Drug Eruptions - UpToDate

27/3/22, 20:13 Drug eruptions - UpToDate
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Drug eruptions
Authors: Andrew D Samel, MD, Chia-Yu Chu, MD, PhD
Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Maja Mockenhaupt, MD, PhD
Deputy Editor: Rosamaria Corona, MD, DSc
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2022. | This topic last updated: Jul 13, 2021.
INTRODUCTION
Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of hospitalized

patients, and are a significant cause of outpatient morbidity [1]. It is estimated that 1 in 1000
hospitalized patients has a serious cutaneous drug reaction.
Classic and uncommon cutaneous drug reactions will be reviewed here. Drug allergy,
hypersensitivity reactions, infusion reactions, and cutaneous complications of tumor
necrosis factor inhibitors and antineoplastic drugs are discussed elsewhere.
● (See "Drug hypersensitivity: Classification and clinical features".)

● (See "Hypersensitivity reactions to macrolides, aminoglycosides, tetracyclines,
clindamycin, and metronidazole".)
● (See "Hypersensitivity reactions to fluoroquinolones".)
● (See "Hypersensitivity reactions to clopidogrel".)
● (See "Vancomycin hypersensitivity".)
● (See "Progestogen hypersensitivity".)
● (See "Hypersensitivity reactions to systemic glucocorticoids".)
● (See "Hypersensitivity reactions to insulins".)
● (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section
on 'Cutaneous reactions'.)
● (See "Infusion reactions to systemic chemotherapy".)
● (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer
therapy".)
● (See "Cutaneous side effects of conventional chemotherapy agents".)
● (See "Cutaneous adverse events of molecularly targeted therapy and other biologic
agents used for cancer therapy".)
https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 1/78

● (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on

'Dermatologic and mucosal toxicity'.)
CLASSIC DRUG REACTION PATTERNS
Exanthematous drug eruptions — Drug-induced exanthems are the most common

cutaneous reactions to drugs, responsible for approximately 90 percent of all drug rashes
[2]. The rashes are referred to as exanthematous, morbilliform, and maculopapular
eruptions ( picture 1A-B) [3]. The most commonly prescribed medications (eg, antibiotics,
sulfonamides) are implicated in most cases.
The diagnosis and management of exanthematous drug eruptions are discussed in detail
separately. (See "Exanthematous (maculopapular) drug eruption".)
Lichenoid drug eruption (drug-induced lichen planus) — Lichen planus typically presents
with flat-topped, violaceous or hyperpigmented, pruritic papules that typically affect the
ankles and the volar surface of the wrists ( picture 2A-B). The drug-induced form of this
disorder usually develops insidiously, months or up to a year or more after drug initiation,
and can affect any area of the body surface ( picture 3A-B). Beta-blockers, angiotensin-
converting enzyme (ACE) inhibitors, methyldopa, penicillamine, quinidine, antimalarials, and
thiazide diuretics are most frequently implicated [4]. Cases induced by tumor necrosis factor
(TNF)-alpha inhibitors and the tyrosine kinase inhibitor imatinib have also been reported
[5,6]. Oral lichenoid drug eruptions are rare and share clinical features with oral lichen
planus, including reticular or erosive lesions ( picture 4).
The diagnosis and management of lichenoid drug eruptions and oral lichen planus are
discussed in detail separately. (See "Lichenoid drug eruption (drug-induced lichen planus)"
and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".)
Exfoliative dermatitis/erythroderma — Exfoliative dermatitis/erythroderma is a severe

and potentially life-threatening condition characterized by diffuse erythema and scaling
involving ≥90 percent of the body surface area ( picture 5). Drugs are the second most
common cause of erythroderma, accounting for approximately 10 to 20 percent of all
erythrodermas [7]. Allopurinol, ACE inhibitors, penicillins, sulfonamides, carbamazepine,
phenytoin, barbiturates, and other drugs have been associated with exfoliative dermatitis (
table 1).
The diagnosis and management of erythroderma are discussed in detail elsewhere. (See
"Erythroderma in adults".)
Urticaria/angioedema — Urticaria (hives) and angioedema may be manifestations of drug

hypersensitivity reactions that may be immunoglobulin E (IgE)-mediated (type I
hypersensitivity ( table 2)) or due to direct mast cell activation through non-IgE-mediated
mechanisms [8]. Reactions involving urticaria/angioedema can be immediate, accelerated
(hours postexposure), or delayed (days postexposure). As with most drug eruptions, these
reactions are more common during the first weeks of therapy but can happen at any time
(see "New-onset urticaria" and "An overview of angioedema: Pathogenesis and causes"):
● Urticaria is characterized by an intensely pruritic, circumscribed, raised, and

erythematous eruption, often with central pallor ( picture 6A-B). Individual lesions
may enlarge, coalesce with other lesions ( picture 7), and typically disappear over a
few hours. (See "New-onset urticaria", section on 'Clinical manifestations'.)
● Angioedema is swelling of the deeper dermis and subcutaneous tissues that may
coexist with urticaria in as many as 50 percent of cases. Angioedema may be
disfiguring if it involves the face and lips or life threatening if airway obstruction occurs
from laryngeal edema or tongue swelling. (See "An overview of angioedema: Clinical
features, diagnosis, and management".)
Antibiotics (especially penicillins, cephalosporins, and sulfonamides) are common causes of

IgE-mediated drug allergy. IgE-mediated drug reactions tend to become more severe and
progress toward anaphylaxis upon re-exposure to the causative agent. (See "New-onset
urticaria" and "Penicillin allergy: Immediate reactions".)
Other drugs may cause urticaria due to direct mast cell activation by a non-IgE-mediated
mechanism. The most frequently implicated are the opiate analgesics morphine and
codeine. The concomitant use of opiates and vancomycin may increase the risk of
vancomycin hypersensitivity reaction, the so-called "red man syndrome" seen after rapid
vancomycin infusion, which is also due to direct mast cell activation and may have
accompanying urticaria. (See "New-onset urticaria", section on 'Direct mast cell activation'
and "Vancomycin hypersensitivity".)
Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute urticaria/angioedema

through direct mast cell activation or by nonmast cell-mediated mechanisms. The latter
include abnormalities of the complement cascade (inherited and acquired abnormalities of
complement metabolism) and increased activity of vasodilatory kinin pathways ( table 3).
(See "An overview of angioedema: Pathogenesis and causes", section on 'Aspirin and
NSAIDs'.)
Angioedema (in the absence of urticaria) occurs in 2 to 10 per 10,000 new users of ACE
inhibitors and usually affects the mouth or tongue ( picture 8) [9]. Impaired bradykinin
degradation by ACE, leading to elevated blood levels of the vasoactive peptide bradykinin, is
thought to be the underlying mechanism. (See "ACE inhibitor-induced angioedema".)

