273

Review
www.expert-reviews.com ISSN 1746-9872 2011 Expert Reviews Ltd 10.1586/EDM.11.28
Cutaneous adverse drug reactions (ADRs) are
the most common and most reported form of
adverse reactions to drugs, representing approxi-
mately 30% of all reported cases [1]. Its incidence
in hospitalized patients has been estimated to be
approximately 2% [2]. In the USA alone, it is esti-
mated that ADRs (both cutaneous and noncuta-
neous) affect nearly 2 million patients each year,
leading to nearly 100,000 deaths [3]. Several fac-
tors predispose to ADRs and include: advanced
age, polypharmacy, female gender, concomitant
infection (particularly HIV) and genetic predis-
position [4]. ADRs are often wrongly termed aller-
gic; both immune-mediated and non-immune-
mediated mechanisms are involved, and many
are poorly understood. All four classical Gell and
Coombs types of hypersensitivity reactions play a
role in drug eruptions; in some cases it is the reac-
tive drug metabolites acting as a hapten rather
than the parent drug that acts as an antigen for
T-cell activation [5]. Drug-specic CD4 and CD8
positive T cells recognize drugs through their
T-cell receptors in an MHC-dependent way.
The classical and still widely accepted phar-
macological classication of ADRs was described
by Rawlins and Thompson who divided ADRs
into two types; type A reactions are dose depen-
dent and predictable on the basis of the drugs
known pharmacological action, and type B reac-
tions are idiosyncratic and not necessarily dose
dependent [6].
Intrinsic factors, such as genetic variation
in drug metabolism or HLA associations, can
increase the risk of ADRs [5]. More detailed
examples of the pharmacogenetics of ADRs will
be discussed in this article.
Pharmacogenetics &
adverse drug reactions
Genetic factors leading to predisposition for
the development of ADRs have become evident
from cases occurring in identical twins, as well
as hereditary forms in certain families [7]. The
genetic basis for ADRs can be divided into three
main categories: drug-metabolizing enzymes,
drug transporters and HLA-related [8]. Genes
in the rst two categories inuence the phar-
macokinetics and pharmacodynamics of drugs.
The main genetic predisposition to ADRs is
attributed to variation in the regulation and
expression of the cytochrome P-450 enzyme sys-
tem [5,8]. The genetic associations can be both
drug- and phenotype-specic. An example is the
presence of HLA-B*1502 among Han Chinese
that predisposes to serious cutaneous ADRs
(StevensJohnson syndrome [SJS]/toxic epi-
dermal necrolysis [TEN]) with carbamazepine
(drug specic) and not to the common macu-
lopapular drug-induced exanthem [9]. Another
example of the role of pharmacogenetics in
ADRs is the association between HLA-B*5701
in abacavir hypersensitivity [10,11].
Firas Al-Niaimi
Salford Royal Foundation Trust,
Manchester, M6 8HD, UK
ras55@hotmail.com
Adverse drug reactions are common and can range from benign and self-limiting to life-
threatening with a high morbidity and mortality. Prompt identication and accurate diagnosis
of an adverse drug reaction is therefore essential in order to optimally manage the patient,
averting possible signicant complications. Many adverse reactions to drugs involve the skin,
and therefore essential knowledge of such reactions by both dermatologists and nondermatologists
is of paramount importance. In this article a comprehensive review is given on a wide range of
cutaneous adverse drug reactions encompassing both benign and more serious reactions, in
addition to some less common adverse reactions. The article provides a tabular summary of
some of the main features of such reactions, in addition to a separate table with a list of the
common culprit drugs identied for each cutaneous adverse reaction.
KEYWORDS: acute generalized exanthematous pustulosis adverse drug reactions DRESS drug reaction
pharmacogenetics toxic epidermal necrolysis
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), 273286 (2011)
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Expert Rev. Dermatol. 6(3), (2011) 274
Review
Approach to a cutaneous drug eruption
Correct diagnosis of a drug eruption is an essential part of the
management, as withdrawal of the offending drug leads to reso-
lution of the symptoms in most, but not all, cases. In order to
attribute a given reaction to a drug with condence one must
establish that:
The suspected drug is likely to cause the reaction pattern
observed;
An alternative cause for the eruption is unlikely or has been
excluded;
The onset of the eruption corresponds with its administration
(different reaction patterns have different latency periods;
shorter on re-exposure);
The histology of the eruption, where appropriate, is consistent
with the diagnosis;
That it resolves following cessation of drug therapy.
As a general rule, the presence of urticaria, bullae, mucosal
involvement, facial edema, ulcerations, palpable purpura, fever
and lymphadenopathy in a suspected cutaneous ADR may herald
a serious reaction.
Ideally, one would like to conrm that it recurs following
re-challenge, or can be conrmed by a specic test, but the for-
mer is often inadvisable in severe ADRs and the latter is currently
predominantly a research tool. Laboratory testing can aid in the
evaluation of any systemic involvement and may point toward a
specic ADR. An example is the marked peripheral eosinophilia
noted in drug reaction with eosinophilia and systemic symptoms
(DRESS) [12]. Epicutaneous testing is primarily used for the evalu-
ation of IgE-mediated reactions, such as urticaria, whereas patch
testing is employed when a type IV reaction is suspected. However,
the latter has low sensitivity and specicity and is not routinely
used [13].
There are several problem areas the clinician should be aware of:
Late onset of eruption most start within weeks, but onset may
be up to several months in certain drugs and reactions (e.g.,
frusemide-induced vasculitis and penicillamine-induced
pemphigus);
Slow-onset symptoms this is characteristic of problems such
as pruritus due to statins discussed below;
Resemblance to clinical disease the most common difculty
being distinguishing between an antibiotic eruption versus a
viral exanthem, especially in the context of upper respiratory
tract infections and potentially wrongly labeling a patient for
life as being allergic to a group of antibiotics;
Interpreting an eruption starting (or worsening) after the drug
has been stopped as excluding the drug as a cause the most
common, maculopapular, eruption pattern typically starts after
510 days, and therefore may start following completion of a
course of antibiotics, or evolve to peak and fall following
discontinuation of the offending drug;
Polypharmacy many patients take several drugs and, espe-
cially in hospitals, may have had several drugs stopped and
others started;
Remember over-the-counter drugs and the things that patients
do not view as medications (herbal medication as an example);
Ineffective treatment a very common problem, discussed below.
Once a drug eruption is suspected, the morphology of the erup-
tion should be identied based on the primary lesions, such as
exanthematous, urticarial, bullous or pustular. Any associated
fever, lymphadenopathy or tachycardia should also be identied;
these may distinguish between benign cutaneous drug eruptions
and the potentially severe forms with systemic complications, or
a systemic disease with an associated eruption.
Careful ana lysis of drug exposure must be carried out to iden-
tify the culprit; all medications, regardless of the route of admin-
istration, should be considered. De-challenge (improvement after
a decrease in dose or withdrawal of the drug) and re-challenge
(recurrence or exacerbation of eruption following re-exposure to a
drug) are important factors in establishing a suspected ADR [14,15].
Patterns & morphology of various drug eruptions
The presentation of cutaneous ADRs can be very diverse, rang-
ing from acute to a more gradual insidious reaction, and from
mild to severe. Symptoms accompanying drug eruptions vary
and may depend on the type of eruption (e.g., photosensitivity
in phototoxic drug reactions and pruritus in urticaria); whilst
others can be asymptomatic. The diagnosis should be suspected
when there is a history of drug ingestion; however, the eruption
may represent a new dermatological condition or a recurrence
of a previous dermatosis, possibly triggered by the institution of
a new drug. Important aspects to consider include a history of
similar eruptions in the past, and use of over-the-counter medica-
tions. Enquiring about the effects of de- and re-challenge with a
particular drug can be very useful.
Exanthematous pattern
Often also called drug rash or maculopapular eruption by non-
dermatologists, this is the most common form of cutaneous drug
eruption. The underlying mechanism is likely to be immunologi-
cal through cell-mediated hypersensitivity. Once a drug or a
hapten is presented by Langerhans cells to the T lymphocytes,
it can then bind covalently or noncovalently to MHC II-peptide
complexes, which in turn activate both CD4 and CD8 positive
T cells, leading to a cytotoxic effect [16]. Of note, however, is that
sulfamethaxazole can bind directly to the MHC-peptide nonco-
valently [17]. The morphology is one of at erythematous macules/
patches with papules, which can vary in diameter and may become
con uent, often in a symmetrical distribution. The eruption can
occur between days 1 and 14 after starting a new drug; often
beginning on the upper torso and progressing caudally and periph-
erally to involve the limbs. Symptoms of pruritus and mild fever
can accompany the eruption, and mild blood eosinophilia may be
present. Mucosal involvement is typically absent and its presence
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should prompt the physician to consider alternative diagnoses.
Biopsy is nonspecic and serves mainly to exclude other possible
diagnoses in doubtful cases. The eruption is usually self-limiting
and diminishes rapidly following withdrawal of the implicated
drug. If the causative drug is of essential therapeutic importance
(e.g., anti bacterial prophylaxis in AIDS), treating through the
eruption can be considered as an option provided there are no
systemic symptoms, and there is careful monitoring. In extreme
cases, the eruption can progress to exfoliative dermatitis if the drug
is continued and close monitoring is therefore required. However,
desensitization can be performed in cases where prolonged treat-
ment is required.
