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C. Z. Teng et al.
Table 7 Common culprit drugs for eczematous reactions
(Joly et al. 2007; Summers et al. 2013; Thyssen and
Maibach 2008)
8-Methoxypsoralen
Alpha-blockers
5-Aminosalicylic acid
Aminophylline
Analgesics: non-steroidal anti-inammatory drugs,
opiates, paracetamol
Antibiotics: amoxicillin, ceftriaxone, chloramphenicol,
clindamycin, erythromycin, fusidic acid, gentamicin,
isoniazid, miconazole, neomycin, nystatin, quinolones,
streptomycin, sulfamethoxazole-trimethoprim,
terbinane
Antihistamines: cetirizine, diphenhydramine,
hydroxyzine
Antihypertensives: alprenolol, captopril, telmisartan,
hydrochlorothiazide
Anti-inammatories: acetyl salicylic acid,
5-aminosalicylic acid, corticosteroids, cyclooxygenase- 2 inhibitors
Antivirals: aciclovir, valaciclovir
Biological agents: cetuximab
Calcium-channel blockers
Chemotherapy agents: 5-uorouracil, mitomycin C
Clobazam
Clonidine
Doxepin
Ephedrine
Glyceryl trinitrate
Heparin
Hydroxycarbamide
Intravenous human immunoglobulins
Iodinated radiocontrast media
Oestradiol
Phenobarbital
Phenothiazines
Pseudoephedrine
Rivastigmine
Sulphonamides
Suxamethonium
atous reactions on exposure to tolbutamide or
chlorpropamide. However, in many cases of
suspected drug- induced eczematous reactions,
prior sensitization to the index drug or crossreacting compounds cannot be found. In cases
related to calcium channel blockers, nifedipine
in its photodegraded form has been shown to
stimulate iron uptake and retention in human
epidermal keratinocytes (Gruen et al. 2001).
This may induce keratinocyte apoptosis and
spongiosis, resulting in the histological ndings
of spongiosis and keratinocyte necrosis seen in
such patients, and accounting for the long delay
in recovery following drug withdrawal
(Trautmann etal. 2001).
The latency from time of drug initiation to
onset of eczematous eruption is typically
1–2weeks. It is usually a symmetrical eruption
which may initially/most severely involve the
sites of original dermatitis prior to subsequently
becoming generalized.
The differential diagnosis of drug-induced
eczematous reactions include allergic contact
dermatitis, irritant contact dermatitis and idiopathic eczematous reactions. Patch testing may
be positive; however, conrmatory diagnosis
may require oral challenge, and response to dechallenge. Resolution of clinical symptoms
within 1–3weeks of drug withdrawal.
Withdrawal of the culprit drug, with the use of
topical corticosteroids if necessary. Severe reactions may require treatment with systemic
corticosteroids.
6 Drug-Induced Acneiform
Eruptions (Drug-Induced
Acne)
Drug-induced acneiform eruptions refer to
inammatory follicular reactions resembling
acne vulgaris, induced by a medication.
Acneiform eruptions constitute 1% of all druginduced skin reactions (Valeyrie-Allanore et al.
2007).
Acneiform reactions are not hypersensitivity
reactions. The specic pathological mechanisms
vary according to the implicated drug. The pathophysiology of acne vulgaris involves the use of
toll-like receptor 2 (TLR-2) by Propionibacterium
acnes to facilitate inammation. Keratinocytes
treated with glucocorticoids were reported to
have up-regulation of TLR-2, a possible mechanism that explains why corticosteroid-associated
acne consists of predominantly inammatory
Other Drug-Induced Inammatory Skin Reactions
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199
lesions of papules and pustules (Shibata et al.
2009). Androgenic hormones lead to acneiform
eruptions by stimulating keratinocyte production,
promoting sebaceous gland hyperplasia and
increasing sebum production (Melnik etal. 2007;
Scott and Scott 1992). In EGFR-inhibitor related
reactions, the EGFR pathway which plays a key
role in keratinocyte proliferation, differentiation,
migration and survival is directly inhibited. In
concert, an inammatory response ensues resulting in the characteristic acneiform reaction
(Lacouture 2006).
