Download Cutaneous Reactions to Drugs

‫بنام خداوند بخشنده و مهربان‬
‫دکتر مجيد رستمی‬
‫متخصص پوست مو و‬
‫زيبايی‬
‫استاديار دانشگاه علوم‬
‫پزشکی اردبيل‬
‫(عضو هيئت علمی‬
‫دانشگاه)‬
Cutaneous Reactions
to Drugs
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Complications from drug therapy are a
major cause of patient morbidity and
account for a significant number of patient
deaths. Approximately 14 percent of
adverse drug reactions in hospital patients
are cutaneous or allergic in nature. Drug
eruptions range from common nuisance
eruptions to rare or life-threatening druginduced diseases. Drug reactions can be
solely limited to the skin, or they may be
part of a systemic reaction, such as the
drug hypersensitivity syndrome or toxic
epidermal necrolysis (TEN).
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Constitutional factors influencing the risk of cutaneous
eruption include pharmacogenetic variation in drugmetabolizing enzymes and human leukocyte antigen
(HLA) associations .
Acetylator phenotype alters the risk of developing druginduced lupus due to hydralazine, procainamide, and
isoniazid. Acetylator phenotype is also important in many
other drug eruptions.
Fast acetylator status appears to partially protect against
the risk of developing TEN and the drug hypersensitivity
syndrome due to sulfonamide antibiotics.
HLA-DR4 is significantly more common in individuals with
hydralazine-related drug-induced lupus than in those with
idiopathic systemic lupus erythematosus. HLA factors
may also influence the risk of bullous drug reactions.
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Many drugs associated with severe idiosyncratic drug
reactions are metabolized by the body to form reactive, or
toxic, drug products. These reactive products comprise
only a small proportion of a drug's metabolites and are
usually rapidly detoxified. However, patients with the drug
hypersensitivity syndrome, TEN, and Stevens-Johnson
syndrome (SJS), resulting from treatment with sulfonamide
antibiotics and the aromatic anticonvulsants (e.g.,
carbamazepine, phenytoin, and phenobarbital), show
increased sensitivity in in vitro assessments to the
oxidative, reactive drug metabolites of these drugs as
compared to control subjects.
Acquired factors also alter an individual's risk of drug
eruption. Active viral infection and concurrent medications
have been shown to alter frequency of drug-associated
eruptions.
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The course and outcome of drug-induced
disease are also influenced by host
factors. Older age may delay the onset of
drug eruptions and has been associated
with a higher mortality rate in some
severe reactions; a higher mortality rate is
also observed in patients with severe
reactions with underlying malignancy .
Reactivation of latent viral infection with
human herpesvirus (HHV)-6 also appears
common in the drug hypersensitivity
syndrome and may be partially
responsible for some of the clinical
features and/or course of the disease.
Exanthematous Eruptions
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Exanthematous eruptions, known also as
morbilliform or maculopapular, are the most
common form of drug eruptions, accounting for
approximately 95 percent of skin reactions .
Simple exanthems are erythematous changes in
the skin without evidence of blistering or
pustulation. The eruption typically starts on the
trunk and spreads peripherally in a symmetric
fashion. Pruritus is almost always present.
These eruptions usually occur within 1 week of
starting therapy and resolve within 7 to 14 days.
Resolution occurs with a change in color from
bright red to a brownish-red, which may be
followed by scaling or desquamation.
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Exanthematous eruptions can be caused by many drugs
including the penicillins, sulfonamides, and antiepileptic
medications.
Clinical experience and laboratory data have indicated that
T cells are involved in these reactions because they are able
to recognize the drug directly, without covalent hapten
modification of proteins or peptides .
In patients who have concomitant infectious
mononucleosis, the risk of developing an exanthematous
eruption while being treated with an aminopenicillin (e.g.,
ampicillin) increases to 60 to 100 percent. Patients are
able to tolerate all beta-lactam antibiotics, including the
aminopenicillins, after the infectious process has resolved.
A similar drug–viral interaction has been observed in 50
percent of HIV-infected patients who are exposed to
sulfonamide antibiotics.