Anaphylaxis — Drugs are the second or third most common cause of anaphylaxis, the most
severe and potentially life-threatening form of immediate type I hypersensitivity [10,11].
Symptoms include pruritus, urticaria, angioedema, laryngeal edema, wheezing, nausea,
vomiting, tachycardia, sense of impending doom, and, occasionally, shock. (See
"Anaphylaxis: Emergency treatment".)
Cutaneous small vessel vasculitis — Cutaneous small vessel vasculitis (CSVV; also called
hypersensitivity vasculitis, cutaneous leukocytoclastic vasculitis, serum sickness or serum
sickness-like reaction, and allergic vasculitis) is a single-organ vasculitis caused in most cases
by drugs ( table 4) [12-14]. (See "Overview of cutaneous small vessel vasculitis".)
Hydralazine, minocycline, propylthiouracil, and levamisole-adulterated cocaine are most

often reported as causes of CSVV [15]. Penicillins, cephalosporins, sulfonamides (including
most loop and thiazide-type diuretics), phenytoin, and allopurinol have also been implicated
[16-19].
CSVV typically presents with palpable purpura and/or petechiae ( picture 9A-B); additional
clinical findings include fever, urticaria, arthralgias, lymphadenopathy, low serum
complement levels, and an elevated erythrocyte sedimentation rate. In most patients, the
clinical manifestations begin 7 to 10 days after exposure to the offending drug [16].
However, the latent period may be as short as two to seven days with a secondary exposure
or longer than two weeks with a long-acting drug, such as penicillin G benzathine [17].
Discontinuation of the offending drug should lead to resolution of the signs and symptoms
within a period of days to a few weeks. Patients with more severe reactions may require
NSAIDs or corticosteroids.
LESS COMMON DRUG ERUPTIONS
Severe cutaneous reactions
Stevens-Johnson syndrome/toxic epidermal necrolysis — Stevens-Johnson

syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe mucocutaneous eruption that is
frequently triggered by medications. Allopurinol, certain antiepileptics, antibacterial
sulfonamides, and oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are most
frequently implicated ( table 5). This disorder is characterized by epidermal necrosis and
sloughing of the mucous membranes and skin ( picture 10A-E). The amount of skin
detachment related to the body surface area is used to distinguish SJS from TEN;
detachment affects less than 10 percent of the body surface in SJS and more than 30 percent
in TEN.

The diagnosis and management of SJS and TEN are discussed in detail elsewhere. (See
"Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical
manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Management, prognosis, and long-term sequelae".)
Drug reaction with eosinophilia and systemic symptoms — Drug reaction with
eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome
(DIHS) is a severe idiosyncratic reaction characterized by fever (38 to 40°C [100.4 to 104°F]),
malaise, lymphadenopathy, and skin eruption ( picture 11A-C) [20]. Additional systemic
symptoms may be related to visceral involvement (eg, liver, kidney, lung) [21,22]. In most
patients, the reaction begins two to six weeks after the initiation of the offending
medication. The aromatic antiepileptic agents (carbamazepine, phenytoin, lamotrigine,
oxcarbazepine, and phenobarbital), allopurinol, and antibacterial sulfonamides are the most
frequent causes of this disorder ( table 6). The clinical presentation, diagnosis, and
management of DRESS are discussed in detail separately. (See "Drug reaction with
eosinophilia and systemic symptoms (DRESS)".)
Acute generalized exanthematous pustulosis — Acute generalized exanthematous

pustulosis (AGEP) is a rare disorder characterized by the appearance of superficial pustules
after drug ingestion or infection [23,24]. AGEP is remarkable for its short time to onset (24
hours) after the administration of the suspected drug, although in some cases, the onset of
symptoms may be delayed for up to three weeks [25].
The cutaneous eruption begins on the face or intertriginous areas and disseminates within a
few hours. Nonfollicular, small pustules arise on edematous erythema with burning and/or
itching ( picture 12A-B). Antibiotics, particularly penicillins and macrolides, are thought to
play a role in 80 percent of cases [24,26]. The clinical manifestations, diagnosis, and
management of AGEP are discussed separately. (See "Acute generalized exanthematous
pustulosis (AGEP)".)
Fixed drug eruption — A fixed drug eruption is a distinctive reaction characterized acutely
by erythematous and edematous plaques with a grayish center or frank bullae and
characterized chronically by a dark, postinflammatory pigmentation ( picture 13A-B).
Favored sites include the mouth (lips and tongue), genitalia, face, and acral areas [3]. The
defining features of this eruption include postinflammatory hyperpigmentation and
recurrence of lesions at exactly the same sites with drug re-exposure [3]. Patients with
generalized bullous fixed drug eruption (GBFDG) can be misdiagnosed as having SJS/TEN.
However, in GBFDG, mucosal involvement is usually absent or mild, and the clinical course is
favorable, with rapid resolution in 7 to 14 days after drug discontinuation [27]. The drugs
commonly involved include NSAIDs (acetylsalicylic acid, ibuprofen, naproxen, mefenamic
acid), antibacterial agents (trimethoprim-sulfamethoxazole, tetracyclines, penicillins,

quinolones, dapsone), barbiturates, acetaminophen (paracetamol), metamizole, and

antimalarials [3,27-30].
The diagnosis and management of fixed drug eruption are discussed in detail separately.
(See "Fixed drug eruption".)
Erythema multiforme — Erythema multiforme (EM) is an acute, immune-mediated

eruption characterized by distinctive target-like skin lesions that tend to affect the distal
extremities, including the palms and soles ( picture 14) [1,31,32]. Erythema multiforme
major describes EM with mucosal involvement; in severe cases, fever and malaise may be
associated symptoms. Although in the past EM major has often been misdiagnosed as
SJS/TEN, the two conditions are considered to be different entities, with different clinical
presentations and etiologies [31,33,34].
EM is most commonly induced by infection (typically herpes simplex virus or Mycoplasma

pneumoniae), but in approximately 10 percent of cases, it is caused by drugs, including
antibiotics, NSAIDs, sulfonamides, and antiepileptics.
The diagnosis and management of EM are discussed in detail elsewhere. (See "Erythema
multiforme: Pathogenesis, clinical features, and diagnosis".)
Photosensitivity reactions — There are two basic types of photosensitivity reactions,

phototoxic and photoallergic, which differ in clinical appearance and pathogenesis. (See
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and
treatment", section on 'Phototoxicity' and "Photosensitivity disorders (photodermatoses):
Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
Phototoxic eruptions — Phototoxic eruptions are by far the most common drug-induced
photo eruptions. They typically present as an exaggerated sunburn, often with blisters, or
bluish-gray discoloration of the skin ( picture 15A-B). NSAIDs, quinolones, tetracyclines,
amiodarone, and the phenothiazines are the most frequent causes of phototoxicity [35-37].
Phototoxic reactions have also been reported with multitargeted tyrosine kinase inhibitors
(eg, imatinib) and BRAF inhibitors (eg, vemurafenib) [38,39].
The pathogenetic mechanism involves the absorption of ultraviolet light by the causative
drug, which releases energy and damages cells. Ultraviolet A (UVA) light is the most common
wavelength implicated. Ultraviolet B (UVB) light and visible light can elicit reactions with
some drugs. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations,
diagnosis, and treatment", section on 'Phototoxicity' and "Cutaneous adverse events of
molecularly targeted therapy and other biologic agents used for cancer therapy".)
Photoallergic eruptions — Photoallergic eruptions are characterized by widespread