Treatment is supportive, initially the responsible drug is dis-
continued, and this is followed by the use of topical emollients
and a moderate-potency topical steroid. For signicant pruritus,
however, it is prudent to avoid systemic steroids that may cloud
the picture if there is any diagnostic doubt or underlying infec-
tion. Sedative antihistamines may be used to relieve symptoms
of pruritus. The main differential diagnosis is viral exanthems
(particularly EpsteinBarr virus [EBV], parvovirus B19, human
herpes virus [HHV]-6, adeno- and entero-virus); however, the
presence of mucosal involvement, painful macules, marked eleva-
tion in peripheral blood eosinophilia or edema of the face should
alert the physician to consider alternative diagnoses.
Urticaria & angioedema
Drug-induced urticaria is the second most common type of drug
reaction presenting as transient acute eruption of erythematous and
edematous papules and plaques, usually with pruritus. Individual
lesions disappear within 24 h, leaving normal skin with no scar-
ring, but the condition itself can be present as long as the offending
drug is continued. This pattern of eruption can present as isolated
urticaria, angioedema or a combination of both. In severe cases,
the reaction can progress to anaphylaxis. This risk is particularly
high with penicillin and latex [18]. Type I hypersensitivity reaction
is mediated by IgE antibodies leading to mast cell degranulation; a
similar result in the absence of IgE antibodies, through direct, non-
specic, liberation of histamine and other inammatory mediators,
is termed an anaphylactoid reaction, and is often triggered by
drugs, such as opiates, that attach to mast cell membrane receptors
or by contrast infusion for radiological examination [15,18]. Urticaria
usually develops within 36 h of drug exposure, often within a few
hours, and sometimes within minutes, particularly in the case
of re-challenge. The rapid occurrence of urticaria following a re-
challenge is explained by the fact that IgE antibodies to the drug
have been generated through previous exposure [18]. Drugs should
therefore be suspected in cases of acute urticaria. Management is
through withdrawal of the causative agent, combined with the use
of oral antihistamines. Corticosteroids and intramuscular adrena-
line are used in emergency if severe angioedema or anaphylaxis is
present. As a general rule, any IgE-mediated reactions occurring
in the context of a drug should not be re-challenged prior to that
particular drug being investigated [18]. Angiotensin-converting
enzyme inhibitors are an often overlooked cause of isolated
angioedema, owing to altered bradykinin metabolism (therefore
pharmacological rather than idiosyncratic) and are uncommonly
associated with urticaria [19]. The angioedema may occur at any
time, even years following exposure in some patients.
Acute generalized exanthematous pustulosis
This relatively rare acute pustular eruption may resemble pustular
psoriasis clinically. It is characterized by fever (generally on the
same day as the start of the rash) and multiple, small, nonfollicular
pustules that arise on a widespread erythematous background.
It predominantly affects the main body folds and upper trunk,
but facial involvement is possible [20]. The relationship to drugs
is relatively acute, with most cases appearing within 24 h of the
exposure. This short latency period may be due to prior sensitiza-
tion to the drug [21]. The precise mechanism remains unknown,
but the presence of neutrophils in both the skin and blood sug-
gests a role for neutrophil-activating cytokines triggered by drug-
specic T lymphocytes, such as IL-3 and IL-8 [22]. The eruption
lasts for 12 weeks and is followed by supercial desquamation.
Healing occurs without scarring.
The main differential is pustular psoriasis, which may be difcult
to distinguish on clinical grounds alone. However, histo logically
the presence of marked dermal edema, eosinophilic exocytosis and
necrotic keratinocytes may favor the diagnosis of acute generalized
exanthematous pustulosis (AGEP), whilst the presence of acantho-
sis and papillomatosis may point toward pustular psoriasis [21,22].
It is important to note that whilst these subtle differences may
aid in differentiating between the two conditions, these ndings
are not specic or exclusive, and the differentiation may require
other factors, such as a personal or family history of psoriasis and
the probability of a particular drug to cause AGEP. Resolution of
the eruption following discontinuation of a suspected drug is an
important nding and may support the diagnosis of AGEP.
Drug reaction with eosinophilia & systemic
symptoms/drug-induced hypersensitivity syndrome
The acronym DRESS/drug-induced hypersensitivity syndrome
(DIHS), is used to describe a severe drug hypersensitivity eruption
associated with constitutional symptoms, such as fever, malaise,
lymphadenopathy, hepatitis, myocarditis, interstitial nephritis
and pneumonitis. Liver involvement is the most common internal
organ involvement and the most potentially serious complica-
tion, with few cases progressing to fulminant hepatitis [23]. The
eruption may evolve from maculopapular or exfoliative derma-
titis morphology, often with facial involvement and edema [22].
Peripheral eosinophilia is a common nding (the most common
hematological abnormality) and may be signicantly elevated in
some cases, which helps to differentiate it from a mildly elevated
eosinophilia occasionally seen in exanthematous drug eruptions.
Atypical lymphocytes can be seen in almost half of the affected
patients. Fever is common and may be seen in approximately
three-quarters of the patients. Serious complications may include
hypothermia and uid loss; therefore, it is essential to discontinue
the suspected responsible drug as soon as it is suspected. The
exact pathophysiology is not yet fully understood and the reaction
is often idiosyncratic. Immune-mediated mechanisms are likely
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 276
Review
to play an important role through attraction of eosinophils by
IL-5 released from activated drug-specic T lymphocytes [24]. As
eosinophilia is not found in a proportion of patients, it is likely
that other mechanisms are involved. Some evidence suggests a
possible role for reactivation of HHV-6 and -7 [25,26]. It has been
proposed that a transient state of drug-induced hypogamma-
globulinemia in susceptible individuals creates an immuno logical
environment that permits viral reactivation [27]. Some authors
have demonstrated the expansion of CD8-positive T lymphocytes
against several EBV epitopes, leading to the reactivation of EBV
in patients with severe DRESS/DIHS [28].
In practice, anticonvulsants are one of the most common causes
of severe reactions. This is explained by the inability (of the aro-
matic anticonvulsants) to detoxify arene-oxide metabolites [29].
Approximately 1% of patients commencing phenytoin, carbam-
azepine, lamotrigine and other anticonvulsants will develop a severe
reaction [7,22]. The combination of lamotrigine and valproate is par-
ticularly associated with a high risk for developing DRESS/DIHS
[30]. Sulfonamides are the second common group of drugs that can
potentially trigger this serious ADR [21,24]. Risk factors include:
slow acetylator phenotype and the susceptibility of patients lym-
phocytes to the toxic metabolite of hydroxylamine from these drugs
[21,29,30]. Recently, interesting ndings of a possible genetic pre-
disposition to develop DRESS/DIHS, as well as SJS/TEN, was
found in the Han Chinese population with HLA-B*5801 with
allopurinol, suggesting a pharmacogenetic link [31].
DRESS/DIHS typically occurs up to 8 weeks following the
administration of the drug, and therefore has a long latency
period. Oral steroids and supportive care are necessary, but
relapses are common following tapering of the dose or withdrawal,
often leading to a prolonged period of systemic treatment.
StevensJohnson syndrome/toxic epidermal necrolysis
These two cutaneous ADRs are rare, but potentially serious, drug
reactions. They are considered to be variants of the same disease
with different severity. Cell-mediated cytotoxic reactions against
epidermal cells is the main immunopathological etiology [22,32].
Cytokines such as IFN-a and TNF may play a role in the process
of massive and widespread apoptosis of epidermal cells [32,33]. It is
likely that the pathogenesis of SJS/TEN is much more complex,
and the histological appearance of apoptotic keratinocytes with a
relatively low number of accompanying inltrating inammatory
cells suggest the presence of soluble mediators that contribute to
keratinocyte apoptosis [3436]. Until very recently, the hypothesis
that was widely accepted was that the two pathways that were
responsible for SJS/TEN consisted of the granule-mediated exo-
cytosis (perforin and granzyme B) and FasFas ligand interaction,
both leading to apoptosis [35,36]. Nevertheless, recent studies have
argued against the role of these soluble factors as they are also
upregulated in the common drug-induced exanthem, a condition
where massive apoptosis typically does not occur [37].
Recent ndings from Chung et al. in Taiwan showed that
granu lysin (a cationic cytolytic protein released primarily by
T lymphocytes and natural killer cells) was expressed in very high
concentrations in the blister uids of patients with SJS/TEN [38].
The magnitude of granulysin was two- to four-times that of perfo-
rin, granzyme B or soluble Fas ligand concentrations. Interestingly,
their ndings also showed reduced cytotoxicity following reduc-
tion in granulysin levels. The authors concluded that granulysin
is a key molecule responsible for keratinocyte apoptosis, leading to
the clinical presentation of SJS/TEN. Future studies are needed,
but the possibility of granulysin measurement may aid in the dif-
ferential diagnosis of bullous diseases or severe cutaneous ADRs.
These ndings point toward a critical evaluation of the previously
described pathways of perforin, granzyme B and Fas ligand soluble
factors as the key molecules in the development of SJS/TEN.
The association of specic HLA genotypes with certain drugs
leading to SJS/TEN has been highlighted recently. The best-
studied and proven association was with HLA-B*1502 and the
anticonvulsant drug carbamazepine among the Han Chinese
population [39,40]. The association is very high, leading to national
recommendations for HLA-typing of Han Chinese patients prior
to the commencement of carbamazepine in the UK and USA.
The HLA-B*1502 was also shown albeit to a lesser extent to
be associated with phenytoin and SJS/TEN in the same ethnic
population of Han Chinese [41]. Recently, a strong association of
HLA-B*5801 with allopurinol-induced DRESS/DIHS, as well
as SJS/TEN, was found in Han Chinese in Taiwan [42]. This
genotype (HLA-B*5801) was found to be linked to SJS/TEN in
Thai, as well as Japanese, populations [43]. These ndings highly
support the role of pharmacogenetics and the development of
certain cutaneous reactions among susceptible individuals.