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An exanthematous eruption in conjunction with fever and
internal organ involvement (e.g., liver, kidney, central
nervous system) signifies a more serious reaction, known
as the hypersensitivity syndrome reaction (HSR). HSR
occurs most frequently on first exposure to the drug, with
initial symptoms starting 1 to 6 weeks after exposure.
Fever and malaise are often the presenting symptoms.
Atypical lymphocytosis with a subsequent eosinophilia may
occur during the initial phases of the reaction in some
patients. Even though most patients present with an
exanthematous eruption, more serious cutaneous
manifestations may be evident . Internal organ involvement
can be asymptomatic. Some patients may become
hypothyroid approximately 2 months after the first
symptoms appear.
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The formation of toxic metabolites by the
aromatic anticonvulsants, namely
phenytoin, carbamazepine, and
phenobarbital, may play a pivotal role in
the development of the HSR.
Approximately 70 to 75 percent of
patients who develop anticonvulsant HSR
in response to one aromatic
anticonvulsant show cross-reactivity to the
other aromatic anticonvulsants. In
addition, in vitro testing shows that there
is a familial occurrence of HSR due to
anticonvulsants. Thus, counseling of
family members and disclosure of risk is
essential.
Urticarial Eruptions
Urticaria is characterized by pruritic red wheals of various
sizes. Individual lesions generally last for less than 24 h,
although new lesions can continually develop. When deep
dermal and subcutaneous tissues are also swollen, the
reaction is known as angioedema. Angioedema is
frequently unilateral and nonpruritic and lasts for 1 to 2 h,
although it may persist for 2 to 5 days.
Urticaria and angioedema, when associated with drug use, are
usually indicative of an IgE-mediated immediate
hypersensitivity reaction; this mechanism is typified by
immediate reactions to penicillin and other antibiotics.
Nonimmunologic activation of inflammatory mediators
may also result in urticarial reactions. For example,
narcotic analgesics may directly cause release of
histamine from mast cells independent of IgE .
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Angiotensin-converting enzyme (ACE) inhibitors are
frequent causes of angioedema. The onset is usually within
hours of starting ACE-inhibitor therapy but can occur as late
as 1 week to several months into therapy. Angioedema
usually resolves within 48 h with treatment. Angioedema
has also been reported to occur with angiotensin II
antagonists; in many of these patients, a prior history of
angioedema related to an ACE-inhibitor was documented.
Serum sickness-like reactions are defined by the presence
of fever, rash (usually urticarial), and arthralgias 1 to 3
weeks after initiation of drug. Lymphadenopathy and
eosinophilia may also be present; however, in contrast to
true serum sickness, immune complexes,
hypocomplementemia, vasculitis, and renal lesions are
absent.
Cefaclor is associated with an increased relative risk of
serum sickness-like reactions.
Pustular Eruptions
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Acneiform eruptions are associated with iodides,
bromides, adrenocorticotropic hormone (ACTH),
glucocorticoids, isoniazid, androgens, lithium,
actinomycin D, and phenytoin. Drug-induced
acne may appear in atypical areas, such as on
the arms and legs, and is most often
monomorphous. Comedones are usually absent.
The fact that acneiform eruptions do not affect
prepubertal children indicates that previous
hormonal priming is a necessary prerequisite. In
cases where the offending agent cannot be
discontinued, topical tretinoin may be useful.
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Acute generalized exanthematous pustulosis (AGEP) is an acute
febrile eruption that is often associated with leukocytosis ). After
drug administration, it may take 1 to 3 weeks before skin lesions
appear; however, in previously sensitized patients, the skin
symptoms may occur within 2 to 3 days. The lesions often start
on the face or main skin creases. Generalized desquamation
occurs approximately 2 weeks later. The estimated incidence rate
of AGEP is approximately 1 to 5 cases per million per year.
Differential diagnosis includes pustular psoriasis, the
hypersensitivity syndrome reaction with pustulation, subcorneal
pustular dermatosis (Sneddon-Wilkinson disease), pustular
vasculitis, or TEN, especially in severe cases of AGEP. The typical
histopathologic analysis of AGEP lesions shows spongiform
subcorneal and/or intraepidermal pustules, an often marked
edema of the papillary dermis, and perivascular infiltrates with
neutrophils and exocytosis of some eosinophils.