eczema in the photoexposed areas, such as the face, upper chest, and back of hands (
picture 16). Most photoallergic reactions are caused by topical agents, including biocides
added to soaps (halogenated phenolic compounds) and fragrances, such as musk ambrette
and 6-methylcoumarin [40]. Systemic photoallergens, such as the phenothiazines,
chlorpromazine, sulfa products, and NSAIDs, can produce photoallergic reactions, although
most of their photosensitive reactions are phototoxic [40,41].
Photoallergy is a lymphocyte-mediated reaction caused by exposure to UVA. It is postulated

that the absorbed radiation converts the drug into an immunologically active compound
that is then presented to lymphocytes by Langerhans cells, causing a spongiotic dermatitis
(eczema). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations,
diagnosis, and treatment", section on 'Photoallergy'.)
Bullous eruptions
Pemphigus — Pemphigus is a rare autoimmune bullous disease presenting with

widespread mucocutaneous blisters and erosions ( picture 17A-B). It may be induced or
precipitated by drugs, most commonly thiol (SH) compounds (eg, penicillamine, captopril) or
NSAIDs that are metabolized to thiols (eg, piroxicam) [42,43]. Penicillin and its derivatives,
but not cephalosporins, have also been implicated ( table 7).
The pathogenesis, clinical presentation, and management of pemphigus are discussed in

detail elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus"
and "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
Bullous pemphigoid — Bullous pemphigoid (BP) is an autoimmune bullous disease that

presents with tense vesicles and bullae with an inflammatory base distributed on the arms,
legs, and trunk of older patients. BP has been associated with a large number of drugs,
including penicillamine, furosemide, captopril, penicillin and its derivatives, sulfasalazine,
phenacetin, nalidixic acid, and tumor necrosis factor (TNF)-alpha inhibitors, including
adalimumab and etanercept [44-47]. Multiple studies have found an association between BP
and dipeptidyl-peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus [48-
51].
Drug-induced BP may be an acute, self-limited illness that resolves after drug withdrawal or
a chronic type that appears to be merely precipitated by the drug and follows the course of
classic BP. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Infections and drugs'.)
Linear IgA bullous dermatosis — Linear IgA bullous dermatosis is an idiopathic

subepidermal blistering disease characterized histologically by the linear deposition of
immunoglobulin A (IgA) antibodies at the basement membrane zone. A spectrum of clinical
features has been described. Patients with drug-induced disease may have EM-type lesions,

BP-like lesions, or dermatitis herpetiformis-like lesions [52]. Mucosal or conjunctival lesions

are not present in drug-induced disease but are common in the idiopathic form.
Vancomycin is most commonly implicated; lithium, cefamandole, captopril, and diclofenac

have also been associated with this illness. Spontaneous remission occurs in drug-induced
disease once the offending agent is discontinued. (See "Linear IgA bullous dermatosis".)
Pseudoporphyria — Pseudoporphyria is an uncommon bullous photodermatosis with

clinical and histologic features similar to porphyria cutanea tarda that can be induced by
several drugs, including antibiotics, NSAIDs, diuretics, and retinoids ( table 8). It has been
reported in over 10 percent of children treated with naproxen for early-onset pauciarticular
arthritis [53]. Pseudoporphyria presents with bullae and vesicles typically localized on sun-
exposed areas (eg, face, dorsum of the hands ( picture 18), forearms).
The diagnosis and management of pseudoporphyria are discussed in detail elsewhere. (See
"Pseudoporphyria" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria:
Pathogenesis, clinical manifestations, and diagnosis" and "Porphyria cutanea tarda and
hepatoerythropoietic porphyria: Management and prognosis".)
Drug-induced lupus — Drug-induced lupus presents with a phenotype similar to that of

idiopathic systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus
(SCLE), or, rarely, chronic cutaneous lupus erythematosus (CCLE). However, some clinical and
immunologic features may be different [54]. A variety of drugs can induce a lupus-like
syndrome, particularly those agents that are metabolized by acetylation, such as
procainamide and hydralazine [55]. Other drugs implicated in the development of SLE
include minocycline, isoniazid, rifampin, phenytoin, penicillamine, quinidine, phenytoin,
methyldopa, chlorpromazine, carbamazepine, ethosuximide, propylthiouracil, and
sulfasalazine [56]. Anti-TNF agents, such as infliximab, etanercept, and adalimumab, can
induce SLE. Checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, have
also been associated with SCLE [57,58].
The cutaneous and noncutaneous manifestations of drug-induced lupus are discussed in

detail elsewhere. SLE, SCLE, and CCLE are also discussed separately. (See "Drug-induced
lupus" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults"
and "Overview of cutaneous lupus erythematosus".)
Drug-induced Sweet syndrome — Sweet syndrome (acute febrile neutrophilic dermatosis)

is an uncommon reaction to multiple drugs, including targeted anticancer drugs ( table 9)
[59]. It usually develops approximately two weeks after drug exposure in patients who lack a
prior history of exposure to the inciting drug. (See "Sweet syndrome (acute febrile
neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on
'Drug-induced Sweet syndrome'.)

Symmetrical drug-related intertriginous and flexural exanthema — Symmetrical drug-

related intertriginous and flexural exanthema (SDRIFE; intertriginous drug eruption, baboon
syndrome) is an infrequent type of drug-induced eruption [60]. SDRIFE occurs a few hours to
a few days after the administration of the offending drug. The rash presents as a sharply
demarcated, V-shaped erythema in the gluteal/perianal or inguinal/perigenital areas, often
with involvement of at least one other flexural or intertriginous fold, in the absence of
systemic symptoms ( picture 19) [61]. Amoxicillin, ceftriaxone, penicillin, clindamycin, and
erythromycin are thought to be implied in approximately 50 percent of cases [61]. Iodinate
contrast media, pseudoephedrine, acetyl salicylic acid, mitomycin, phenothiazines,
valacyclovir, and many other drugs have also been implicated [62]. Treatment includes
discontinuing the suspected drug and the use of topical or systemic corticosteroids. (See
"Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural
reaction pattern'.)
Acral chemotherapy reactions — Acral erythema (also called hand-foot syndrome, palmar-
plantar erythrodysesthesia, toxic erythema of chemotherapy) is a cutaneous eruption
associated with conventional cytotoxic agents, including liposomal doxorubicin,
capecitabine, cytarabine, fluorouracil, carboplatin, docetaxel, cyclophosphamide,
fludarabine, methotrexate, and many others [60]. (See "Cutaneous side effects of
conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.)
The small molecule tyrosine kinase inhibitors sunitinib and sorafenib and others that target
angiogenesis are also associated with a high incidence of hand-foot skin reaction, but the
clinical and histologic patterns differ from the classic, acral erythema caused by conventional
cytotoxic agents. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase
inhibitors".)
In both types of acral reactions, dysesthesia of the involved areas (eg, paresthesia, tingling,
burning, painful sensation) precedes the development of the skin lesions. Acral erythema is
most often characterized by a symmetric edema and erythema of the palms and soles, which
may progress to blistering and necrosis ( picture 20A-B). In contrast, hand-foot skin
reaction is characterized by well-demarcated, bean- to coin-sized, hyperkeratotic, painful
plaques with underlying erythema localized to the pressure areas of the soles ( picture 21)
[63].
Drug-induced hair loss — Drugs cause hair loss by two major mechanisms: inducing an
abrupt cessation of mitotic activity in rapidly dividing hair matrix cells (anagen effluvium) or
precipitating the follicles into premature rest (telogen effluvium) [64,65]. In the former, hair
loss usually occurs within days to weeks of drug administration; in the latter, hair loss occurs
two to four months after starting treatment.