Clinically, SJS/TEN begins within 4 weeks of initial drug expo-
sure (more rapidly with re-challenge) and occasionally begins a
few days following the withdrawal of the drug. The initial skin
lesions are characterized by irregularly shaped, erythematous, pur-
puric macules that progressively coalesce. Conuence of necrotic
lesions leads to extensive and diffuse erythema, which becomes
tender and sloughs off as sheets, leaving eroded areas predisposing
to sepsis and uid loss. Fever, malaise, arthralgia and headache
may accompany the cutaneous eruption, and mucosal involve-
ment is common. The mortality is approximately 510% in SJS
and 30% in TEN [44]. The latter can vary based on the severity of
the disorder and the presence of comorbid factors. The classica-
tion of SJS/TEN is based on the percentage of skin detachment
and predetachment epidermal necrosis; SJS refers to less than 10%
of body surface area (BSA) being affected, TEN involves more
than 30% BSA and SJS/TEN overlap is used when the affected
area is between 10 and 30%. Intense supportive therapy is needed,
ensuring maintenance of uid and electrolyte balance, nutritional
support and prevention of infection. Active interventions are still
debated; intravenous immunoglobulins are usually used, but evi-
dence is conicting, steroids are used variably (but may predispose
to infection) and ciclosporin has some support [45,46]. Early with-
drawal of all suspected drugs is essential and is the only factor
that directly correlates to a reduction in morbidity/mortality [33].
Drug-induced lupus erythematosus
Numerous drugs can cause a reaction that resembles lupus ery-
thematosus (LE) clinically and pathologically. It is important to
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distinguish between drug-induced systemic LE (SLE) and drug-
induced subacute cutaneous LE (SCLE). The current understand-
ing is that reactive drug metabolites interact with nuclear histones,
which may act as haptens, leading to activation of the complement
cascade [47].
Drug-induced SLE may have a genetically determined basis [48].
It manifests clinically with fever, malar rash, pericardial and pleu-
ral involvement and a positive antinuclear antibody (ANA; 90%
having antihistone antibodies, although these can be found in
idiopathic SLE too); symptoms can take up to a year to develop.
Renal and neurological involvement is rare [49]. Antibodies against
double-stranded DNA are typically absent. Seroconversion to ANA
may precede systemic symptoms and in asymptomatic individuals
do not require discontinuation of the drug. Close monitoring is
suggested and the drug should be withdrawn when symptoms
occur. The presence of ANA may persist for several months fol-
lowing discontinuation of the drug [47,49]. Although many agents
that classically caused drug-induced SLE are used less nowadays,
biological therapies (e.g., anti-TNF) are an increasingly recognized
cause of drug-induced SLE [50,51].
Drug-induced SCLE presents in an indistinguishable form
from the idiopathic form, with annular or psoriasiform lesions
pre dominantly on the upper trunk and extremities and sparing
the face. Positivity to Ro and La antibodies can be found in some
patients [52]. Although withdrawal of the drug leads to resolu-
tion of the symptoms in most of the cases, the subacute form in
particular may persist even after withdrawal of the responsible
drug [53].
Photosensitivity
Drug-induced photosensitivity occurs due to the combination of a
drug and ultraviolet radiation (UVR), either UVA (320400 nm)
and/or UVB (290320 nm); however, UVA is most often
implicated [54]. Photosensitive drug reactions are divided into
phototoxic and photoallergic types.
Phototoxic reactions are the most common; they resemble
exagg erated sunburn, followed by hyperpigmentation. This pat-
tern occurs within a few hours after ingestion of the photosen-
sitizing drug if there is also exposure of the skin to UVR of the
relevant wavelength and intensity. The reaction is dose dependent
for both drug and UVR, and can therefore occur in any patient
receiving high enough doses of both drug and UV wavelength [55].
Association of light with a photosensitizing chemical in the skin
creates unstable singlet or triplet states within the electrons as
a result of energy transfer. This leads to the generation of free
radicals and specic cellular toxins that damage the cellular lipids
and proteins leading to this pattern of inammation [56]. Photo-
onycholysis and pseudo-porphyria are examples of phototoxic
reactions to drugs [57,58]. Management requires removal of the
causative agent and avoidance of sun exposure with the use of
suitable sunscreen. In cases when the drug is essential and cannot
be discontinued or substituted, reduction in the dose with strict
UVR avoidance may still limit and reduce the phototoxic reac-
tion. In drugs with a short half-life, administration of the drug
in the evening may be an alternative option.
Photoallergic reactions have an immunological basis and are
considered to be a result of cell-mediated hypersensitivity [55,56].
They require previous exposure to the photosensitizing drug
and appear between 24 and 48 h following further exposure.
Absorption of UVR enables the drug to conjugate with a car-
rier protein to form an antigen, leading to cell-mediated hyper-
sensitivity identical to that found in allergic contact dermatitis.
Clinically this manifests with erythema, edema, exudation
and desquamation. Sulfur-moiety containing drugs such as
thiazide diuretics, sulfonamide antibiotics and phenothiazines
are most commonly associated with photoallergy [58,59] (see
also TABLE 1).
Both photosensitive reactions occur preferentially in sun-
exposed areas of the skin such as the face, V region of the neck
and dorsal aspects of the hands, sparing the shaded areas, such as
the submental and retro-auricular areas. This pattern of distribu-
tion aids in the diagnosis. Drug withdrawal is recommended in all
cases of photoallergy because of the risk of chronicity, even with
low UVR doses [56,58]. The distribution of the eruption tends to
extend with photoallergic forms, as they take longer to settle and
the skin often remains photosensitive for several months after-
wards. The use of topical steroids and oral antihistamines may
be benecial in such cases.
Pruritus
Generalized pruritus that truly occurs with no visible dermatosis
is a relatively uncommon complication of drug therapy, although
it is often suspected. The mechanism by which drugs can cause
pruritus can be due to cholestasis, neurogenic, xerosis (common
with retinoids) and pseudoallergic (nonimmunological mast cell
degranu lation) [60]. The most common, and most commonly
missed, are:
Statins the exact pathophysiology is unknown. Gradually
increasing itch with, sometimes subtle, skin dryness is the
common pattern [61];
Opiates these cause nonimmunological mast cell degranula-
tion, releasing histamine and other inammatory mediators [62].
Itch may last for some days afterwards, and is frequently
incorrectly diagnosed.
Drug-induced pigmentary changes
The pigment changes that may occur due to certain drugs
result from a variety of mechanisms, including increased mela-
nin and/or lipofuscin synthesis, deposition of the drug or their
metabolites in the skin and postinammatory hyperpigmentation
[63]. Minocycline can produce either a gray slate pigmentation on
sun-exposed areas or pigmentation on areas of previous inam-
mation. Mepacrine, which can be used with hydroxychloroquine
in the management of discoid LE, can give a yellow/orange or
gray skin discoloration and gray pigmentation of the palate [64].
Amiodarone can give a grayblue photosensitive discoloration
that may persist for years after withdrawal [65]. Bleomycin is well-
known to cause agellate hyperpigmentation in a linear fashion,
most commonly on the back [66].
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 278
Review
Fixed drug eruption
This is a relatively rare, but distinctive and fascinating drug erup-
tion. The rst manifestation of xed drug eruption (FDE) may
occur within the rst 10 days of drug administration and usually
within 24 h on subsequent administration. The lesions may be
solitary or few in number, round or oval, sharply demarcated
erythematous plaques that may blister. FDE can be confused
with autoimmune or mechanically induced blistering disorders.
Pruritus is not often a feature, but the inammation intensi-
es as a dusky red plaque that subsequently subsides, persisting
approximately a week following drug withdrawal and leaving
brown post inammatory hyperpigmentation. Lesions recur at
exactly the same site when re-challenged, and recurrent episodes
gradually cause more pigmentation. Widespread generalized FDE
with blistering may in rare cases mimic more severe drug-induced
blistering conditions such as SJS/TEN, and a skin biopsy in this
case can sometimes be indistinguishable between the two condi-
tions (TABLE 2). The eruption can occur anywhere on the body but
is commonly found on the hands, feet and genitalia. To date, no
exact explanation has been found for this pattern of eruption, but
it is caused mainly by drugs and, to a lesser extent, some food
additives. Some studies have shown that lesional skin contains
T lymphocytes, with some CD8-positive T cells persisting within
lesional skin, contributing to the immunological memory [67].
Some speculate a role for IL-15, derived from lesional epidermis,
in maintaining the survival of the intra-epidermal CD8-positive
T cells [68].
Lichenoid drug eruptions
Lichenoid drug eruptions resemble lichen planus clinically, having
violaceous papular, often polygonal, pruritic lesions. However,
lichenoid drug eruptions tends to have more conuent areas
Table 1. Reaction patterns and the causative drugs.