Bullous Eruptions
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Pseudoporphyria is a cutaneous phototoxic disorder that
can resemble either porphyria cutanea tarda (PCT) in adults
or erythropoietic protoporphyria (EPP) in children .
Pseudoporphyria of the PCT variety is characterized by skin
fragility, blister formation, and scarring in photodistribution;
it occurs in the presence of normal porphyrin levels. The
other clinical pattern mimics EPP and manifests as
cutaneous burning, erythema, vesiculation, angular chicken
pox-like scars, and waxy thickening of the skin. The
eruption may begin within 1 day of initiation of therapy or
may be delayed for as long as 1 year. The course is
prolonged in some patients, but most reports describe
symptoms that disappear several weeks to several months
after the offending agent is withdrawn. Because of the risk
of permanent facial scarring, the implicated drug should be
discontinued if skin fragility, blistering, or scarring occurs.
In addition, broad-spectrum sunscreen and protective
clothing should be recommended.
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Pemphigus may be considered as drug-induced or drug-triggered
(i.e., a latent disease that is unmasked by the drug exposure).
Drug-induced pemphigus caused by penicillamine and other thiol
drugs tends to remit spontaneously in 35 to 50 percent of cases,
presents as pemphigus foliaceus, has an average interval to onset
of 1 year, and is associated with the presence of antinuclear
antibodies in 25 percent of patients.
Most patients with nonthiol drug-induced pemphigus manifest
clinical, histologic, immunologic, and evolutionary aspects similar
to those of idiopathic pemphigus vulgaris with mucosal
involvement with a 15 percent rate of spontaneous recovery after
drug withdrawal. Treatment of drug-induced pemphigus begins
with drug withdrawal. Systemic glucocorticoids are often required
until all symptoms of active disease disappear. Vigilant follow-up
is required after remission to monitor the patient and the serum
for autoantibodies to detect an early relapse.
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Drug-induced bullous pemphigoid (see Chap. 61) can
encompass a wide variety of presentations, ranging from
the classic features of large, tense bullae arising from an
erythematous, urticarial base, with moderate involvement
of the oral cavity, through mild forms with few bullous
lesions, or scarring plaques and nodules with bullae. In
contrast to the idiopathic form, patients with drug-induced
bullous pemphigoid are generally younger; as well, the
histopathologic findings are of a perivascular infiltration of
lymphocytes with few eosinophils and neutrophils,
intraepidermal vesicles with foci of necrotic keratinocytes,
thrombi in dermal vessels, and a possible lack of tissuebound and circulating antibasal membrane zone IgG.
In the acute, self-limited condition, resolution occurs after
the withdrawal of the culprit agent, with or without
glucocorticoid therapy. However, in some patients, the drug
may actually trigger the idiopathic form of the disease.
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Erythema multiforme-major (EM-major), SJS ,
and TEN , which may represent variants of the
same disease process, encompass a spectrum of
serious dermatologic eruptions ( . The more
severe the reaction, the more likely it is that it
has been drug-induced. A large percentage of
cases of EM/SJS are not drug related and may
develop after a variety of other predisposing
factors including infections (e.g., herpes simplex ,
Mycoplasma pneumoniae), neoplasia, and
autoimmune diseases. The risk of TEN has been
estimated to be 1 per million per year and 1 to 6
per million per year for SJS .
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Treatment of EM, SJS, and TEN includes
discontinuation of the suspected drug and
supportive measures, such as careful wound
care, hydration, and nutritional support. The use
of glucocorticoids to treat SJS and TEN is
controversial. Intravenous immunoglobulin
(IVIG, 0.2 to 0.75 g/kg for 4 consecutive days)
has rapidly reversed disease progression within
48 hours. A limited number of patients have been
treated with cyclophosphamide and cyclosporine.
Patients who have developed a severe cutaneous
adverse reaction (i.e., EM/SJS/TEN) should not
be rechallenged with the drug or undergo
desensitization with the medication.
