate-gray pig- temic agents inducing a photoallergic response, the
mentation, lichenoid eruption, pseudoporphyria, and evidence of such response remains unclear.30
photodistributed telangiectasia is symptomatic only, As with phototoxicity, persistence of photosensi-
and patients should be advised that it will take months tivity and evolution to chronic actinic dermatitis (see
after the discontinuation of the offending agent for the Chapter 91) have been reported after exposure to
condition to resolve. Patients with nonsteroidal anti- photoallergens, including chlorpromazine, dioxopro-
inflammatory drug-induced (NSAID-induced) pseu- methazine, halogenated salicylanilides, ketoprofen,
Section 16

doporphyria who require NSAIDs should be switched musk ambrette, olaquindox, and quinidine.33,34 The
to a different class of agents or to those that are less mechanism is not completely understood. One pos-
photosensitizing, such as indomethacin or sulindac.29 sible explanation is that UV radiation alters the carrier
protein that originally binds the photoallergen; this
results in the formation of a neoantigen that stimulates

PHOTOALLERGY the immune system over the long term. This hypoth-
Disorders Due to Ultraviolet Radiation

esis is supported by the observation that the histidine

PATHOPHYSIOLOGY moiety in albumin can undergo oxidation in the pres-
ence of salicylanilide, which binds to albumin.
Photoallergy is a type IV delayed hypersensitivity
response requiring the presence of both photoallergen
and the activating wavelengths of radiation, which for PHOTOALLERGENS
most agents are in the UVA range.30 After the absorp-
tion of UV energy, a photoallergen may be converted to TOPICAL AGENTS. Topical exposure is the most
an excited state molecule, which subsequently reverts common route of sensitization to photoallergens.30,35
to ground state by releasing the energy. In this process, Table 92-4 lists the common groups of photoallergens.
the molecule may conjugate with a carrier protein to
form a complete antigen. This is thought to be the SYSTEMIC AGENTS. Photoallergy caused by sys-
mechanism of photoallergy induced by halogenated temic agents is much less frequent, and not as well
salicylanilides, chlorpromazine, and para-aminoben- documented, than that induced by topical agents. All
zoic acid (PABA). Alternatively, a photoallergen may but one of these photoallergenic agents (pyridoxine)
form a stable photoproduct on exposure to radiation, are also phototoxic and have been discussed previ-
which in turn may conjugate with a carrier protein ously in this chapter (see Section “Systemic Agents”
to form a complete antigen. Sulfanilamide and chlor- under Section “Phototoxic Agents” and Table 92-3).
promazine have both been shown to participate in this
Once the complete antigen is formed, the mechanism
of photoallergy is identical to that of contact allergy. The
The histologic features of photoallergy are similar to
antigen is taken up and processed by Langerhans cells,
those of allergic contact dermatitis. There is epidermal
which then migrate to regional lymph nodes to pres-
spongiosis associated with infiltrate of mononuclear
ent the antigen to T lymphocytes. Cutaneous lesions
cells in the dermis (see Table 92-1).
develop when the activated T lymphocytes circulate to
the exposed site to initiate an inflammatory response.
Management is identical to that of phototoxicity: iden-
In sensitized individuals, exposure to the photoaller- tification and avoidance of the photoallergen, sun-
gen and sunlight results in the development of a pru- protective measures, and symptomatic therapy.
ritic, eczematous eruption within 24 to 48 hours after
exposure (see Table 92-1). Although the morphology is
clinically indistinguishable from that of allergic con- EVALUATION OF PATIENTS
tact dermatitis, the distribution of the eruption in pho- WITH PHOTOTOXICITY AND
toallergy is predominantly confined to sun-exposed
areas; however, in severe cases, it may spread to the PHOTOALLERGY
covered areas, albeit at a lower intensity. Unlike the
lesions in phototoxicity in fair-skinned individuals, The evaluation of patients with phototoxicity and
1072 those in photoallergy usually resolve without signifi- photoallergy is similar to the evaluation of patients
with other photosensitivity disorders and is described
in greater detail in Chapter. A history of exposure to
titis and irritant contact dermatitis occur at sites of con-
tact, in both sun-exposed and in sun-protected areas.
known photosensitizers is most important. It is also Other photodermatoses can be differentiated from
helpful to ascertain whether window glass-filtered phototoxicity and photoallergy by their characteristic
sunlight can induce the cutaneous eruption, because time course and morphology and lack of a compatible
UVB is filtered out by window glass. Distribution of exposure history. Polymorphous light eruption mani-
the cutaneous eruption is a helpful clue to the type fests itself within a few hours of sun exposure as pru-
of photosensitizer responsible. Widespread eruption ritic papules, plaques, and, uncommonly, vesicles on
suggests systemic photosensitizers, whereas topical sun-exposed sites and resolves in a few days. Chronic
photosensitizers produce lesions only in areas that actinic dermatitis presents as chronically lichenified
have been exposed to both sensitizers and radiation. plaques on sun-exposed areas. Lesions of solar urti-
Vesicular and bullous eruptions are most commonly caria appear within minutes of sun exposure as mildly
associated with phototoxicity, whereas eczematous pruritic urticaria and resolve within a few hours.
eruptions strongly suggest photoallergy; usually, the
former is associated with a burning sensation, the lat-

Chapter 92
ter with pruritus. Skin biopsy findings may also be OTHER EXOGENOUS AGENT-
helpful in differentiating these two conditions: necrotic
keratinocytes are commonly seen in phototoxicity, INDUCED PHOTODERMATOSES
whereas spongiotic dermatitis is associated with pho- AND PHOTOEXACERBATED
toallergy (see Table 92-1).