Reaction patterns Causative drugs
Exanthematous
(maculopapular) reaction
Allopurinol, barbiturates, benzodiazepines, captopril, carbamazepine, cephalosporins, gentamycin, gold,
lithium, NSAIDs, penicillin, phenytoin, sulfonamides and thiazides
Urticaria ACE inhibitors, aspirin, cephalosporins, contrast media, monoclonal antibodies, NSAIDs, opiates, penicillin,
phenytoin, quinine, tetracycline and sulfonamides
Pruritus Bleomycin, chloroquine, isotretinoin, lansoprazole, lithium, penicillamine, statins and tamoxifen
Fixed-drug eruption Allopurinol, aspirin, barbiturates, carbamazepine, clindamycin, dapsone, NSAIDs, paracetamol, penicillin,
phenolphthalein, sulfonamides, tetracyclines and trimethoprim
Lichenoid eruptions ACE inhibitors, b-blockers, chlorpropamide, frusemide, gold, hydroxychloroquine, lithium, methyldopa,
phenothiazine and thiazides
Photosensitive drugs Amiodarone, griseofulvin, isotretinoin, mesalazine, methotrexate, NSAIDs, phenothiazine, sulfonamides,
tetracycline and thiazides
Lupus-like reactions b-blockers, carbamazepine, chlorpromazine, griseofulvin, hydralazine, isoniazid, lithium, methyldopa,
minocycline, penicillamine, phenytoin, procainamide, propylthiouracil and quinidine
Acneiform eruptions Androgenic hormones, corticosteroids, danazol, disulfram, EGF receptor antagonists, isoniazide, lithium, oral
contraceptive (progesterone), phenobarbital, rifampicin, vitamins B2, B6 and B12
Vasculitis ACE inhibitors, allopurinol, amiodarone, ampicillin, cephalosporins, cimetidine, frusemide, hydralazine,
NSAIDs, penicillin, propylthiouracil, quinidine, sulfonamides and thiazides
ANCA-positive: hydralazine, minocycline and propylthiouracil
Acute generalized
exanthematous
pustulosis
b-lactams, carbamazepine, diltiazem, doxycycline, isoniazid, macrolides, nystatin, penicillin, quinolones,
sulfonamides and terbinane
Exfoliative dermatitis Allopurinol, barbiturates, captopril, carbamazepine, cimetidine, codeine, frusemide, gold, isoniazide, lithium,
NSAIDs, penicillins, phenytoin and sulfonamides
DRESS/DIHS Anticonvulsants (many), allopurinol, co-trimoxazole, dapsone, minocycline, sulfonamides and terbinane
(lamotrigine in combination with valproate is a high risk)
SJS/TEN Allopurinol, barbiturates, carbamazepine, cephalosporins, lamotrigine, nevirapine, NSAIDs (oxicams), penicillin,
pentamidine, phenytoin and sulfonamide
Bullous eruptions Pemphigus: penicillamine (most cases historically), captopril and piroxicam
Pemphigoid: frusemide, spironolactone, rarely clonidine or sulfasalazine
Linear IgA disease: vancomycin (most common), also ciprooxacin, diclofenac, granulocyte colony-stimulating
factor, lithium, penicillins and rifampicin
Pseudoporphyria: frusemide, NSAIDs and thiazide diuretics
ACE: Angiotensin converting enzyme; ANCA: Anti-neutrophil cytoplasmic antibody; DIHS: Drug-induced hypersensitivity syndrome; DRESS: Drug reaction with
eosinophilia and systemic symptoms; SJS: StevensJohnson syndrome; TEN: Toxic epidermal necrolysis.
Al-Niaimi
www.expert-reviews.com
279
Review
with a slightly more eczematous nature and less (if any) mucosal
involvement [69]. The eruption often appears weeks or months fol-
lowing exposure to the responsible agent and may take the same
length of time to disappear following withdrawal of the drug,
often leaving postinammatory hyperpigmentation, particularly
in dark-complexioned individuals.
Acneiform eruptions
This pattern of eruption represents a small percentage of drug-
induced skin eruptions. Clinically it presents as a papulo-pustu-
lar inammatory eruption on the face and upper trunk resem-
bling acne vulgaris; however, there are few clues that can aid
in differentiating both entities [70]. Drug-induced acne should
be considered if:
The onset is sudden
There is worsening of existing acne
Comedones are absent
Monomorphic appearance of the papules and pustules
There is an exposure to a potentially responsible drug
Few drugs can cause acneiform eruptions (TABLE 1); historically,
corticosteroids have been a common cause. However, the new
EGF receptor (EGFR) antagonists used in cancer treatment, such
as erlotinib, are associated with an acneiform eruption that car-
ries a good prognostic factor for the treatment of the underlying
condition as evidence of effect on another organ that expresses
EGFR [71]. Withdrawal of the culprit drug and treatment with
tetracycline or erythromycin antibiotics is often all that is needed
in terms of treatment.
Vasculitis & necrosis
Drug-induced cutaneous vasculitis is rare, accounting for no more
than 510% of the vasculitides [72]. It typically manifests as pal-
pable purpura, although urticarial lesions, ulcers, nodules, pustules
and digital necrosis may all be a manifestation of drug-induced
vasculitis. Histologically the process is characterized by inam-
mation and necrosis of blood vessels (mostly, but not exclusively,
small vessels), mainly owing to an immunologically mediated
response to antigens (drug-related haptens) that result in vessel
wall damage [73]. Direct drug toxicity against the vessel wall or cell-
mediated cytotoxic reactions against vessels are also possible. The
above mechanisms result in activation of the complement system
with a consequence of the release of proinammatroy cytokines
and vaso-active amines, leading to increased vascular permeability
and recruitment of neutrophils. Drug-induced vasculitis usually
occurs 721 days post-drug administration, but can occur within
48 h in the case of re-challenge. Withdrawal of the drug usually
leads to rapid resolution of the lesions. Systemic corticosteroids may
benet some patients if systemic symptoms and, in particular, renal
involvement is present. Nonvasculitic eruptive telangiectasia has
been reported with calcium-channel blockers [74,75].
Drug-induced skin necrosis has many causes. Levisamole-
induced necrosis has become increasingly recognised recently [76].
Anticoagulant-induced skin necrosis, most commonly associ- most commonly associ-
ated with commencing warfarin therapy, is a rare but impor-
tant mimic of vasculitis in which vascular thrombosis occurs.
Approximately one in 10,000 patients who receive warfarin will
develop this condition. It typically begins 35 days after initia-
tion of therapy and it is related to a transient hypercoagulable
state due to a rapid fall in (anticoagulant) protein C and S levels,
occurring before clotting factors are inhibited [77]. Thus, natural
anticoagulant levels fall before procoagulant factors are inhibited,
and a prothrombotic state results. The condition occurs particu-
larly in people who have protein C/S deciency, or a common
mutation called Factor V Leiden [77,78]. Clinically, it presents with
erythematous, painful plaques that evolve to necrosis, hemor-
rhagic blisters and ulcers. It can sometimes be life-threatening if
not recognized at an early stage and if treatment with warfarin
is not discontinued. An unrelated phenomenon of purple toes
secondary to warfarin has been reported [79].
Heparin necrosis is rare but may be suspected as it is often
limited to the site of injection. Unlike warfarin, the pathophysi-
ology here involves antibodies that bind to complexes of heparin
platelet factors, leading to platelet aggregation and thrombosis.
Contrary to coumarin-induced necrosis, proteins C and S are not
involved [80]. Substituition of heparin is therefore often required.
Drug-induced cutaneous ulceration
& exfoliative dermatitis
Few drugs cause ulceration of the skin and mucosa as a primary
pathology. Ulceration secondary to vasculitis or necrosis due to
drugs is a separate entity and is not discussed in this section.
Nicorandil has been increasingly reported to cause ulceration,
which has been reported in peri-anal and peri-stomal, as well as
other cutaneous sites [81,82]. Oral ulceration tends to occur with
relatively low doses of the drug. Hydroxyurea has been known to
cause skin ulceration, usually mimicking a venous leg ulcer [83].
Interferon therapy can cause ulceration, mainly at the injection
site [84]. A relatively uncommon complication of methotrexate
therapy in the treatment of psoriasis is epidermal necrosis leading
to erosions within the psoriatic plaques [85].
Drug-induced exfoliative dermatitis is a relatively rare, but
potentially serious, reaction that is characterized by erythema,
pruritus and desquamation involving large areas of the skin [86]. It
often begins a few weeks following the administration of a respon-
sible drug either progressing from a maculopapular eruption or
developing as erythematous edematous patches that progress to
desquamation. It is a potentially dangerous pattern, having all
the complications of erythroderma of any cause uid balance
problems, loss of body temperature control and hypoprotein-
emia. Complete resolution occurs with hyperpigmentation and
occasionally with loss of hair and nails.
Drug-induced Sweets syndrome
Sweets syndrome caused by drugs represents a very small minor-
ity of this neutrophilic disorder. In contrast to classic Sweets
syndrome, the drug-induced variant tends to affect the upper
extremities more than the face, and tends to cease in 330 days
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 280
Review
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Al-Niaimi
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281
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following discontinuation of the drug; unlike the classic variant
in which recurrences are common [87]. In addition, peripheral
neutrophilia is often absent in the drug-induced cases, whilst it is
almost always present in the classic forms. The major drugs associ-
ated with this condition include granulocyte-colony stimulating
factor (G-CSF) and all-trans-retinoic acid [88].
Serum sickness & serum sickness-like reaction
Serum sickness (SS) reactions are becoming increasingly uncom-
mon due to the decreased use of heterologous sera. SS is a type-III
hypersensitivity reaction mediated by the formation of immune-
complexes to foreign antigens, such as anti-thymocyte globulins
[89]. The deposition of these immune complexes leads to comple-
ment activation and small-vessel vasculitis with subsequent tissue
inammation. This drug reaction is usually self-limited, lasting
12 weeks before resolution. Clinically it manifests with fever,
arthralgia, morbilliform eruption (less commonly urticarial),
lymphadenopathy and renal involvement. A serpiginous band of
erythema along the sides of the ngers, hands, toes and feet was
found in eight out of 11 patients in one study [90]. Complement
levels are typically low; and this can aid in differentiating this
condition from SS-like reaction, which in addition lacks circulat-
ing immune complexes, vasculitis and renal involvement [22]. The
latter is almost always found in children at an incidence of one in
2000 secondary to cephalosporins [91].