The histological features of drug-induced
acneiform reactions vary according to the underlying drug. Initial lesions of steroid-induced acne
demonstrate features of focal necrosis in the
infundibulum of the follicular epithelial, with a
localized intrafollicular and perifollicular neutro-
philic inammatory reaction (Fung and Berger
2000). In contrast, acneiform eruptions associ-
ated with EGFR show ectatic follicular infundibula with rupture of the epithelial lining associated
with supercial neutrophilic folliculitis
(Lacouture 2006).
Features that suggest drug-induced acne
include a monomorphic pattern, unusual age of
onset, sudden/abrupt new onset acne, distribution beyond seborrheic regions, poor response to
conventional acne treatment and the context of
recent drug initiation (Fung and Berger 2000)
(Fig.5). The latency period between initiation of
the drug and onset of acne depends on the type
of drug, with latencies ranging from 1month or
less in systemic corticosteroids, androgens and
vitamin B) to greater than 1month in ciclosporin, lithium, antiepileptics and anti-tuberculosis
agents.
Drug-induced acneiform reactions present
with monomorphic papules and pustules, typically lacking comedones and cysts. Of note,
they may extend beyond seborrheic areas such
as the arms, lower back and genitalia. Acneiform
eruptions induced by EGFR inhibitors is generally distributed in the seborrheic areas (i.e.
neck, chest, shoulders, upper back) (Lacouture
2006).
The list of drug triggers for acneiform eruptions is summarized in Table8 (Valeyrie-Allanore
et al. 2007; Shibata et al. 2009; Melnik et al.
2007; Scott and Scott 1992; Lacouture 2006;
Fung and Berger 2000; Brodell et al. 2013;
Bencini etal. 1986; Grunwald etal. 1990; Martín
etal. 2006).
Acne vulgaris, gram-negative folliculitis,
Pityrosporum folliculitis.
Drug-induced acneiform eruptions generally
improve once the offending drug is withdrawn.
Additionally, standard systemic and topical acne
medications may be used.
Fig. 5 Steroid-induced acneiform eruption
200
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C. Z. Teng et al.
Table 8 Common culprit drugs acneiform eruptions
(Valeyrie-Allanore etal. 2007; Shibata etal. 2009; Melnik
etal. 2007; Scott and Scott 1992; Lacouture 2006; Fung
and Berger 2000; Brodell etal. 2013; Bencini etal. 1986;
Grunwald etal. 1990; Martín etal. 2006)
Hormones
Corticosteroids
Androgens and anabolic steroids
Hormonal contraceptives
Danazol
Neuropsychiatric drugs
Tricyclic antidepressants
Lithium
Valproate
Phenytoin
Dantrolene
Aripiprazole
Selective serotonin reuptake inhibitors
Vitamins
Vitamins B1, B6, B12
Immunomodulators
Ciclosporin
Sirolimus
Azathioprine
Chemotherapeutic agents
Dactinomycin
Thiourea, thiouracil
Epidermal growth factor receptors inhibitors
Multikinase inhibitors: imatinib
Histone deacetylase inhibitor: vorinostat
Halogens
Iodine
Bromine
Chlorine
Antituberculosis drugs
Isoniazid
Rifampicin
Ethionamide
Miscellaneous
Granulocyte colony-stimulating factor
Dantrolene
Targeted therapies
EGF inhibitors (cetuximab, panitumumab)
Multitargeted tyrosine kinase inhibitors (getinib,
erlotinib, lapatinib, imatinib, sorafenib, sunitinib)
VEGF inhibitor (bevacizumab)
Proteasome inhibitor (bortezomib)
TNF-alpha inhibitors (lenalidomide, iniximab)
Histone deacetylase inhibitor (vorinostat)
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Drug-Induced Photosensitivity
https://t.me/medicina_free
SallyH.Ibbotson
1 Introduction
Abnormal photosensitivity may occur when skin
photosensitised by a drug or chemical is exposed
to light, generally ultraviolet radiation. Typically,
drug-induced photosensitivity presents as an
exaggerated sunburn-like reaction, or as a rash on
exposed skin. Most prescribed medications
absorb ultraviolet and/or visible light and can
theoretically cause photosensitivity. However in
clinical practice drug-induced photosensitivity is
caused by a relatively limited number of medications. The interaction of exogenous chemical and
UV radiation can also be used therapeutically, for
example in psoralen-UVA photochemotherapy
(PUVA) and photodynamic therapy (PDT) (Ling
etal. 2016; Wong etal. 2019).