Fixed Drug Eruptions
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Fixed drug eruptions (FDE) usually appear as solitary,
erythematous, bright red or dusky red macules that may
evolve into an edematous plaque; bullous-type lesions may
be present. FDE are most commonly found on the genitalia
and in the perianal area, although they can occur anywhere
on the skin surface. Some patients may complain of
burning or stinging, and others may have fever, malaise,
and abdominal symptoms. FDE can develop 30 min to 8 to
16 h after ingestion of the medication. After the initial acute
phase lasting days to weeks, residual grayish or slatecolored hyperpigmentation develops. Upon rechallenge, not
only do the lesions recur in the same location, but also new
lesions often appear .
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More than 100 drugs have been implicated in FDE,
including ibuprofen, sulfonamides, and tetracyclines. A
haplotype linkage in the setting of trimethoprimsulfamethoxazole–induced FDE was recently documented.
Histologically, FDE resembles erythema multiforme, with an
interface dermatitis with lymphocytes at the dermal–
epidermal junction and degenerative changes .
A challenge or provocation test with the suspected drug
may be useful in establishing the diagnosis. Patch testing at
the site of a previous lesion yields a positive response in up
to 43 percent of patients. In some patients, prick and
intradermal skin tests may be positive in 24 and 67 percent
of patients, respectively.
Drug-Induced Lichenoid
Eruptions
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Drug-induced lichen planus produces lesions that are
clinically and histologically indistinguishable from idiopathic
lichen planus; however, lichenoid drug eruptions often
appear initially as eczematous with a purple hue and
involve large areas of the trunk. Usually the mucous
membranes and nails are not involved. Many drugs,
including beta blockers, penicillamine, and ACE-inhibitors,
especially captopril, reportedly produce this reaction. The
mean latent period is between 2 months and 3 years for
penicillamine, approximately 1 year for β-adrenergic
blocking agents, and 3 to 6 months for ACE inhibitors. The
latent period may be shortened if the patient has been
previously exposed to the drug. Resolution usually occurs
with 2 to 4 months. Rechallenge with the culprit drug has
been attempted in a few patients, with reactivation of
symptoms within 4 to 15 days.
Drug-Induced Cutaneous
Pseudolymphoma
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Pseudolymphoma is a process that simulates lymphoma but
has a benign behavior and does not meet the criteria for
malignant lymphoma. Drugs are a well-known cause of
cutaneous pseudolymphomas, but the condition may also
be provided by foreign agents such as insect bites,
infections (e.g., HIV), and idiopathic causes.
Anticonvulsant-induced pseudolymphoma generally occurs
after 1 week to 2 years of exposure to the drug. Within 7 to
14 days of drug discontinuation, the symptoms generally
resolve. The eruption often manifests as single lesions but
can also be widespread erythematous papules, plaques, or
nodules. Most patients also have fever, marked
lymphadenopathy and hepatosplenomegaly, and
eosinophilia. Mycosis fungoides-like lesions are also
associated with these drugs.
Drug-Induced Vasculitis
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Drug-induced vasculitis represents approximately 10 percent of the acute
cutaneous vasculitides and usually involves small vessels. Drugs that are
associated with vasculitis include allopurinol, penicillins, and thiazide
diuretics. The average interval from initiation of drug therapy to onset of
drug-induced vasculitis is 7 to 21 days.
The clinical hallmark of cutaneous vasculitis is palpable purpura, classically
found on the lower extremities. Urticaria can be a manifestation of small
vessel vasculitis, with individual lesions remaining fixed in the same
location for more than 1 day. Other features include hemorrhagic bullae,
urticaria, ulcers, nodules, Raynaud's disease, and digital necrosis. The
same vasculitic process may also affect internal organs such as the liver,
kidney, gut, and central nervous system and can be potentially lifethreatening.
Drug-induced vasculitis can be difficult to diagnose and is often a
diagnosis of exclusion. In some cases, serology has revealed the presence
of perinuclear-staining antineutrophil cytoplasmic autoantibodies (p-ANCA)
against myeloperoxidase. Alternative etiologies for cutaneous vasculitis
such as infection or autoimmune disease must be eliminated. Treatment
consists of drug withdrawal. Systemic glucocorticoids may be of benefit.