Drug-induced hair problems
Hair problems related to drugs are categorized into three
groups: alopecia, hirsutism and hypertrichosis. Causes are listed
below, rather than in the table, owing to the various different
mechanisms involved.
Alopecia induced by drugs is nonscarring and is reversible
following discontinuation of the offending drug [92]. It affects
females more than males and is often limited to the scalp. There
are various mechanisms, including telogen efuvium, anagen
efuvium (usually due to cytostatics) or interference with normal
keratinization (as with statins). Typically, the onset is much earlier
(23 weeks) following drug ingestion in anagen efuvium, in
contrast to the slightly delayed onset (34 months) in the case of
telogen efuvium [93]. Other drugs that can cause hair loss include
carbamazepine, valproate, cimetidine, acitretin, ketoconazole and
carbimazole [92,93].
Hirsutism is dened as excessive growth of androgenic pattern
coarse hairs in females. It is usually localized on the face and may
be caused by anabolic steroids and testosterone [94].
Hypertrichosis is reversible and is mainly localized on the face
and arms. The main responsible drugs are ciclosporin, diaz oxide,
acetazolamide, minoxidil, interferon, penicillamine, danazol,
phenytoin and zidovudine [93].
Blistering drug eruptions
Blistering conditions caused by drugs encompass pemphigus,
pemphigoid, linear IgA disease and pseudoporphyria.
Drug-induced pemphigus resembles autoimmune pemphigus
vulgaris clinically and histologically. However, the presence of a
chronic urticated/eczematous preblistering prodrome may help
distinguish between drug-induced and autoimmune pemphigus.
Another important nding is the lack of strong positivity rates in
direct immune-uorescence (DIF) in the drug-induced form as
opposed to the autoimmune variant which often although not
always has a high positive rate of DIF ndings [95]. Mucosal
involvement is common in both forms. The main offending
drugs contain a thiol(sulfhydryl) group. The explanation for the
reaction caused by such drugs is that as the desmosomes con-
tain disulde bonds, it is likely that drugs containing sulfhydryl
groups bind to them (or their haptens) and consequently inducing
a humoral immune response leading to the clinical manifesta-
tion of blistering [96]. Discontinuation of the drugs often leads to
cessation of the disease in non-thiol-containing drugs. It is now
widely accepted that many thiol-containing drugs may unmask
an indolent autoimmune pemphigus, hence withdrawal of these
drugs does not necessarily lead to cessation of the condition.
In vitro studies have shown that some angiotensin-converting
enzyme inhibitor drugs cause direct acantholysis in the absence
of auto-antibody formation; a mechanism that may explain
the negative DIF ndings in some patients with drug-induced
pemphigus [97].
Drug-induced pemphigoid may present with classical bullous
pemphigoid-like lesions, manifesting as tense bullae on an ery-
thematous or urticarial base, or less often may be predominantly
mucosal, resembling cicatricial pemphigoid. Histology from drug-
induced bullous pemphigoid shows similar changes to the auto-
immune form and does not aid in differentiating between these
two entities [98]. However, autoimmune bullous pemphigoid is
unusual in young patients and its presence should therefore raise
suspicion of drug-induced bullous pemphigoid.
Drug-induced linear IgA disease manifests a vesiculobullous
eruption mainly on the trunk and pelvic region that may resemble
dermatitis herpetiformis clinically, but is usually less pruritic with
larger blisters, asymmetric distribution and annular arrangement
of lesions. Although the disease is an autoantibody-mediated sub-
epidermal bullous disease, the majority of patients lack circulat-
ing autoimmune IgA antibodies against the basement membrane
zone in their circulation [99]. Most drug-induced cases are due to
vancomycin and b-lactam antibiotics and may occur anytime
within the rst 2 weeks of administration.
Drug-induced pseudoporphyria clinically and histologically
resembles porphyria cutanea tarda, with features of skin fragil-
ity and blistering, which heal with scarring, milia and hyper-
pigmentation. The blisters occur preferentially on sun-exposed
areas. The differentiating factor is the absence of abnormal por-
phyrin levels in the drug-induced form [100]. The blistering and
skin fragility may persist for months after the withdrawal of the
responsible drug.
TNF antagonists-induced cutaneous eruptions
The use of TNF-a antagonists has increased in recent years in
the treatment of many conditions, including psoriasis in dermat-
ology. Their use has been linked with several cutaneous eruptions
reported in the literature. These ADRs are not linked to a specic
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 282
Review
underlying disease and have been found in patients with psoriasis,
rheumatoid arthritis and Crohns disease. The most common
cutaneous ADRs reported with TNF-a antagonists are localized
erythema and edema to the injection site. Other cutaneous ADRs
include eczematous eruptions, cutaneous infections (both viral
and bacterial), lichenoid reactions, pityriasis rosea-like reactions,
erythema multiforme, vasculitis, LE (cutaneous and systemic),
AGEP and paradoxical induction of psoriasis [101]. The latter is of
particular interest as these agents are widely used for the treatment
of psoriasis. Several hypotheses exist with regards to this paradoxi-
cal ADR and include a possible cross-regulation between TNF-a
and interferon, induced by plasmacytoid dendritic cells. Another
explanation is the possibility of homing of T helper-1 lymphocytes
to the skin leading to the inammatory pathway seen in psoriasis
[102]. The exact hypothesis remains speculative to date.
In a review of 104 cases of paradoxical induction of psoriasis in
patients receiving TNF-a blockers, 50% of patients were treated
for rheumatoid arthritis [103]. All three currently licensed TNF-a
blockers for psoriasis (adalimumab, etanercept and iniximab)
have been reported to trigger or worsen existing psoriasis. The
incidence of both pustular and plaque psoriasis was relatively
similar. An interesting nding was the response to treatment
observed in some patients when the drug was switched to a dif-
ferent TNF-a blocker, suggesting that class effects cannot explain
this ADR in its entirety.
EGFR inhibitors & cutaneous ADRs
EGF receptor inhibitors (EGFRIs) are a group of relatively new
drugs used for the treatment of certain solid tumors. EGFR is a
transmembrane protein that results in the activation of signal trans-
duction of proliferation, differentiation, migration and apoptosis
pathways following ligand binding [104]. EGFRs are overexpressed
in many tumor types and play a role in the development and pro-
gression of these tumors. The expression of EGFR is abundant in
malignant cells of solid tumors often associated with progression
of the tumor such as those of the lung, breast, ovary, prostate and
colon [104,105]. EGFR is also expressed in normal, non-malignant
cells, including epidermal keratinocytes, sebocytes, the outer root
sheath of hair follicles and in the endothelium of dermal capillar-
ies [105]. There are two classes of drugs that inhibit the EGFRs;
monoclonal antibodies, such as cetuximab, bind to the extracellular
domain of the EGFR blocking activation and signal transduction
of the receptor, and selective tyrosine kinase inhibitors, such as
erlotinib, that act by inhibiting the tyrosine kinase activity of the
intracellular domain and therefore prevent autophosphorylation
and subsequent activation of the signaling cascades [106].
Several cutaneous ADRs (or more appropriately predicted side
effects) with the use of EGFRIs have been observed and their
incidence and severity are associated with therapeutic efcacy of
the underlying tumor [105]. These ADRs can be explained as a
result of changes in cellular signaling in the skin causing increased
inammation, altered growth, survival and differentiation [104,105].
The most common cutaneous ADR observed in EGFRIs is an
acneiform papulo-pustular eruption occurring mostly within the
rst 2 weeks of drug administration. Comedones are typically
absent and secondary bacterial impetiginization may occur. The
eruptions are often dose dependent and have been classied
into different severity grades [107]; the most severe necessitating
discontinuation of the drug. In other milder forms, treatment
with topical and oral agents commonly used for acne vulgaris
may sufce. In several cases, treatment with oral isotretinoin
may be required and this does not appear to interfere or interact
adversely with EGFRIs. It is possible that the acneiform eruption
occurs due to an imbalance in the differentiation and matu-
ration of keratinocytes, sebocytes and hair follicles, caused by
the drug [106,107]. A role for p27 (a cell cycle inhibitor) in the
pathogenesis of EGFRI-induced acneiform eruption has been
proposed [106,108].
Other relatively early-onset side effects of EGFRIs include xero-
sis, nonscarring alopecia and trichomegaly. The latter is thought
to be a result of increased terminal differentiation due to the
inhibition of EGFR [109]. Relatively late-onset (34 months post-
treatment) side effects include paronychia, hyperpigmentation
and telangiectasias [107].
Targeted therapies & ADRs
Recent advances in the treatment of cancer through the use of
various monoclonal antibodies other than the EGFRIs dis-
cussed previously have led to the observation of several new
cutaneous ADRs.
Imatinib mesylate (Gleevec

) is a potent tyrosine kinase inhibi-

tor targeting predominantly the BCR-ABL oncoprotein, and c-kit
to some degree [110]. It is used in chronic myeloid leukemia and
has been associated with several cutaneous ADRs. Supercial
edema is the most common observed ADR occurring in almost
three-quarters of the patients receiving this drug [111]. Other
cutaneous ADRs include maculopapular eruptions, xerosis, pru-
ritus, SJS/TEN, exfoliative dermatitis, AGEP, photosensitivity,
panniculitis and pigmentary changes. The most unusual and yet
unexplained nding is the repigmentation of gray hair observed
in several patients [112].