2 Epidemiology
The prevalence of drug photosensitivity in the
general population is unknown and is likely to be
under-reported as affected subjects are likely to
stop a suspected drug without seeking a medical
consultation. In one report of cutaneous adverse
drug reactions, photosensitivity was the third
commonest reaction type in a series of 118 sub-
jects (Chaabane etal. 2013). In specialist photodiagnostic units systemic drug-induced
photosensitivity generally accounts for 2–15% of
diagnosed photosensitivity diseases (Kerr and
Lim 2007; Khoo etal. 1996; Stratigos etal. 2003;
Wong and Khoo 2005; Wadhwani et al. 2013)
and our own experience in the Scottish
Photobiology Service is similar, with druginduced photosensitivity representing 4% of photodermatoses and photocontact allergic dermatitis
to topical drugs or chemicals being an additional
2% (Ibbotson 2018).
Not all individuals exposed to photoactive
drug and light will be affected; it is likely that
genetic factors inuence susceptibility to druginduced photosensitivity (Ferguson and Johnson
1990). Drug photosensitivity has been reported
more commonly in Caucasians than in AfricanAmericans, possibly suggesting a protective
effect of constitutive skin pigmentation
(Nakamura etal. 2014). There may be susceptibility in specic patient groups, a notion suggested by the relatively high incidence of
drug-induced photosensitivity in patients with
cystic brosis (Tolland etal. 2012).
3 Pathogenesis
S. H. Ibbotson (*)
Photobiology Unit, Ninewells Hospital & Medical
School, University of Dundee, Dundee, UK
e-mail: s.h.ibbotson@dundee.ac.uk
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_17
The clinical pattern of presentation of druginduced photosensitivity will depend on whether
the drug is delivered systemically or topically,
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Table 1 Characteristics of phototoxicity versus
photo allergy
Phototoxicity Photoallergy
Common Uncommon
Non-immunological Immunological (Type IV
cell-mediated)
No sensitisation needed Sensitisation essential
Can occur on rst
exposure
May be immediate onset Delayed onset
Dose-dependency Not dose-dependent (can
Occurs at site of drug/
chemical+light
Often exaggerated
sunburn, erythema,
oedema
Histopathology:
Necrotic keratinocytes,
minimal inammation
Further episodes
unlikely
Usually systemic route Usually topical route
Can be used in a
controlled way
therapeutically, e.g.
PUVA + PDT
Not on rst exposure
occur with exposure to
minute amounts of
photoallergen)
Can extend beyond sites of
drug/chemical+light—Can
generalise
Usually dermatitis
Histopathology: Spongiotic
dermatitis with eosinophils
Further episodes likely
Not used therapeutically
and on the pathogenetic mechanisms involved in
disease expression. Most drug-induced photosensitivity to systemically administered medications
occurs through phototoxicity (Ferguson 2002)
(Table 1). This is a non-immunological event,
which can occur in any individual exposed to
enough drug (or photoactive chemical) and irradiated with enough light of the appropriate wavelengths. The process will occur on rst exposure
to drug+light and demonstrates a dose- dependent
relationship (Layton and Cunliffe 1993). The
general pathogenetic principles centre on
photochemical activation of tissue-localised drug
by ultraviolet and/or visible light, resulting in
excitation and production of oxidative stress, free
radicals and photoproducts. The resulting substrate effects manifest in the skin as phototoxicity. Photoallergy (as opposed to phototoxicity) to
systemic drugs is less common and is poorly
understood pathogenetically (Ohshima et al.
2000). However, the mechanisms behind topical
photocontact allergy are clearer. Incident light
interacts with the topically applied drug inducing
a chemical alteration in that drug which subsequently becomes allergenic. This photoallergen
can thereafter elicit a delayed cell-mediated
hypersensitivity reaction (Table 1). On subsequent re-exposure to drug+light, a hypersensitivity reaction occurs in involved skin, which
manifests as dermatitis. In clinical practice, topical photocontact allergy is encountered most frequently to absorbent sunscreen chemicals and to
topical NSAIDs. Following initial sensitisation to
both drug and light, a reaction may occur to tiny
amounts of photoallergen (Kochevar and Harber
1977). Once a photocontact allergy reaction has
been initiated dermatitis can spread beyond the
sites of exposure.