Drug-Induced Lupus
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Drug-induced lupus is characterized by frequent musculoskeletal
complaints, fever, weight loss, pleuropulmonary involvement in
more than half of patients, and, rarely, renal, neurologic, or
vasculitic involvement. Most patients have no cutaneous findings
of lupus erythematosus. The most common serologic
abnormalities are positivity for antinuclear antibodies with a
homogeneous pattern, as well as the presence of antihistone
antibody. The recent identification of minocycline as a cause of
drug-induced lupus makes it important for dermatologists to
recognize this syndrome. Minocycline-induced lupus typically
occurs after 2 years of therapy. The patient presents with a
symmetric polyarthritis. Hepatitis is often detected on laboratory
evaluation. Cutaneous findings include livedo reticularis, painful
nodules on the legs, and nondescript eruptions. Antihistone
antibody is seldom present. A study of HLA class II alleles
revealed the presence of HLA-DR-4 or HLA-DR-2 in many of the
patients.
DIAGNOSIS AND
MANAGEMENT
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These iatrogenic disorders are distinct disease entities,
although they may closely mimic many infective or
idiopathic diseases. A drug cause should be considered in
the differential diagnosis of a wide spectrum of
dermatologic diseases, particularly when the presentation
or course is atypical.
A wide variety of cutaneous drug-associated eruptions may
also warn of associated internal toxicity . Hepatic, renal,
joint, respiratory, hematologic, and neurologic changes
should be sought, and any systemic symptoms or signs
investigated. Fever, malaise, pharyngitis, and other
systemic symptoms or signs should be investigated. A usual
screen would include a full blood count, liver and renal
function tests, and a urine analysis.
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Skin biopsy should be considered for all patients with
potentially severe reactions, such as those with systemic
symptoms, erythroderma, blistering, skin tenderness,
purpura, and pustulation, or in those cases where diagnosis
is uncertain. Some cutaneous reactions, such as FDE, are
virtually always due to drug therapy, and nearly 90 percent
of TEN cases are also drug related. Other more common
eruptions, including exanthematous or urticarial eruptions,
have many nondrug causes.
There is no gold standard investigation for confirmation of a
drug cause. Instead, diagnosis and assessment of cause
involve analysis of a constellation of features such as timing
of drug exposure and reaction onset, course of reaction
with drug withdrawal or continuation, timing and nature of
a recurrent eruption on rechallenge, a history of a similar
reaction to a cross-reacting medication, and previous
reports of similar reactions to the same medication.
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Several in vitro investigations can help to confirm causation in individual
cases, but their exact sensitivity and specificity remain unclear. Penicillin
skin testing with major and minor determinants is useful for confirmation
of an IgE-mediated immediate hypersensitivity reaction to penicillin.
Patch testing has been used in patients with ampicillin-induced
exanthematous eruptions and in the ancillary diagnosis of fixed drug
eruptions. Patch testing has greater sensitivity if performed over a
previously involved area of skin.
Cutaneous drug eruptions do not usually vary in severity with dose. Lesssevere reactions may abate with continued drug therapy (e.g., transient
exanthematous eruptions associated with commencement of a new HIV
antiretroviral regimen). However, a reaction suggestive of a potentially
life-threatening situation should prompt immediate discontinuation of the
drug, along with discontinuation of any interacting drugs that may slow
the elimination of the suspected causative agent(s). Resolution of the
reaction over a reasonable time frame after the drug is discontinued is
consistent with drug cause but also occurs for many infective and other
causes of transient cutaneous eruptions. Patients should not be
rechallenged if they have suffered a potentially serious reaction.
PREVENTION
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Cutaneous reactions to drugs are largely idiosyncratic and
unexpected; serious reactions are rare. Once a reaction has
occurred, however, it is important to prevent future similar
reactions in the patient with the same drug or a cross-reacting
medication. For patients with hypersensitivity and severe
reactions, wearing a bracelet (e.g., MedicAlert) detailing the
nature of the allergy is advisable, and patient records should be
appropriately labeled.
Host factors appear important in many reactions. Some of these
can be inherited, placing first-degree relatives at increased risk
over the general population of a similar reaction to the same or a
metabolically cross-reacting drug. This finding appears to be
important in SJS, TEN, and drug hypersensitivity syndrome.
Reporting reactions to the manufacturer or regulatory authorities
is important. Postmarketing voluntary reports of rare, severe, or
unusual reactions remain crucial to enhance the safe use of
pharmaceutical agents.