Bevacizumab is a recombinant humanized monoclonal anti-
body directed against VEGF. It is used in the treatment of various
solid organ tumors as VEGF plays a central role in tumor angio-
genesis [113]. Poor wound healing, exfoliative dermatitis, hand and
foot syndrome, and perforating dermatosis have all been observed
with bevacizumab [114].
Sorafenib and sunitinib are mutlitargeted kinase inhibitors
that have shown benet in the treatment of certain solid organ
tumors. Sorafenib inhibits the RAS/RAF/MEK/ERK pathway,
as well as VEGF, PDGFR, FLT3, c-KIT and RET tyrosine-
kinase receptors, all promoting tumor angiogenesis and progres-
sion [115]. Sunitinib does not affect the RAS/RAF/MEK/ERK
pathway. Both agents have been associated with a wide spectrum
of cutaneous ADRs, handfoot skin reaction (HFSR) being the
most common [116]. HFSR presents as tender, scaly, erythematous
lesions on the palms and soles, localized to areas of pressure or
exure developing within the rst 4 weeks of treatment. The
HFSR observed with these drugs (sorafenib and sunitinib) differs
from the classic chemo therapy-induced handfoot syndrome in
Al-Niaimi
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283
Review
being well-demarcated and often have a yellow painful hyper-
keratotic base with a surrounding rim of erythema [117]. Other
cutaneous ADRs include a seborrheic-dermatitis-like or exan-
thematous eruption with or without desquamation, facial ery-
thema, scalp dysesthesias, alopecia, yellowish discoloration of
the skin, xerosis and erythema multiforme [115117]. Recently,
multiple keratoacanthomas, actinic keratoses and squamous cell
carcinomas have been reported with sorafenib [118,119]. Similar
to EGFRIs, the cutaneous ADRs observed with sorafenib and
sunitinib, are associated with a positive prognosis, suggesting that
the reactions are an indicator of therapeutic activity.
Bortezomib is a proteosome inhibitor that works by blocking
NF-kB, a factor essential in the survival and growth of tumor
cells. It is used in the treatment of multiple myeloma and has
been associated with several cutaneous ADRs. Morbilliform
hypersensitive reactions, lupus tumidus and asymptomatic ery-
thematous nodules have all been observed in patients treated
with bortezomib [120].
Conclusion
Cutaneous ADRs are diverse and range from benign and self-
limiting to severe and life-threatening. To date, there are no spe-
cic diagnostic tools for many of the ADRs and knowledge of
the reaction patterns and the drugs is essential. Treatment is by
withdrawal of the drug and supportive measures in the majority
of the cases. There have been considerable advances recently in the
pharmacogenetics of ADRs with some genotype-specic reactions
to specic drugs. It is hoped that future diagnostic tools can aid
in early and prompt recognition of ADRs.
Expert commentary
There are currently no uniform classications for ADRs, and
in my view this should be developed in order to be able to accu-
rately classify ADRs, particularly for the nondermatologists.
Classication of ADRs with and without fever and with or
without systemic involvement could be a starting point. In my
view, the enhanced understanding of drug metabolisms and its
pharmaco genetic inuences will mean that this eld will expand
in the future with studies in pharmacogenetics entangling many
of the currently unexplained ADRs.
Five-year view
Our knowledge and experience with ADRs is changing with the
introduction of new therapies such as the multikinase inhibitors
and monoclonal antibodies. It is anticipated that with the intro-
duction of more of such drugs, we will encounter new ADRs. Our
knowledge in the pharmacogenetics and their prediction for seri-
ous drug reactions will continue to be implicated in daily practice
and it is envisaged that this will become more of a standard test
for certain drugs in the near future.
Financial & competing interests disclosure
The author has no relevant afliations or nancial involvement with any
organization or entity with a nancial interest in or nancial conict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this
manuscript.
Key issues
Drug eruptions are common and may have various presentations.
Management is by withdrawal/substitution of the responsible drug in most cases.
Drugs should be considered as a potential cause in any new dermatosis, as some mimic infammatory or blistering dermatoses that also
occur sporadically.
The acneiform eruption found with the EGF receptor antagonists has a prognostic importance in the response of the underlying disease.
Anticonvulsant reactions may be severe with systemic involvement and require aggressive therapy.
StevensJohnson syndrome/toxic epidermal necrolysis is a dermatological emergency requiring specialist therapy.
The emergence of new targeted therapies has led to various therapy-related cutaneous adverse drug reactions, some with
prognostic importance.
References
1 Naldi L, Conforti A, Venegoni M et al.
Cutaneous reactions to drugs. An analysis
of spontaneous reports in four Italian
regions. Br. J. Clin. Pharmacol. 48,
839846 (1999).
2 Bigby M, Jick S, Jick H, Arndt K. Drug
induced cutaneous reactions. A report
from the Boston Collaborative Drug
Surveillance Program on 15,438
consecutive inpatients, 1975 to 1985.
JAMA 256, 33583363 (1986).
3 Lazorou J, Pomeranz BH, Corey PN.
Incidence of adverse drug reactions in
hospitalized patients. JAMA 279,
12001205 (1998).
4 Andersen WK, Feingold DS. Adverse drug
interactions clinically important for the
dermatologist. Arch. Dermatol. 131(4),
468473 (1995).
5 Shapiro LE, Shear NH. Drug interactions:
proteins, pumps, and P-450s. J. Am. Acad.
Dermatol. 47(4), 467484 (2002).
6 Rawlins MD, Thompson JD. Pathogenesis
of adverse drug reactions. In: Textbook of
Adverse Drug Reactions. Davis DM (Ed.).
Oxford University Press, Oxford, UK, 10
(1977).
7 Edwards SG, Hubbard V, Aylett S,
Wren D. Concordance of primary
generalized epilepsy and carbamazepine
hypersensitivity in monozygotic twins.
Postgrad. Med. J. 75, 680681 (1999).
8 Wilke RA, Lin DW, Roden DM et al.
Identifying genetic risk factors for serious
adverse drug reactions: current progress
and challenges. Nat. Rev. Drug Discov.
6(11), 904916 (2007).
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 284
Review
9 Chung WH, Hung SI, Hong HS et al.
Medical genetics: a marker for
StevensJohnson syndrome. Nature 428,
486 (2004).
10 Mallal S, Nolan D, Witt C et al.
Association between presence of
HLA-B*5701, HLA-DR7, and HLA-DQ3
and hypersensitivity to HIV-1 reverse-
transcriptase inhibitor abacavir. Lancet
359, 727732 (2002).
11 Gatanaga H, Honda H, Oka S.
Pharmacogenetic information derived
from analysis of HLA alleles.
Pharmacogenomics 9, 207214 (2008).
12 Roujeau JC, Stern RS. Severe adverse
cutaneous reactions to drugs. N. Engl. J.
Med. 331, 12721285 (1994).
13 Waton J, Trechot P, Loss-Ayav C et al.
Negative predictive value of drug skin
tests in investigating cutaneous adverse
drug reactions. Br. J. Dermatol. 160,
786794 (2009).
14 Messaad D, Sahla H, Benahmed S et al.
Drug provocation tests in patients with a
history suggesting an immediate drug
hypersensitivity reaction. Ann. Intern.
Med. 140(12), 10011006 (2004).
15 Gruchalla RS, Pirmohamed M. Clinical
practice. Antibiotic allergy. N. Eng. J.
Med. 354, 601609 (2006).
16 Pichler WJ, Yawalker N. Allergic reactions
to drug: involvement of T cells. Thorax
55(Suppl. 2), S61S65 (2000).
17 Schnyder B, Mauri-Hellweg D, Zanni M
et al. Direct, MHC-dependent
presentation of the drug sulfamethoxazole
to human ab T cell clones. J. Clin. Invest.
100(1), 136141 (1997).
18 Kozel MM, Mekkes JR, Bossuyt PM,
Bos JD. The effectiveness of a history-
based diagnostic approach in chronic
urticaria and angioedema. Arch. Dermatol.
134, 15751580 (1998).
19 Hedner T, Samuelsson O, Lunde H,
Lindholm L, Andrn L, Wiholm BE.
Angio-oedema in relation to treatment
with angiotensin converting enzyme
inhibitors. BMJ 304, 941946 (1992).
20 Pecina JL, Cappel MA. Acute generalized
exanthematous pustulosis. Skinmed 8(4),
210214 (2010).
21 Speeckaert MM, Speeckaert R, Lambert J,
Brochez L. Acute generalized
exanthematous pustulosis: an overview of
the clinical, immunological and diagnostic
concepts. Eur. J. Dermatol. 20(4),
425433 (2010).
22 Roujeau JC, Bioulac-Sage P, Bourseau C
et al. Acute generalized exanthematous
pustulosis. Analysis of 63 cases.
Arch. Dermatol. 127(9), 13331338 (1991).
23 Amante MF, Filippini AV, Cejas N et al.
Dress syndrome and fulminant hepatic
failure induced by lamotrigine.
Ann. Hepatol. 8(1), 7577 (2009).
24 Choquet-Kastylevsky G, Intrator L,
Chenal C et al. Increased levels of
interleukin 5 are associated with the
generation of eosinophilia in drug-induced
hypersensitivity syndrome. Br. J. Dermatol.
139(6), 10261032 (1998).
25 Descamps V, Bouscarat F, Laglenne S et al.
Human herpesvirus 6 infection associated
with anticonvulsant hypersensitivity
syndrome and reactive haemophagocytic
syndrome. Br. J. Dermatol. 137(4),
605608 (1997).