Phototests and photopatch tests are an integral part

Abnormal Responses to Ultraviolet Radiation: Exogenous

of the evaluation of photosensitivity when history and
physical examination alone are insufficient to deter- PORPHYRIA CUTANEA TARDA
mine the responsible agent. Approximately 10% of
patients who undergo photopatch testing have clini- (See Chapter 132)
cally relevant positive results, which leads to the diag- Ingestion of wheat treated with hexachlorobenzene
nosis of photoallergic contact dermatitis.2,11 (HCB) as a preservative resulted in an outbreak of a
The procedures for phototesting and photopatch porphyria cutanea tarda-like syndrome in Turkey in
testing are generally as follows, although there are the 1950s.36 Inhibition of the enzyme uroporphyrino-
variations in testing methods.5,10 On day 1, exposure gen decarboxylase by HCB was thought to be respon-
to UVB and UVA to determine minimal erythema dose sible for the clinical manifestations. However, a study
(MED) is carried out, and duplicate sets of photoal- of adults highly exposed to HCB in Catalonia, Spain,
lergens are applied symmetrically to another site on and of children from the same area, did not show any
the back and covered by an opaque tape. On day 2, increase in prevalence of porphyria cutanea tarda or
the MEDs are determined. One of the duplicate set of increased urinary concentrations of porphyrins.37
photoallergens is exposed to 10 J/cm2 of UVA or 50%
of the MED to UVA, whichever is lower. After irradia-
tion, the exposed site is covered again with an opaque LUPUS ERYTHEMATOSUS
tape. On day 3, both irradiated and nonirradiated test
sites are uncovered, and the reactions are graded. On (See Chapter 155)
day 5 or day 8, the irradiated and nonirradiated sites Drug-induced systemic lupus erythematosus pres-
are evaluated for delayed reactions. Reaction only at ent with purpura, erythema nodosum, urticarial and
an irradiated site indicates photoallergy. Reaction of necrotizing vasculitis, and/or photosensitivity. It is
equal intensity at both irradiated and covered sites most commonly associated with exposure to hydral-
indicates allergic contact dermatitis. Reaction at both azine, procainamide, isoniazid, and minocycline;
sites, but with higher intensity at the irradiated site, antinuclear antibody (ANA) test is positive and anti-
signifies both photoallergy and allergic contact der- histone antibodies are characteristically present.38
matitis. Well-defined erythema that resolves promptly Drug-induced subacute cutaneous lupus erythema-
indicates an irritant dermatitis. tosus (SCLE) presents with similar cutaneous lesions as
idiopathic SCLE, although blisters and targetoid lesions
may occur, and lower extremities may be involved. Anti-
nuclear antibody and anti-Ro/SSA antibodies are fre-
DIFFERENTIAL DIAGNOSIS quently present, while antihistone antibodies are usually
OF PHOTOTOXICITY AND absent. Drugs associated with this condition include cal-
cium channel blockers, angiotensin-converting enzyme
PHOTOALLERGY inhibitors, thiazide diuretics, terbinafine and tumor
necrosis factor(TNF)-α antagonists.38
Airborne allergic contact dermatitis is characterized Drug-induced discoid lupus erythematosus is very
by involvement of skinfolds on exposed areas, such as rare; it has been reported with exposure to fluorouracil
the nasolabial folds, and the eyelids that receive mini- and TNF-α antagonists.
mal direct sunlight. It also involves exposed areas that Identification and avoidance of the precipitating
are relatively sun protected, such as the postauricular agent is the treatment of drug-induced lupus erythe-
areas and area under the chin. Allergic contact derma- matosus. 1073
16 KEY REFERENCES 13. Ferguson J, DeLeo VA: Drug and chemical photosensitiv-
ity: Exogenous. In: Photodermatology, edited by HW Lim,
H Hönigsmann, JLM Hawk. New York, Informa Health-
Full reference list available at care, 2007, p. 199-218
DVD contains references and additional content 14. Moore DE: Drug-induced cutaneous photosensitivity: In-
cidence, mechanism, prevention and management. Drug
5. Kerr HA, Lim HW: Photodermatoses in African Ameri- Saf 25:345-72, 2002
cans: A retrospective analysis of 135 patients over a 7-year 30. Kerr A, Ferguson J: Photoallergic contact dermatitis. Pho-
period. J Am Acad Dermatol Oct;57(4):638-43, 2007 todermatol Photoimmunol Photomed 26(2):56-65, 2010
10. Victor FC, Cohen DE, Soter NA: A 20-year analysis of pre- 35. Scheuer E, Warshaw E. Sunscreen allergy: A review of
vious and emerging allergens that elicit photoallergic con- epidemiology, clinical characteristics, and responsible
tact dermatitis. J Am Acad DermatolApr 62(4):605-10, 2010 allergens. Dermatitis 17(1):3-11, 2006
Section 16
Disorders Due to Ultraviolet Radiation