Topical phototoxicity may occur following
contact with psoralen-containing plants and sunlight exposure, as with phytophotodermatitis, or
can be used in a controlled way in PUVA (Ling
etal. 2016). Other presentations, such as pseudoporphyria, drug-induced lupus erythematosus,
erythema multiforme, lichenoid reactions and
pellagra, are less common mechanisms of druginduced photosensitivity.
4 Systemic Drug Phototoxicity
andCommon Culprits
Photosensitivity has been reported in association
with a diverse range of drugs; however there is a
collection of medicines, which feature most frequently (Table 2) (Ibbotson 2018; Glatz and
Hofbauer 2012; Drucker and Rosen 2011;
Bakkour et al. 2013; Kim et al. 2018; Blakely
etal. 2019; Dawe and Ibbotson 2014). In our own
experience, in the Scottish Photobiology Service,
thiazides are the most commonly documented
drug photosensitisers along with doxycycline,
demeclocycline, ciprooxacin, retinoids, furosemide, NSAIDs, quinine, amiodarone, allopurinol, calcium antagonists and chlorpromazine.
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Table 2 Examples of phototoxic drugs
Psoralens
Diuretics and
cardiovascular drugs
Antibiotics Doxycycline, demeclocycline,
Antifungals Voriconazole, griseofulvin
Antipsychotics Phenothiazines, protriptyline
Retinoids Acitretin, isotretinoin,
Quinine
Non-steroidal
anti-inammatory
drugs
Hypoglycaemics Sulphonylureas
Porphyrins
Azathioprine
BRAF inhibitors
EGFR inhibitors
Pirfenidone
Thiazides, furosemide,
amiodarone, calcium channel
antagonists, quinidine, statins
uoroquinolones, nalidixic acid,
sulphonamides
alitretinoin
Diclofenac, naproxen
5 Clinical Presentation ofDrug
Photosensitivity
Table 3 Patterns of clinical presentation of drug photo-
sensitivity and examples of culprit drugs
Immediate
burning/prickling
Immediate
erythema/urticaria
‘Exaggerated
sunburn’ (Fig.1)
Delayed erythema Psoralens
Sun-exposed site
telangiectasia
Dermatitis Thiazides
Pseudoporphyria NSAIDS, uoroquinolones,
Lichenoid Thiazides, quinine
Altered
pigmentation
Photo-onycholysis Doxycycline, psoralens, NSAIDs
Lupus Thiazides, proton pump inhibitors
Amiodarone, chlorpromazine,
porphyrins
Amiodarone, chlorpromazine,
porphyrins
Thiazides, quinine,
demeclocycline, doxycycline,
voriconazole, uoroquinolones,
chlorpromazine, amiodarone
Calcium channel antagonists
doxycycline, retinoids,
amiodarone, furosemide,
voriconazole, nalidixic acid
Chlorpromazine,
uoroquinolones, quinine,
thiazides, amiodarone, psoralens
There is diversity in clinical presentation of
drug- induced phototoxicity (Table3). One of the
more usual presentations is of an immediate
‘prickling’ sensation on light exposure, a symptom which is common with chlorpromazine and
amiodarone. Another typical clinical feature is
an erythema of exposed skin, often with an
‘exaggerated sunburn’ phenotype. This reaction
occurs with quinine, thiazides, doxycycline and
demeclocycline (Fig.1). Urticaria may also be a
presenting sign of drug- induced phototoxicity.
Phototoxicity due to the calcium channel antagonists may be evident as photo-exposed site telangiectasiae (Bakkour et al. 2013; Collins and
Ferguson 1993; Cooper and Wojnarowska 2003).