26 Shiohara T, Iijima M, Ikezawa Z,
Hashimoto K. The diagnosis of a DRESS
syndrome has been sufciently established
on the basis of typical clinical features and
viral reactivations. Br. J. Dermatol. 156(5),
10831084 (2007).
27 Kano Y, Inaoka M, Shiohara T. Association
between anticonvulsant hypersensitivity
syndrome and human herpesvirus 6
reactivation and hypogammaglobulinemia.
Arch. Dermatol. 140(2), 183188 (2004).
28 Picard D, Janela B, Descamps V et al. Drug
reaction with eosinophilia and systemic
symptoms (DRESS): a multiorgan antiviral
T cell response. Sci. Transl. Med. 2(46),
46ra62 (2010).
29 Gaedigk A, Spielberg S, Grant D.
Characterization of the microsomal epoxide
hydrolase gene in patients with
anticonvulsant adverse drug reactions.
Pharmacogenetics 4, 142153 (1994).
30 Pirmohamed M, Graham A, Roberts P et al.
Carbamazepine hypersensitivity: assessment
of clinical and in vitro chemical cross
reactivity with phenytoin and oxcarbazepine.
Br. J. Clin. Pharmacol. 32, 741749 (1991).
31 Hung SI, Chung WH, Liou LB et al.
HLA-B*5801 allele as a genetic marker for
severe cutaneous adverse reactions caused
by allopurinol. Proc. Natl Acad. Sci. USA
102, 41344139 (2005).
32 Bastuji-Garin S, Rzany B, Stern RS et al.
Clinical classication of cases of toxic
epidermal necrolysis, StevensJohnson
syndrome, and erythema multiforme.
Arch. Dermatol. 129, 9296 (1993).
33 Garcia-Doval I, LeCleach L, Bocquet H
et al. Toxic epidermal necrolysis and
StevensJohnson syndrome: does early
withdrawal of causative drugs decrease the
risk of death? Arch. Dermatol. 136,
323327 (2000).
34 Murata J, Abe R. Soluble Fas ligand: is it a
critical mediator of toxic epidermal
necrolysis and StevensJohnson syndrome?
J. Invest. Dermatol. 127(4), 744745
(2007).
35 Murata J, Abe R, Shimizu H. Increased
soluble Fas ligand levels in patients with
StevensJohnson syndrome and toxic
epidermal necrolysis preceding skin
detachment. J. Allergy Clin. Immunol. 122,
9921000 (2008).
36 Abe R, Yoshioka N, Murata J et al.
Granulysin as a marker for early
diagnosis of the StevensJohnson
syndrome. Ann. Intern. Med. 151, 514515
(2009).
37 Stur K, Karlhofer FM, Stingl G. Soluble
FAS ligand: a discriminating feature
between drug-induced skin eruptions and
viral exanthemas. J. Invest. Dermatol. 27,
802807 (2007).
38 Chung WH, Hung SI, Yang JY et al.
Granulysin is a key mediator for
disseminated keratinocyte death in
StevensJohnson syndrome and toxic
epidermal necrolysis. Nat. Med. 14(12),
13431350 (2008).
39 Man CB, Kwan P, Baum L et al.
Association between HLA-B*1502 allele
and antiepileptic drug-induced cutaneous
reactions in Han Chinese. Epilepsia 48,
10151018 (2007).
40 Chung WH, Hung SI, Hong HS et al.
Medical genetics: a marker for
StevensJohnson syndrome. Nature 428,
486 (2004).
41 Min FL, Shi YW, Liu XR, Liao WP.
HLA-B*1502 genotyping in two Chinese
patients with phenytoin-induced
StevensJohnson syndrome. Epilepsy
Behav. 20(2), 390391 (2011).
42 Hung SI, Chung WH, Liou LB et al.
HLA-B*5801 allele as a genetic marker for
severe cutaneous adverse reactions caused
by allopurinol. Proc. Natl Acad. Sci. USA
102, 41344139 (2005).
43 Tassaneeyakul W, Jantararoungtong T,
Chen P et al. Strong association between
HLA-B*5801 and allopurinol-induced
StevensJohnson syndrome and toxic
epidermal necrolysis in a Thai population.
Pharmacogenet. Genomics 19(9), 704709
(2009).
44 Pereira FA, Mudgil AV, Rosmarin DM.
Toxic epidermal necrolysis. J. Am. Acad.
Dermatol. 56(2), 181200 (2007).
45 Hewitt J, Ormerod AD. Toxic epidermal
necrolysis treated with cyclosporin.
Clin. Exp. Dermatol. 17, 264265 (1992).
Al-Niaimi
www.expert-reviews.com
285
Review
46 Renfro L, Grant-Kels JM, Daman LA.
Drug-induced toxic epidermal necrolysis
treated with cyclosporine. Int. J. Dermatol.
28, 441444 (1989).
47 Katz U, Zandman-Goddard G. Drug-
induced lupus: an update. Autoimmun. Rev.
10(1), 4650 (2010).
48 Gunnarsson I, Kanerud L, Pettersson E et al.
Predisposing factors in sulphasalazine-
induced systemic lupus erythematosus. Br. J.
Rheum. 36, 10891094 (1997).
49 Vasoo S. Drug-induced lupus. An update.
Lupus 15, 12961299 (2006).
50 Al-Niaimi F. Adalimumab-induced lupus
erythematosus. Eur. J. Derm. 19(4), 380
(2009).
51 Levine D, Switlyk SA, Gottlieb A.
Cutaneous lupus erythematosus and
anti-TNF-a therapy: a case report with
review of the literature. J. Drugs Dermatol.
9(10), 12831287 (2010).
52 Callen JP. Drug-induced subacute cutaneous
lupus erythematosus. Lupus 19(9),
11071111 (2010).
53 Marzano AV, Vezzoli P, Crosti C. Drug-
induced lupus: an update on its
dermatologic aspects. Lupus 18(11),
935940 (2009).
54 OReilly FM, McKenna D, Murphy GM. Is
monochromatic irradiation testing useful in
the differentiation of drug-induced
photosensitivity from chronic actinic
dermatitis? Clin. Exp. Dermatol. 24(2),
118121 (1999).
55 Harber LC, Bickers DR. Drug-induced
photosensitivity (phototoxic and photo-
allergic drug reactions). In: Photosensitivity
Diseases: Principles of Diagnosis and
Treatment, 2nd Edition. Harber LC, Bickers
DR (Eds). Decker, Toronto, Canada (1989).
56 Ferguson J. Drug and chemical
photosensitivity. In: Photodermatology.
Hawk JLM (Ed.). Arnold Publishers,
London, UK (1999).
57 Piraccini BM, Iorizzo M, Starace M,
Tosti A. Drug-induced nail diseases.
Dermatol. Clin. 24(3), 387391 (2006).
58 Stein KR, Scheinfeld NS. Drug-induced
photoallergic and phototoxic reactions.
Expert Opin. Drug Saf. 6(4), 431443
(2007).
59 Addo HA, Ferguson J, Frain-Bell W.
Thiazide-induced photosensitivity: a study
of 33 subjects. Br. J. Dermatol. 116(6),
749760 (1987).
60 Reich A, Stnder S, Szepietowski JC.
Drug-induced pruritus: a review. Acta Derm.
Venereol. 89(3), 236244 (2009).
61 Stoebner PE, Michot C, Ligeron C et al.
Simvastatin-induced lichen planus
pemphigoides. Ann. Dermatol. Venereol.
130, 187190 (2003).
62 Szarvas S, Harmon D, Murphy D.
Neuraxial opioid-induced pruritus: a review.
J. Clin. Anesth. 15, 234239 (2003).
63 Dereure O. Drug-induced skin
pigmentation. Epidemiology, diagnosis and
treatment. Am. J. Clin. Dermatol. 2(4),
253262 (2001).
64 Sokol RJ, Lichtenstein PK, Farrell MK.
Quinacrine hydrochloride-induced yellow
discoloration of the skin in children.
Pediatrics 69(2), 232233 (1982).
65 Nikolidakis S, Kyriakides ZS, Barbatis C.
Images in cardiology. Blue-grey cutaneous
discolouration secondary to amiodarone
treatment. Heart 92(4), 436 (2006).
66 Spedini P, Bergonzi C, Morandi S.
Cutaneous agellate pigmentation by
bleomycin. Haematologica 85(8), 870
(2000).
67 Mizukawa Y, Shiohara T. Fixed drug
eruption: a prototypic disorder mediated by
effector memory T cells. Curr. Allergy
Asthma Rep. 9(1), 7177 (2009).
68 Mizukawa Y, Yamazaki Y, Shiohara T.
In vivo dynamics of intraepidermal CD8
+

T cells and CD4
+
T cells during the
evolution of xed drug eruption. Br. J.
Dermatol. 158(6), 12301238 (2008).
69 Bleicher PA, Dover JS, Arndt KA. Lichenoid
dermatoses and related disorders. I. Lichen
planus and lichenoid drug-induced
eruptions. J. Am. Acad. Dermatol. 22(2 Pt
1), 288292 (1990).
70 Momin SB, Peterson A, Del Rosso JQ.
A status report on drug-associated acne and
acneiform eruptions. J. Drugs Dermatol.
9(6), 627636 (2010).
71 Lacouture ME, Melosky BL. Cutaneous
reactions to anticancer agents targeting the
epidermal growth factor receptor:
a dermatology-oncology perspective. Skin
Therapy Lett. 12(6), 15 (2007).