Anagen effluvium is most commonly caused by antineoplastic drugs ( table 10). Telogen
effluvium is seen in association with many drugs, including anticoagulants, retinoids,
interferons, and antihyperlipidemic drugs ( table 11) [65]. (See "Alopecia related to
systemic cancer therapy" and "Telogen effluvium".)
Lymphomatoid drug eruption — Lymphomatoid drug eruption, also called cutaneous

pseudolymphoma, usually presents as a solitary, erythematous nodule or plaque most
frequently located on the trunk or head that mimics cutaneous T cell lymphomas (
picture 22) [66-69]. Anticonvulsants, antidepressants, antihypertensives, beta blockers,
calcium channel blockers, diuretics, antibiotics, NSAIDs, antihistamines, and biologics have
been linked to lymphomatoid drug eruptions. In most patients, the skin lesions resolve when
the offending drug is discontinued. (See "Cutaneous T cell pseudolymphomas", section on
'Lymphomatoid drug reaction'.)
DRUGS OF SPECIAL CONCERN
Anticoagulants
Warfarin — Warfarin-induced skin necrosis typically occurs during the first several days of
warfarin therapy, often in association with the administration of large loading doses [70].
The skin lesions occur on the extremities, breasts, trunk, and penis (in males) and marginate
over a period of hours from an initial, central, erythematous macule ( picture 23). Biopsies
demonstrate fibrin thrombi within cutaneous vessels with interstitial hemorrhage.
Skin necrosis appears to be mediated by the reduction in protein C levels on the first day of
therapy, which induces a transient hypercoagulable state. Approximately one-third of
patients have underlying protein C deficiency, although skin necrosis is an infrequent
complication of warfarin therapy among patients with protein C deficiency [71]. Case reports
have also described this syndrome in association with an acquired functional deficiency of
protein C, heterozygous protein S deficiency, and factor V Leiden. (See "Protein C deficiency",
section on 'Warfarin-induced skin necrosis'.)
Heparin — Heparin may induce several skin reactions, including delayed-type

hypersensitivity reactions and, rarely, immediate hypersensitivity reactions, skin necrosis, or
bullous hemorrhagic dermatosis (BHD) [72]:
● Delayed-type hypersensitivity reactions − Delayed-type hypersensitivity reactions

may occur with both unfractionated and low molecular weight heparins, generally
within two weeks of heparin treatment. Delayed-type reactions present most often with
localized erythema at the injection site but may progress to generalized, eczematous,
or maculopapular eruption.

● Immediate hypersensitivity reactions − Immediate hypersensitivity reactions are

rare and manifest as anaphylactic (IgE-mediated) or anaphylactoid (non-IgE-mediated)
reactions [73]. Clinical symptoms include localized or generalized urticaria,
hypotension, angioedema, allergic rhinoconjunctivitis, tachycardia, or bronchospasm.
● Skin necrosis − Skin necrosis may develop in 10 to 20 percent of patients with heparin-
induced, immune-mediated thrombocytopenia, a rare and life-threatening
complication of treatment with unfractionated or low molecular weight heparins
[74,75]. Cutaneous necrosis is caused by intradermal microvascular thromboses
occurring locally or distantly from the injection site. Lesions appear 3 to 15 days after
the initiation of therapy as erythematous patches that progress to skin necrosis. (See
"Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
● Bullous hemorrhagic dermatosis – Bullous hemorrhagic dermatosis (BHD) is an

uncommon adverse reaction to low molecular weight heparins characterized by the
acute onset of rapidly expanding, tense, hemorrhagic bullae [76-78]. Blisters appear
days to weeks after heparin treatment initiation in areas distant from the injection site,
most often on the extremities, and generally resolve spontaneously in a few weeks,
regardless of whether heparin treatment is maintained or discontinued.
The pathophysiology of BHD remains unclear. On histopathology, there is an

intraepidermal or subcorneal blister filled with erythrocytes and plasma and dermal
extravasation of erythrocytes, in the absence of significant inflammatory infiltrate.
Gold — Dermatitis and stomatitis account for most adverse gold reactions. Gold rashes are
highly variable and may mimic many other skin conditions. In a prospective study of 74
patients with rheumatoid arthritis, 39 patients developed a mucocutaneous reaction to gold
[79]. A variety of morphologic features were noted, the bulk of which were characterized as
nonspecific dermatitis. Most patients had pruritus. Gold-associated eruptions had a median
duration of two months, with a range of one week to two years. Most cases resolved
promptly with discontinuation of gold or with dose reduction; application of topical steroids
was also helpful.
Lithium — Cutaneous side effects from lithium therapy have been reported in 3 to 34
percent of patients [80]:
● Psoriasis is one of the most common reactions. It may begin for the first time during
therapy, or a mild case may be exacerbated when the patient begins the drug.
● Acne and acneiform eruptions are also common. Pustular lesions may be the result of
lysosomal enzyme release and increased neutrophil chemotaxis [80]. Acneiform lesions

may be seen on the forearms and legs in addition to the sites commonly involved in
acne vulgaris.
● Hair loss, especially in women during the first few months of therapy, has frequently
been reported.
Halogens — Ingestion of halogens, such as iodides, bromides, and fluorides, can rarely
cause cutaneous reactions [81]. Iodides (such as those in seaweed, salt, amiodarone, and
radiocontrast media) can cause acneiform lesions, typically on the face, as well as vesicular,
pustular, hemorrhagic, urticarial, fungating, suppurative, nodular, and ulcerative lesions (
picture 24). Swelling of the parotid and submandibular glands has been previously
described as iodine mumps.
Iododerma due to the administration of intravenous radiocontrast media is commonly seen

as an acute eruption. With oral iodine exposure, the onset is insidious [82,83]. Declining
renal function may be a factor in radiocontrast-induced iododerma. (See "Patient evaluation
prior to oral or iodinated intravenous contrast for computed tomography".)
Bromides can cause verrucous, ulcerating plaques, most often located on the lower
extremities [81,84,85]. Discontinuation of the causative agent is sufficient in most patients,
with gradual resolution of lesions expected over four to six weeks [81].
Epidermal growth factor receptor (EGFR) inhibitors — Epidermal growth factor receptor
(EGFR) inhibitors and other tyrosine kinase inhibitors used to treat cancers are known to
cause an inflammatory, acneiform eruption involving the face, neck, and upper trunk in the
majority of patients receiving these medications ( picture 25). (See "Acneiform eruption
secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
Cytokine therapy — Hematopoietic colony-stimulating factors are a heterogeneous group

of cytokines that induce proliferation and differentiation of bone marrow precursor cells.
They are most frequently administered in the setting of neutropenia secondary to
chemotherapy (eg, recombinant human granulocyte or granulocyte-macrophage colony-
stimulating factor). (See "Use of granulocyte colony stimulating factors in adult patients with
chemotherapy-induced neutropenia and conditions other than acute leukemia,
myelodysplastic syndrome, and hematopoietic cell transplantation".)
Serious cutaneous adverse effects of colony-stimulating factors are distinctly rare but
include neutrophilic dermatoses and necrotizing vasculitis [86,87]. Upregulation of
neutrophil function and secondary release of cytokines may induce these complications.
Immune checkpoint inhibitors — Immune checkpoint inhibitors, including