Pigmentation may also occur as a sequel to phototoxicity, particularly with drugs such as chlorpromazine and amiodarone. Fluoroquinolone
phototoxicity may induce melanin pigmentation
which can persist for a year or more. Quinine
and thiazide phototoxicity may be associated
with leucoderma (Masuoka etal. 2011; Lecleach
etal. 1995; Beberok etal. 2017). Photo-exposed
site skin fragility can be caused by drug photo-
Fig. 1 Drug-induced phototoxicity. ‘Exaggerated sunburn’ reaction from demeclocycline phototoxicity. Note
the sparing of exed photo-protected distal phalanges and
under the watch strap
toxicity and, since it mimics porphyria cutanea
tarda, is referred to as pseudoporphyria. The
drugs associated with pseudoporphyria include
furosemide, NSAIDs (such as diclofenac or
naproxen), doxycycline, demeclocycline, uoroquinolones, oral contraceptives and retinoids.
Pseudoporphyria can also be caused by haemodialysis and excess use of sunbeds (Gould etal.
1995; Khandpur et al. 2017; Al-Khenaizan
etal. 1999).
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Certain drugs, such as psoralens, produce a
delayed erythema which peaks at 3 or 4 days
after exposure. This temporal relationship contrasts with typical sunburn, which peaks at
12–24h post-exposure.
The uoroquinolones are a drug group of particular interest since some are highly phototoxic,
particularly in the longer UVA range and visible
parts of the spectrum. The uoroquinolone reaction is usually rapid in onset, with reversibility of
phototoxicity occurring within 48h of stopping
the drug (Ferguson and Johnson 1990, 1993;
Traynor etal. 2000; Ferguson and Dawe 1997;
Oliveira etal. 2000; Kimura et al. 1996; Leone
etal. 2003). However, there is wide variation in
phototoxicity within this drug class, depending
on molecular structure (Ibbotson 2018; Ferguson
2002; Dawe et al. 2018). These drugs are also
photogenotoxic, photomutagenic and photocarcinogenic following single dose exposure in animals (Johnson etal. 1997), although there is no
convincing evidence of skin cancer risk with uoroquinolone use in humans.
6 Wavelength Dependency
The absorption spectra of photosensitising drugs,
or their photoactive metabolites, indicate that the
action spectrum for most drug phototoxicity lies in
the UVA part of the electromagnetic spectrum. A
history of the clinical reaction occurring with wintertime daylight exposure or with light passing
through windows also implicates the role of
UVA.Some drugs, such as benoxaprofen, amiodarone, uoroquinolones, quinine and porphyrins
(used in PDT), also photosensitise into the visible
part of the spectrum. Although the vast majority of
drug-induced photosensitivity reactions are UVAmediated, a minority of drugs including thiazides,
quinine, NSAIDs and retinoids can also photosensitise in the UVB region (Ibbotson 2018).
7 Investigations forDrug-
Induced Phototoxicity
If the possibility of drug photosensitivity is considered from the patient’s history then clinical
examination may yield relevant cutaneous signs.
Thereafter the gold standard investigation is
monochromator phototesting, undertaken whilst
the patient is on the suspected drug (MacKenzie
and Frain-Bell 1973). Monochromator light testing will usually show disproportionate UVA photosensitivity, sometimes extending into UVB
and/or visible wavelengths (Ibbotson 2018;
O’Reilly etal. 1999). Phototesting is also used to
distinguish drug-induced photosensitivity from
other photodermatoses, in particular chronic
actinic dermatitis (CAD) in which UVB sensitivity predominates.
Monochromator phototesting involves the use
of a ltered xenon arc lamp, coupled to a monochromator and bre optic light guide (MacKenzie
and Frain-Bell 1973). This enables narrow waveband testing across the solar spectrum to establish, rstly, if there is abnormal photosensitivity
and, secondly, which wavebands are involved.
The responses are evaluated immediately after
irradiation (occasionally phototoxic drugs cause
an urticarial reaction on phototesting) and at 24h
after testing. At the phototest readings the minimal erythema dose (MED) at each waveband is
determined. It is important that a normal population range for MEDs is available for comparison
(Moseley etal. 2009). Solar simulator phototesting may also be of benet as this allows phototesting to broader wavebands. The solar simulator
is not, however, an exact mimic of sunlight since
the output has a UVB weighting. Drug- induced
UVA sensitivity can be missed if only solar simulator phototesting is undertaken, although the
output of the solar simulator can be ltered to
deliver light without UVB.