72 Calabrese LH, Michel BA, Bloch DA et al.
The American College of Rheumatology
1990 criteria for the classication of
hypersensitivity vasculitis. Arthritis Rheum.
33(8), 11081113 (1990).
73 Carlson JA. The histological assessment of
cutaneous vasculitis. Histopathology 56(1),
323 (2010).
74 Al-Niaimi F, Lyon C. Felodipine-induced
eruptive telangiectasia following mastectomy
and radiotherapy. Br. J. Dermatol. 162(1),
210211 (2010).
75 Karonen T, Stubb S, Keski-Oja J. Truncal
telangiectases coinciding with felodipine.
Dermatology 196(2), 272273 (1998).
76 Farhat EK, Muirhead TT, Chafns ML,
Douglass MC. Levamisole-induced
cutaneous necrosis mimicking
coagulopathy. Arch. Dermatol. 146(11),
13201321 (2010).
77 Nazarian RM, Van Cott EM,
Zembowicz A, Duncan LM. Warfarin-
induced skin necrosis. J. Am. Acad.
Dermatol. 61(2), 325332 (2009).
78 Inayatullah S, Phadke G, Vilenski L et al.
Warfarin-induced skin necrosis. South Med.
J. 103(1), 7475 (2010).
79 Al-Niaimi F, Clark C. A case of unilateral
purple toes due to warfarin. Clin Exp
Dermatol. 34(4), 527528 (2009).
80 Tonn ME, Schaiff RA, Kollef MH.
Enoxaparin-associated dermal necrosis:
a consequence of cross-reactivity with
heparin-mediated antibodies.
Ann. Pharmacother. 31(3), 323326 (1997).
81 Claeys A, Weber-Muller F, Trechot P et al.
Cutaneous, perivulvar and perianal
ulcerations induced by nicorandil. Br. J.
Dermatol. 155(2), 494496 (2006).
82 Williams C, Tamuno P, Smith AJ et al.
Perianal ulceration and other cutaneous
ulcerations complicating nicorandil therapy.
J. Am. Acad. Dermatol. 56(5 Suppl.),
S116S117 (2007).
83 Dissemond J, Krber A. Hydroxyurea-
induced ulcers on the leg. CMAJ 180(11),
1132 (2009).
84 Inafuku H, Kasem Khan MA, Nagata T,
Nonaka S. Cutaneous ulcerations following
subcutaneous interferon b injection to a
patient with multiple sclerosis. J. Dermatol.
31(8), 671677 (2004).
85 Warner J, Brown A, Whitmore SE,
Cowan DA. Mucocutaneous ulcerations
secondary to methotrexate. Cutis 81(5),
413416 (2008).
86 Karakayli G, Beckham G, Orengo I,
Rosen T. Exfoliative dermatitis. Am. Fam.
Physician 59(3), 625630 (1999).
87 Roujeau JC. Neutrophilic drug eruptions.
Clin. Dermatol. 18(3), 331337 (2000).
88 Hasegawa M, Sato S, Nakada M et al.
Sweets syndrome associated with
granulocyte colony-stimulating factor. Eur.
J. Dermatol. 8(7), 503505 (1998).
89 Bielory L, Yancey KB, Young NS et al.
Cutaneous manifestations of serum sickness
in patients receiving antithymocyte
globulin. J. Am. Acad. Dermatol. 13(3),
411417 (1985).
Drug eruptions in dermatology
Expert Rev. Dermatol. 6(3), (2011) 286
Review
90 Lawley TJ, Bielory L, Gascon P et al.
A prospective clinical and immunologic
analysis of patients with serum sickness.
N. Engl. J. Med. 311(22), 14071413
(1984).
91 Isaacs D. Serum sickness-like reaction to
cefaclor. J. Paediatr. Child Health 37(3),
298299 (2001).
92 Pillans PI, Woods DJ. Drug-associated
alopecia. Int. J. Dermatol. 34(3), 149158
(1995).
93 Piraccini BM, Iorizzo M, Rech G, Tosti A.
Drug-induced hair disorders. Curr. Drug
Saf. 1(3), 301305 (2006).
94 Mustafa R, Hashmi HA. Drug-induced
hirsutism. J. Coll. Physicians Surg. Pak.
16(7), 485486 (2006).
95 Brenner S, Bialy-Golan A, Ruocco V.
Drug-induced pemphigus. Clin. Dermatol.
16(3), 393397 (1998).
96 Ong CS, Cook N, Lee S. Drug-related
pemphigus and angiotensin converting
enzyme inhibitors. Australas. J. Dermatol.
41(4), 242246 (2000).
97 Ruocco V, de Angelis E, Lombardi ML,
Pisani M. In vitro acantholysis by captopril
and thiopronine. Dermatologica 176(3),
115123 (1988).
98 Lee JJ, Downham TF 2nd. Furosemide-
induced bullous pemphigoid: case report
and review of literature. J. Drugs Dermatol.
5(6), 562564 (2006).
99 Paul C, Wolkenstein P, Prost C et al.
Drug-induced linear IgA disease: target
antigens are heterogeneous. Br. J. Dermatol.
136(3), 406411 (1997).
100 Ramsay CA. Drug induced
pseudoporphyria. J. Rheumatol. 18(6),
799800 (1991).
101 Moustou AE, Matekovits A, Dessinioti C
et al. Cutaneous side effects of anti-tumor
necrosis factor biologic therapy: a clinical
review. J. Am. Acad. Dermatol. 61(3),
486504 (2009).
102 Tracey D, Klareskog L, Sasso EH et al.
Tumor necrosis factor antagonist
mechanisms of action: a comprehensive
review. Pharmacol. Ther. 117, 244279
(2008).
103 Collamer AN, Guerrero KT, Henning JS,
Battafarano DF. Psoriatic skin lesions
induced by tumor necrosis factor antagonist
therapy: a literature review and potential
mechanisms of action. Arthritis Rheum.
59(7), 9961001 (2008).
104 Salomon DS, Brandt R, Ciardiello F,
Normanno N. Epidermal growth factor-
related peptides and their receptors in
human malignancies. Crit. Rev. Oncol.
Hematol. 19, 183232 (1995).
105 Nanney LB, Stoscheck CM, King LE Jr
et al. Immunolocalization of epidermal
growth factor receptors in normal
developing human skin. J. Invest. Dermatol.
94, 742748 (1990).
106 Malik SN, Siu LL, Rowinsky EK et al.
Pharmacodynamic evaluation of the
epidermal growth factor receptor inhibitor
OSI-774 in human epidermis of cancer
patients. Clin. Cancer Res. 9, 24782486
(2003).
107 Galimont-Collen AFS, Vos LE,
Lavrijsen APM et al. Classication and
management of skin, hair, nail and mucosal
side-effects of epidermal growth factor
receptor (EGFR) inhibitors. Eur. J. Cancer
43, 845851 (2007).
108 Busam KJ, Capodici P, Motzer R et al.
Cutaneous side-effects in cancer patients
treated with the antiepidermal growth factor
receptor antibody C225. Br. J. Dermatol.
144, 11691176 (2001).
109 Dueland S, Lund-Johansen F, Ostenstad B
et al. Epidermal growth factor receptor
inhibition induces trichomegaly. Acta Oncol.
42, 345346 (2003).
110 Druker BJ, Tamura S, Buchdunger E et al.
Effects of a selective inhibitor of the ABL
tyrosine kinase on the growth of BCR-ABL
positive cells. Nat. Med. 2, 561566 (1996).
111 Curran MP, Croom KF, Goa KL. Spotlight
on imatinib mesylate in chronic myeloid
leukemia. BioDrugs 18(3), 207210 (2004).
112 Valeyrie L, Bastuji-Garin S, Revuz J et al.
Adverse cutaneous reactions to imatinib
(STI571) in Philadelphia chromosome-
positive leukemias: a prospective study of
54 patients. J. Am. Acad. Dermatol. 48,
201206 (2003).
113 Homsi J, Daud AI. Spectrum of activity
and mechanism of action of VEGF/PDGF
inhibitors. Cancer Control 14, 285294
(2007).
114 Vano-Galvan S, Moreno C, Medina J et al.
Perforating dermatosis in a patient
receiving bevacizumab. J. Eur. Acad.
Dermatol. Venereol. 23, 972974 (2009).
115 Grandinetti CA, Goldspiel BR. Sorafenib
and sunitinib: novel targeted therapies for
renal cell cancer. Pharmacotherapy 24,
2535 (2007).
116 Lacouture ME, Wu S, Robert C et al.
Evolving strategies for the management of
handfoot skin reaction associated with the
multitargeted kinase inhibitors sorafenib
and sunitinib. Oncologist 13, 10011101
(2008).
117 Fife DJ, Wu JJ, Behnam SE, Linden KG.
Sunitinib-induced hand-foot syndrome:
a new, distinct form. Clin. Exp. Dermatol.
35, 200201 (2009).
118 Kong HH, Cowen EW, Azad NS et al.
Keratoacanthomas associated with
sorafenib therapy. J. Am. Acad. Dermatol.
56, 171172 (2007).
119 Dubauskas Z, Kunishige J, Prieto VG et al.
Cutaneous squamous cell carcinoma and
inammation of actinic keratoses
associated with sorafenib. Clin. Genitourin.
Cancer 7, 2023 (2009).
120 Wu KL, Heule F, Lam K, Sonneveld P.
Pleomorphic presentation of cutaneous
lesions associated with the proteasome
inhibitor bortezomib in patients with
multiple myeloma. J. Am. Acad. Dermatol.
55(5), 897900 (2006).
Al-Niaimi
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