antiprogrammed death-1 (anti-PD-1), antiprogrammed death ligand-1 (anti-PD-L1), and
anticytotoxic T cell lymphocyte-associated antigen-4 (anti-CTLA-4) monoclonal antibodies,
have shown great benefits and have been widely used in the treatment of multiple cancer
types. Cutaneous immune-related adverse events (irAEs) are one of the most frequently
encountered adverse events in clinical practice. Various types and presentations of
cutaneous irAEs, including maculopapular eruption, pruritus, eczematous eruption, vitiligo,
and neutrophilic dermatosis, have been described [59,88-90]. Vitiligo, a possible indicator for
better outcome, was present at approximately 7.5 to 11 percent in nivolumab- and
pembrolizumab-treated melanoma patients and was lower in those who were treated with
ipilimumab [91,92]. (See "Mucocutaneous toxicities associated with immune checkpoint
inhibitors".)
SUMMARY AND RECOMMENDATIONS
● Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of

hospitalized patients. Drug-induced exanthems, also called morbilliform eruptions, are
the most common cutaneous reactions to drugs, responsible for approximately 90
percent of all drug rashes ( picture 1A-B). The most frequently prescribed
medications (eg, antibiotics, sulfonamides) are implicated in most cases. Less
frequently, drugs may cause lichenoid eruptions ( picture 3A-B), exfoliative dermatitis
( picture 5), urticaria/angioedema ( picture 6A-B), anaphylaxis, or cutaneous small
vessel vasculitis ( picture 9A-B). (See 'Classic drug reaction patterns' above.)
● Severe and potentially life-threatening reactions are rare and include Stevens-Johnson
syndrome/toxic epidermal necrolysis (SJS/TEN) ( picture 10A-E), drug reaction with
eosinophilia and systemic symptoms (DRESS) ( picture 11A-C), and acute generalized
exanthematous pustulosis (AGEP) ( picture 12A-B). The aromatic antiepileptic agents
(carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and phenobarbital),
allopurinol, and the sulfonamides are most frequently implicated in SJS/TEN and
DRESS. Antibiotics are associated with most AGEP cases. (See 'Severe cutaneous
reactions' above.)
● Other uncommon drug eruptions include phototoxic and photoallergic reactions,

bullous eruptions (eg, pemphigus, bullous pemphigoid, linear IgA bullous dermatosis,
pseudoporphyria), cutaneous pseudolymphoma, and drug-induced lupus. (See 'Less
common drug eruptions' above.)
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Topic 2089 Version 40.0

GRAPHICS
Exanthematous (morbilliform) drug eruption
Numerous erythematous macules and papules are present in this

child with a morbilliform drug eruption.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.
Graphic 54205 Version 9.0

Exanthematous (morbilliform) drug eruption
Drug-induced exanthems, such as this morbilliform eruption, often

begin in dependent areas and generalize.
Courtesy of Andrew Samel, MD.

Lichen planus
Violaceous and hyperpigmented, polygonal papules are present on ankles and ventral wrists.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Lichen planus
Violaceous, polygonal papules are present on the ventral wrists.

Lichenoid drug eruption
Erythematous to violaceous papules with fine scale are present in

this patient with a lichenoid drug eruption.

reserved.

Lichenoid drug eruption
A lichenoid drug eruption manifesting as violaceous and

hyperpigmented papules is present in this patient with dark skin.

reserved.

Oral lichenoid drug eruption
White lesions with a reticular pattern (Wickham striae) can be seen

on the tongue and oral mucosa of this patient with oral lichenoid
drug eruption.

reserved.

Drug-induced erythroderma
Red and scaly skin involving more than 90 percent of the body surface area in a
patient with erythrodermic skin reaction.

Drugs most frequently reported as cause of erythroderma
ACE inhibitors (enalapril, lisinopril)
Allopurinol
Bevacizumab
Carbamazepine
Chlorpromazine
Dapsone
Erythropoietin
Gold salts
Hydroxychloroquine
Imatinib
Isoniazid
Penicillin
Phenobarbital
Phenytoin
Piroxicam
Proton pump inhibitors (omeprazole, esomeprazole, pantoprazole)
Retinoids (acitretin, isotretinoin)
Streptomycin
Sulfasalazine
Terbinafine
Thalidomide
Trimethoprim/sulfamethoxazole
Vancomycin
ACE: angiotensin-converting enzyme.
Data from: Grant-Kels JM, Fedeles F, Rothe MJ. Exfoliative dermatitis. In: Fitzpatrick's Dermatology in General Medicine, 8th ed,
Goldsmith L, Katz S, Gilchrest B, et al (Eds), McGraw-Hill, 2012.

Classification of allergic reactions (Gell and Coombs)
Clinical
Type Description Mechanism
features
I Anaphylactic, Antigen exposure causes release of vasoactive Anaphylaxis

immediate-type substances, such as histamine, prostaglandins, and
Immediate Angioedema
hypersensitivity leukotrienes from mast cells or basophils. This
reaction
response is usually, but not always, IgE-dependent. Bronchospasm
(30 to 60
min) Urticaria
(hives)
Accelerated
reaction (1
to 72
hours)
II Antibody- An antigen or hapten that is intimately associated Hemolytic

dependent with a cell binds to antibody, leading to cell or tissue anemia
cytotoxicity injury.
Interstitial
nephritis
III Immune Damage is caused by formation or deposition of Serum

complex antigen-antibody complexes in vessels or tissue. sickness
disease
IV Cell-mediated Antigen exposure sensitizes T cells, which then Contact

or delayed mediate tissue injury. dermatitis
hypersensitivity
V Uncertain, but probably involving T cell cytotoxicity. Maculopapular

rash
(>72 hours)
IgE: immunoglobulin E.
Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy
1988; 18:515.

Urticaria
Edematous and erythematous plaques, some annular with central pallor.

Urticaria (hives)
Markedly edematous and erythematous plaques on arm and back.

Confluent urticaria on child's abdomen
Urticaria often coalesce as individual lesions enlarge.

Causes of angioedema classified by mechanism
Known or presumed
Mechanism Examples
pathophysiology
Activation of mast cells IgE-mediated mast cell Allergic reactions to foods,

activation (type I drugs, latex, insect stings, other
Clinical characteristics – Often
hypersensitivity) allergens
associated with pruritus and
urticaria. Direct mast cell activation Opioids, radiocontrast agents
May present as part of an Perturbations in arachidonic Aspirin and other NSAIDs
allergic reaction or anaphylaxis. acid metabolism
Immunologic and other non- Idiopathic histaminergic

IgE-mediated mast cell angioedema, often associated
activation with chronic spontaneous
urticaria or inducible urticaria
Generation of bradykinin Inhibition of enzymes involved ACE inhibitors, DPP-4 inhibitors

in degradation of bradykinin
Clinical characteristics – Not
associated with pruritus or Deficiency or dysfunction of Hereditary angioedema (also
urticaria. complement C1 inhibitor due to known as hereditary C1 inhibitor
May present with abdominal mutation deficiency or dysfunction)
symptoms due to bowel wall Deficiency or dysfunction of Acquired C1 inhibitor deficiency

edema. complement C1 inhibitor often
due to anti-C1 inhibitor antibody
or an underlying malignancy
Defects in several genes have Hereditary angioedema with

been implicated, including those normal C1 inhibitor
for coagulation factor XII,
plasminogen, and angiopoietin-
1.
Other cases are idiopathic.
Unknown pathophysiology Idiopathic nonhistaminergic

angioedema
Clinical characteristics –
Variable. Infections (especially in children)
Sometimes associated with Drugs – Calcium channel
urticaria. blockers, fibrinolytic agents,
herbal medicines, other
hypereosinophilic syndrome
Hypereosinophilic syndrome
Gleich syndrome
Urticarial vasculitis

IgE: immunoglobulin E; NSAIDs: nonsteroidal anti-inflammatory drugs; ACE inhibitors: angiotensin-

converting enzyme inhibitors.