If photosensitivity is conrmed, phototesting
should then be repeated once the culprit agent has
been discontinued, since drug-induced phototoxicity is reversible. The interval until repeat phototesting will depend on the drug implicated:
uoroquinolone phototoxicity resolves in
24–48 h, whereas thiazide phototoxicity may
take 3–6 months and quinine and amiodarone
almost a year to settle once the drug is stopped
(Ibbotson 2018). Photopatch testing is not a reliable investigation for systemic drug photosensitivity and should be restricted to the investigation
of suspected topical photoallergy (Kerr and
Ferguson 2010; Kerr etal. 2010, 2012; Gonçalo
etal. 2013). Some drugs may cause abnormali-
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ties in endogenous porphyrins (Gelot etal. 2013;
Woods etal. 2015) or may cause photosensitivity
through a lupus erythematosus mechanism.
Analysis of plasma porphyrin levels and spectrouorimetry may be necessary, along with antinuclear antibody, extractable nuclear antigens
and anti-histone antibodies.
8 Regulatory Requirements
forPhotosafety Evaluation
Photosafety investigations are required by both
the European Medicines Agency (EMA) and the
US Food and Drug Administration (FDA) for any
drug that absorbs light between 290 and 700nm
(https://www.fda.gov/regulatory- information/
search- fda- guidance- documents/s10- photosafety evaluation- pharmaceuticals). Initial invitro test-
ing using the neutral red phototoxicity assay
should be undertaken and, if there is a positive
signal for phototoxicity, animal phototoxicity
studies should be undertaken. Thereafter, if phototoxicity is conrmed, human photosafety investigations in healthy volunteers should be
considered (Dawe etal. 2018, 2003). A negative
human study would then supersede pre-clinical
data. It is important that knowledge of drug phototoxicity is established prior to drugs going to
market to minimise the risk of signicant phototoxicity being detected during post-marketing
surveillance (Morgado et al. 2019; Yin et al.
2019; Tashkent and Aiyappan 2018). A healthy
volunteer study may be undertaken as part of
photosafety evaluation using a randomised, controlled, assessor-blinded, clinical trial design
with positive and negative controls (Dawe etal.
2018, 2003). Ciprooxacin may be used as a pos-
itive control and phototesting performed with
monochromator and solar simulator at baseline
and on steady state of drug. If phototoxicity is
established, as determined by phototoxic index
(the baseline minimal erythema dose pre-drug as
a ratio of the MED on steady state of drug) then
phototesting should be repeated at intervals in
order to establish how long phototoxicity per-
sists. These photosafety evaluations have enabled
accurate objective data to be established for many
potential drug culprits, such as the uoroquinolones. Interestingly, whilst the molecular structure of uoroquinolones inuences phototoxic
potential, there also seems to be variability within
subjects (as seen with ciprooxacin) indicating
that genetic polymorphisms in drug metabolism
may be involved in phototoxicity (Ferguson and
Johnson 1990; Dawe etal. 2018, 2003). Whilst
there does appear to be reasonable correlation
between invitro and invivo phototoxicity testing
with uoroquinolones, human volunteer testing
is still not able to predict or rule out rare idiosyncratic phototoxic reactions.
9 Topical Photoallergy
Photocontact allergy to topically applied drug or
chemical is well documented. Initial reports in
the 1960s of topical photocontact allergy to halogenated salicylanilides emerged following an
outbreak of photoallergic dermatitis caused by
use of soaps containing tetrachlorosalicylanilide
(Wilkinson 1962). In current times, the absorbent
sunscreen chemicals and topical NSAIDs are the
most common culprits for topical photoallergy.
The investigation of choice in topical photocontact allergy is photopatch testing. At present, a
standard European photopatch test methodology
is established, although ongoing review is underway (Kerr etal. 2012; Gonçalo etal. 2013). This
involves application of duplicate series of allergens to the back, as in patch testing, with one set
being irradiated using a sub-erythemal UVA dose
(generally 5 J/cm2) at either 24 or 48 h after
application of the patches, and readings undertaken at intervals following irradiation. Fortyeight hours is the key reading point after
irradiation, although some centres also read at
24h and 72 h. A positive reaction on the irradiated site and a negative response on the control
site signify a photoallergic reaction. Reactions on
both irradiated and control sites generally indicate contact allergy.
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