ACE inhibitor-induced angioedema
ACE: angiotensin-converting enzyme.
From: Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme
inhibitor-induced angioedema. Otolaryngol Head Neck Surg 2007; 137:931. Copyright © 2007.
Reprinted by permission of SAGE Publications.

Drugs alleged to cause cutaneous small vessel vasculitis
Anti-infective agents Cardiovascular and diuretic Intravenous formulations

drugs, thiazides
Penicillin Radiocontrast media
Procainamide containing iodine
Doxycycline
Quinidine Iron-dextran preparations
Clindamycin
Atenolol Antiseizure medications
Rifampicin
Acebutolol Sodium valproate
Gentamicin
Diltiazem Phenytoin
Ciprofloxacin
Captopril Carbamazepine
Trimethoprim-
sulfamethoxazole Hydrochlorothiazide
Miscellaneous substances
Chloramphenicol Furosemide
Acetaminophen
Ampicillin Amiodarone (paracetamol)
Griseofulvin Hydralazine Allopurinol
Acyclovir Spironolactone Azathioprine
Isoniazid Guanethidine Cimetidine
Ofloxacin Methyldopa Colchicine
Zidovudine Anticoagulants and Drug abuse
thrombolytic agents D-penicillamine
Cancer chemotherapeutic and
adjuvants Heparin Food additives
Cyclophosphamide Warfarin G-CSF
Methotrexate Anisoylated streptokinase GM-CSF
activator complex
Tamoxifen Gold
Streptokinase
Levamisole Influenza vaccination
Hexamethylene bisacetamide Beta-adrenergic receptor
Interferon-alfa
agonists
Busulfan Metformin
Ritodrine
Anastrozole Methylthiouracil
Terbutaline
Tyrosine kinase inhibitors Pneumococcal vaccination
(eg, ibrutinib) Nonsteroidal
Potassium iodine
Rituximab antiinflammatory drugs
Propylthiouracil
Acetylsalicylic acid
Immunosuppressive therapies
Quinine
Diclofenac
TNF inhibitors
Retinoids
Ibuprofen
Secukinumab
Vaccination with BCG
Indomethacin
Psychoactive drugs Vitamin B6
Flurbiprofen
Amitriptyline
Naproxen
Maprotiline
Tenoxicam
Trazodone Fenbufen
TNF: tumor necrosis factor; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-
macrophage colony-stimulating factor; BCG: Bacille Calmette-Guérin.

Cutaneous small vessel vasculitis
Numerous petechiae are present on the lower leg.

reserved.

Hypersensitivity vasculitis
Palpable purpura involving the lower legs of a patient with drug-induced hypersensitivity
vasculitis.

Drugs associated with Stevens-Johnson syndrome/toxic epidermal necrolysis

(SJS/TEN)
Strongly associated*
Allopurinol
Lamotrigine
Sulfamethoxazole
Carbamazepine
Phenytoin
Nevirapine
Sulfasalazine
Other sulfonamides
Oxicam NSAIDs (piroxicam, tenoxicam¶ )
Phenobarbital
Etoricoxib¶
AssociatedΔ
Diclofenac
Doxycycline
Amoxicillin/ampicillin
Ciprofloxacin
Levofloxacin
Amifostine
Oxcarbazepine
Rifampin (rifampicin)
Suspected association/lower risk◊
Pantoprazole
Glucocorticoids
Omeprazole
Tetrazepam§
Dipyrone (metamizole)¶
Terbinafine
Levetiracetam
Agents are presented in order of decreasing number of cases included in the European Registry
(RegiSCAR).

NSAID: nonsteroidal anti-inflammatory drug; RegiSCAR: International Registry of Severe Cutaneous

Adverse Reactions.
* Significant association in case-control studies with a lower limit of the confidence interval ≥5 and
unpublished data from the RegiSCAR.
¶ Etoricoxib, tenoxicam, and dipyrone are NSAIDs available in some countries outside of North
America.
Δ Significant association in case-control studies with a lower limit of the confidence interval <5.
◊ Some cases with plausible causality in medical literature and/or RegiSCAR European Registry.
§ A benzodiazepine is available in some countries outside of North America.
Data from: The RegiSCAR Project. Available at: http://www.regiscar.org/index.html (Accessed on April 4, 2018).

Stevens-Johnson syndrome
Vesicles and bullae are characteristic cutaneous findings in Stevens-Johnson

syndrome.

Mucosal changes in Stevens-Johnson syndrome/toxic

epidermal necrolysis
Changes similar to those observed in SJS/TEN can also be observed in

erythema multiforme majus.
SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.

Toxic epidermal necrolysis
Multiple bullae and areas of denuded epidermis are present.

reserved.

Diffuse erythema and large areas of denuded epidermis are present.

reserved.

Multiple bullae overlying diffuse erythema are present.

reserved.

Drug reaction with eosinophilia and systemic symptoms

(DRESS)
Confluent morbilliform skin eruption with follicular accentuation in a patient with

drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic

symptoms
Diffuse and confluent skin eruption in a patient with DRESS.
DRESS: drug reaction with eosinophilia and systemic symptoms.

reserved.

Drug reaction with eosinophilia and systemic

symptoms
Diffuse, confluent, infiltrated, erythematous skin eruption in a

patient with DRESS.
DRESS: drug reaction with eosinophilia and systemic symptoms.

reserved.

Drugs associated with drug reaction with eosinophilia and systemic

symptoms (DRESS)
Frequently reported
Allopurinol
Carbamazepine
Lamotrigine
Phenytoin
Sulfasalazine
Vancomycin
Minocycline
Dapsone
Sulfamethoxazole
Also reported
Phenindione
Fluindione
Beta-lactam antibiotics
Nevirapine
Olanzapine
Oxcarbazepine
Strontium ranelate
Telaprevir
Lenalidomide

Acute generalized exanthematous pustulosis

(AGEP)
Confluent nonfollicular pustules superimposed on edematous

erythema in a 46-year-old woman with AGEP. A skin biopsy showed
intracorneal pustules with numerous neutrophils and neutrophilic
infiltration of the epidermis and upper dermis.
Copyright © Vincent CB Lin, MD, Dermatlas; http://www.dermatlas.org.

Acute generalized exanthematous pustulosis

(AGEP) detail
Nonfollicular, pinhead-sized pustules on a background of

edematous erythema are characteristic of AGEP.
Courtesy of Werner J Pichler, MD.

Fixed drug eruption
Fixed drug eruption. An oval lesion occurred at the identical site

where it had occurred previously. In both episodes, the rash
emerged after this patient ingested a sulfonamide antibiotic. Note
the eroded blister in the center of the lesion.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of

Common Skin Disorders, 2nd Edition, Lippincott Williams & Wilkins, Philadelphia
2003. Copyright © 2003 Lippincott Williams & Wilkins.

Fixed drug eruption
Fixed drug eruption. An oval erosion on the glans penis occurred in

this patient who was taking minocycline. According to the patient,
an identical lesion appeared when he was given minocycline
previously.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of

Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins,
2003. Copyright © 2003 Lippincott Williams & Wilkins.

Erythema multiforme
Characteristic target lesions of the palm in erythema multiforme

begin with a central vesicle.
Courtesy of Nesbitt LT Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV,
Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.
http://www.lww.com

Phototoxic eruption
A bright red, confluent rash on the "V" of the neck of a patient with drug-induced
photosensitivity reaction.

Amiodarone-induced pigmentation
Amiodarone causes a striking slate-gray pigmentation in a

photodistribution of the face. The blue color (ceruloderma) is due to
the deposition of melanin and lipofuscin contained in macrophages
and endothelial cells in the dermis. The pigmentation is reversible,
but it may take up to a year or more to complete resolution.
Reproduced with permission from: Fitzpatrick TB, Johnson AB, Wolff K, Suurmond D.
Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 4th
ed, McGraw-Hill, New York 2001. Copyright © 2001 The McGraw-Hill Companies, Inc.

Photoallergic eruption
This 45-year-old woman developed an acute, well-demarcated,

erythematous plaque with vesicles after topical application of
ketoprofen gel followed by sun exposure. The patient wore socks,
which protected the foot from the sun, creating the line of
demarcation that is visible in the image.
Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org.

Pemphigus vulgaris
Multiple erosions on the trunk of this patient with pemphigus vulgaris.

Pemphigus vulgaris – oral lesions
Multiple erosions on the palate in a patient with pemphigus vulgaris.

reserved.

Drugs involved in pemphigus
SH drugs
SH drugs
Bucillamine
Captopril
D-penicillamine
Gold sodium thiomalate
Pyritinol
Thiopronine
Drugs with SH metabolites
Carbimazole
Penicillin
Piroxicam
Non-SH drugs
Antibiotics
Cephalosporins
Ethambutol
Isoniazid
Pentachlorophenol
Rifampicin
Pyrazole drugs
Aminophenazone
Aminopyrine
Azapropazone
Noramidopyrine
Phenylbutazone
Other drugs
Acenocoumarol
Enalapril
Heroin
Hydantoin
Imiquimod
Immunomodulators: interleukin-2, interferon alpha, interferon beta, isosorbide trinitrate

Isotretinoin
Levodopa
Lysine acetylsalicylate
Phenobarbital
Progesterone
Propranolol
SH: sulfhydryl group.
Reproduced with permission from: Maruani A, Machet MC, Carlotti A, et al. Immunostaining with antibodies to desmoglein
provides the diagnosis of drug-induced pemphigus and allows prediction of outcome. Am J Clin Pathol 2008; 130:369.
Copyright © 2008-2013 American Society for Clinical Pathology.

Drugs and chemicals inducing pseudoporphyria
Antibiotics
Nalidixic acid
Tetracycline
Ciprofloxacin
Voriconazole
Nonsteroidal anti-inflammatory drugs

Naproxen
Nabumetone
Oxaprozin
Ketoprofen
Mefenamic acid
Diflunisal
Celecoxib
Diuretics
Furosemide
Chlorthalidone
Hydrochlorothiazide-triamterene
Bumetanide
Torsemide
Retinoids
Isotretinoin
Etretinate
Miscellaneous
Imatinib
Cyclosporine
Fluorouracil (intravenous)
Carisoprodol-aspirin
Pyridoxine
Amiodarone
Flutamide
Metformin
Dapsone
Baker's yeast
Oral contraceptives

Pseudoporphyria
Vesiculation and crusting are present on the dorsal hand.

Medications associated with drug-induced Sweet syndrome
Antibiotics Minocycline
Nitrofurantoin
Norfloxacin
Ofloxacin
Quinupristin-dalfopristin
Trimethoprim-sulfamethoxazole
Antiseizure medications Carbamazepine
Diazepam
Anti-HIV drugs Abacavir (synthetic carbocyclic nucleoside analogue)
Antihypertensives Hydralazine
Antineoplastics Bortezomib
Imatinib mesylate
Ipilimumab
Lenalidomide
Topotecan
Vemurafenib
Antipsychotics Clozapine
Antithyroid hormone Propylthiouracil

synthesis drugs
Colony-stimulating factors Granulocyte colony-stimulating factor
Granulocyte macrophage colony-stimulating factor
Pegfilgrastim
Contraceptives Ethinyl estradiol and levonorgestrel
Levonorgestrel-releasing intrauterine system
Diuretics Furosemide
Immunosuppressants Azathioprine
Nonsteroidal anti- Celecoxib

inflammatory drugs
Diclofenac
(NSAIDs)
Retinoids All-trans retinoic acid
13-cis-retinoic acid
Adapted from: Cohen PR. Sweet's syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J
Rare Dis 2007; 2:34. Copyright © 2007 BioMed Central Ltd.


Symmetrical drug-related intertriginous and

flexural exanthema (SDRIFE)
Sharply demarcated erythema in the gluteal/perianal area in a

patient with SDRIFE. Note the involvement of the popliteal folds.

Acral erythema
Bilateral erythema is present on the hands in this patient with acral

erythema.

reserved.

Acral erythema
Acral erythema of the hand.
Reproduced with permission from: Payne AS, James WD, Weiss RB. Dermatologic
toxicity of chemotherapeutic agents. Semin Oncol 2006; 33:86. Illustration used with
the permission of Elsevier Inc. All rights reserved.

Hand-foot skin reaction in patients given sorafenib
Note the patchy hyperkeratosis on plantar pressure areas.
Reproduced with permission from: Robert C, Mateus C, Spatz A, et al. Dermatologic

symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol
2009; 60:299. Illustration used with the permission of Elsevier Inc. All rights reserved.

Frequency and severity of alopecia for selected chemotherapy agents and

combinations
Severe Moderate Mild
Frequent Doxorubicin (>40 Mechlorethamine Bleomycin

mg/m2 ) Methotrexate
Epirubicin (>30 Carboplatin (AUC 5
mg/m2 ) to 6)
Daunorubicin Paclitaxel (weekly)
Paclitaxel (every 2 to
3 weeks)
Docetaxel
Cyclophosphamide
(IV at doses >300
mg/m2 )
Ifosfamide
Etoposide (IV)
Ixabepilone
Eribulin
Combination
chemotherapy with
doxorubicin,
docetaxel,
paclitaxel, etoposide
Infrequent Vincristine Oxaliplatin Fluorouracil

Vinblastine Cyclophosphamide Capecitabine
Etoposide (oral) (oral) Hydroxyurea
Thiotepa
Carboplatin (weekly)
Cisplatin
IV: intravenous; AUC: area under the curve.
Data from:
1. Rugo HS, Klein P, Melin SA, et al. Association Between Use of a Scalp Cooling Device and Alopecia After Chemotherapy
for Breast Cancer. JAMA 2017; 317:606.
2. Nangia J, Wang T, Osborne C, et al. Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy
for Breast Cancer: The SCALP Randomized Clinical Trial. JAMA 2017; 317:596.
3. Batchelor D. Hair and cancer chemotherapy: consequences and nursing care--a literature study. Eur J Cancer Care
(Engl) 2001; 10:147.
4. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002; 14:212.
5. Chon SY, Champion RW, Geddes ER, Rashid RM. Chemotherapy-induced alopecia. J Am Acad Dermatol 2012; 67:e37.

Drugs and drug classes* linked to telogen effluvium
Allopurinol
Androgens
Anticholesterol agents (statins)
Anticoagulants
Antiseizure medications
Antifungals
Antihistamines (H2)
Anti-inflammatory agents
Antimitotic agents
Antithyroid agents
Benzimidazoles
Beta blockers
Bromocriptine
Ergots
Heavy metals
Hormones (oral contraceptives, hormone replacement therapy, octreotide)
Immunomodulators
Intravenous immunoglobulin
Interferon
Levodopa
Retinoids
Proguanil
Psychotropics
Sulfasalazine
Minoxidil
Nonsteroidal anti-inflammatory drugs
Selective estrogen receptor modulators and phytoestrogen
* Not all drugs within the classes described have been linked to telogen effluvium.

Lymphomatoid drug eruption (T cell pseudolymphoma)
Lymphomatoid drug eruption without systemic symptoms due to antiseizure medications presenting with
back.
Courtesy of Rein Willemze, MD.

Cutaneous necrosis: Warfarin
Bilateral areas of cutaneous infarction with purple-to-black

coloration of both breasts, surrounded by an area of erythema,
occurred on the fifth day of warfarin therapy.
Reproduced with permission from: Fitzpatrick TB, Johnson AB, Wolff K, Suurmond D.
Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 4th
edition. McGraw-Hill, New York 2001. Copyright © 2001 The McGraw-Hill Companies.

Iododerma
Pustular eruption with secondary impetiginization in a patient exposed to iodides.

Acneiform eruption secondary to EGFR inhibitor

therapy
Diffuse, erythematous, follicular papules on the back of this patient

treated with gefitinib.
EGFR: epidermal growth factor receptor.
Courtesy of Aimee S Payne, MD, PhD.

Contributor Disclosures
Andrew D Samel, MD No relevant financial relationship(s) with ineligible companies to disclose. Chia-
Yu Chu, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Robert P
Dellavalle, MD, PhD, MSPH Equity Ownership/Stock Options: Altus Labs [Itch, eczema].
Grant/Research/Clinical Trial Support: Pfizer [Patient decision aids, inflammatory and immune-
mediated skin disease]. Consultant/Advisory Boards: Altus Labs [Itch, eczema];ParaPRO [Scabies, lice].
Other Financial Interest: Cochrane Council meetings [Expense reimbursement]. All of the relevant
financial relationships listed have been mitigated. Maja Mockenhaupt, MD,
PhD Grant/Research/Clinical Trial Support: Boehringer Ingelheim [Severe cutaneous adverse
reactions]; Janssen Pharmaceuticals [Cutaneous adverse reactions]. Consultant/Advisory Boards: Bial
[Cutaneous adverse reactions]. All of the relevant financial relationships listed have been
mitigated. Rosamaria Corona, MD, DSc No relevant financial relationship(s) with ineligible companies
to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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27/3/22, 20:13 Drug eruptions - UpToDate

Official reprint from UpToDate®

Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of hospitalized

● (See "Drug hypersensitivity: Classification and clinical features".)

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 1/78

● (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on

CLASSIC DRUG REACTION PATTERNS

Exanthematous drug eruptions — Drug-induced exanthems are the most common

Exfoliative dermatitis/erythroderma — Exfoliative dermatitis/erythroderma is a severe

Urticaria/angioedema — Urticaria (hives) and angioedema may be manifestations of drug

● Urticaria is characterized by an intensely pruritic, circumscribed, raised, and

Antibiotics (especially penicillins, cephalosporins, and sulfonamides) are common causes of

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute urticaria/angioedema

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 3/78

Hydralazine, minocycline, propylthiouracil, and levamisole-adulterated cocaine are most

LESS COMMON DRUG ERUPTIONS

Severe cutaneous reactions

Stevens-Johnson syndrome/toxic epidermal necrolysis — Stevens-Johnson

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 4/78

Acute generalized exanthematous pustulosis — Acute generalized exanthematous

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 5/78

quinolones, dapsone), barbiturates, acetaminophen (paracetamol), metamizole, and

Erythema multiforme — Erythema multiforme (EM) is an acute, immune-mediated

EM is most commonly induced by infection (typically herpes simplex virus or Mycoplasma

Photosensitivity reactions — There are two basic types of photosensitivity reactions,

Photoallergic eruptions — Photoallergic eruptions are characterized by widespread

Photoallergy is a lymphocyte-mediated reaction caused by exposure to UVA. It is postulated

Pemphigus — Pemphigus is a rare autoimmune bullous disease presenting with

The pathogenesis, clinical presentation, and management of pemphigus are discussed in

Bullous pemphigoid — Bullous pemphigoid (BP) is an autoimmune bullous disease that

Linear IgA bullous dermatosis — Linear IgA bullous dermatosis is an idiopathic

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 7/78

BP-like lesions, or dermatitis herpetiformis-like lesions [52]. Mucosal or conjunctival lesions

Vancomycin is most commonly implicated; lithium, cefamandole, captopril, and diclofenac

Pseudoporphyria — Pseudoporphyria is an uncommon bullous photodermatosis with

Drug-induced lupus — Drug-induced lupus presents with a phenotype similar to that of

The cutaneous and noncutaneous manifestations of drug-induced lupus are discussed in

Drug-induced Sweet syndrome — Sweet syndrome (acute febrile neutrophilic dermatosis)

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 8/78

Symmetrical drug-related intertriginous and flexural exanthema — Symmetrical drug-

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 9/78

Lymphomatoid drug eruption — Lymphomatoid drug eruption, also called cutaneous

DRUGS OF SPECIAL CONCERN

Heparin — Heparin may induce several skin reactions, including delayed-type

● Delayed-type hypersensitivity reactions − Delayed-type hypersensitivity reactions

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 10/78

● Immediate hypersensitivity reactions − Immediate hypersensitivity reactions are

● Bullous hemorrhagic dermatosis – Bullous hemorrhagic dermatosis (BHD) is an

The pathophysiology of BHD remains unclear. On histopathology, there is an

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 11/78

Iododerma due to the administration of intravenous radiocontrast media is commonly seen

Cytokine therapy — Hematopoietic colony-stimulating factors are a heterogeneous group

Immune checkpoint inhibitors — Immune checkpoint inhibitors, including

SUMMARY AND RECOMMENDATIONS

● Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of

● Other uncommon drug eruptions include phototoxic and photoallergic reactions,

Use of UpToDate is subject to the Terms of Use.

https://www.uptodate.com/contents/drug-eruptions/print?search=dress syndrome&topicRef=16420&source=see_link 13/78

2. Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001; 137:765.