Assessment of cutaneous drug reactions

Drugs can cause, exacerbate or simulate the full spectrum of skin conditions from pigment disorders to cutaneous lymphoma. Consider a cutaneous drug reaction in any patient with a new onset skin reaction, especially if the patient started a new drug in the preceding days to weeks.

A drug-induced reaction is diagnosed largely on clinical criteria, but laboratory tests can be useful to exclude differential diagnoses. Less severe cutaneous drug reactions with no systemic features usually only need clinical assessment for diagnosis. These reactions do not routinely warrant skin biopsy, and histology is often nonspecific. Skin biopsy can assist with diagnosis of pustular, blistering, vasculitic (eg cutaneous vasculitis), lichenoid, photoallergic and lupus-like reactions.

Most skin reactions occur during the first prolonged exposure to the drug. Occasionally, reactions occur after dose modification, introduction of an interacting drug, or if there is liver or kidney impairment. Take a detailed drug history, including recent changes in drug or dose, and confirm that these changes preceded the onset of symptoms. In addition to prescription drugs, ask about over-the-counter, alternative and complementary drugs, vaccines and contrast media for imaging studies. Types of cutaneous drug reactions, their time courses, and some commonly implicated drugs outlines some commonly implicated drugs and typical onset times for different types of cutaneous drug reactions; a printable PDF version of this table is also available.

Table 1. Types of cutaneous drug reactions, their time courses, and some commonly implicated drugs
Printable PDF
exanthematic urticarial phototoxic eruption photoallergic eruption lichenoid cutaneous vasculitis fixed drug eruption Stevens–Johnson syndrome (SJS) toxic epidermal necrolysis (TEN) drug rash with eosinophilia and systemic symptoms (DRESS) acute generalised exanthematous pustulosis (AGEP)
exanthematic (morbilliform; most common)
signs and symptoms	typically begins on trunk and upper limbs polymorphous exanthematic or urticarial lesions on limbs confluent lesions on upper chest purpuric lesions on ankles and feet exanthematic reaction photos
typical onset after drug exposure [NB1] [NB2]	1 week to 1 month
some commonly implicated drugs	almost all drugs, but most frequent with antibacterials (eg beta lactams, macrolides, quinolones, sulfonamides), many antiepileptics, allopurinol, antiretrovirals, NSAIDs, gold, blood products, cytotoxic drugs
urticarial
signs and symptoms	transient erythematous or oedematous patches urticarial reaction photo
typical onset after drug exposure [NB1] [NB2]	hours to 6 days
some commonly implicated drugs	antibacterials, NSAIDs (ACEIs trigger angioedema, usually without urticaria)
phototoxic eruption
signs and symptoms	presents as an exaggerated sunburn (eg erythema, oedema, blistering, weeping, desquamation) confined to sun-exposed areas
typical onset after drug exposure [NB1] [NB2]	hours to 2 days
some commonly implicated drugs	doxycycline, NSAIDs (eg piroxicam, naproxen), amiodarone [NB3], retinoids, sulfonamides, thiazides, griseofulvin, voriconazole
photoallergic eruption
signs and symptoms	eczematous or lichenoid can extend beyond sun-exposed areas
typical onset after drug exposure [NB1] [NB2]	24 to 48 hours after sun exposure
some commonly implicated drugs	chlorpromazine, piroxicam, thiazides, sulfonylureas, amiodarone, sulfonamides
lichenoid
signs and symptoms	widespread, itchy, erythrodermic, scaly, lumpy rash mucous membrane involvement unusual may be photosensitive
typical onset after drug exposure [NB1] [NB2]	months or even years
some commonly implicated drugs	ACEIs, beta blockers, chloroquine, ethambutol, gold, hydroxychloroquine, hydroxycarbamide (hydroxyurea), interferon alfa, lithium, methyldopa, penicillamine, sulfonylureas, thiazide diuretics
cutaneous vasculitis
signs and symptoms	usually presents as palpable purpura on the lower legs may spread or form plaques, bullae or ulcers
typical onset after drug exposure [NB1] [NB2]	7 to 21 days
some commonly implicated drugs	allopurinol, beta lactams, sulfonamides, carbamazepine, diuretics (furosemide [frusemide], thiazides), NSAIDs, phenytoin
fixed drug eruption
signs and symptoms	round to oval, sharply marginated, red to violet inflamed plaques that sometimes evolve to blisters solitary or few lesions on face, hands, feet or genital area may involve lips and mouth fixed drug eruption photo
typical onset after drug exposure [NB1] [NB2]	up to 2 weeks (after first exposure) or faster onset (after subsequent exposure)
some commonly implicated drugs	NSAIDs, sulfonamides, pseudoephedrine, penicillins, tetracyclines, phenobarbital (phenobarbitone), lamotrigine, phenytoin, quinine
Stevens–Johnson syndrome (SJS)—severe cutaneous adverse reaction [NB4]
signs and symptoms	significant initial influenza-like symptoms widespread mucocutaneous exfoliation with or without blisters (over 10% of body surface area) Stevens–Johnson syndrome photo
typical onset after drug exposure [NB1] [NB2]	within weeks (up to 2 months for antiepileptics)
some commonly implicated drugs	antiepileptics, sulfonamides, allopurinol, NSAIDs, beta lactams
toxic epidermal necrolysis (TEN)—severe cutaneous adverse reaction [NB4]
signs and symptoms	significant initial influenza-like symptoms widespread mucocutaneous exfoliation with or without blisters (over 30% of body surface area) toxic epidermal necrolysis photos
typical onset after drug exposure [NB1] [NB2]	within 1 week (up to 2 months for antiepileptics)
some commonly implicated drugs	antiepileptics, sulfonamides, allopurinol, NSAIDs, beta lactams
drug rash with eosinophilia and systemic symptoms (DRESS)—severe cutaneous adverse reaction
signs and symptoms	initial influenza-like symptoms exanthematic rash (may also be exfoliative or erythrodermic) nonfollicular pustules facial oedema, lymphadenopathy, peripheral eosinophilia (over 1.5 x 10⁹/L) and internal organ involvement (frequently liver involvement)
typical onset after drug exposure [NB1] [NB2]	1 to 8 weeks, occasionally up to 4 months
some commonly implicated drugs	aromatic antiepileptics (phenytoin, carbamazepine, oxcarbazepine), barbiturates, lamotrigine, sulfonamides, dapsone, minocycline, azathioprine, abacavir, nevirapine, allopurinol
acute generalised exanthematous pustulosis (AGEP)—severe cutaneous adverse reaction
signs and symptoms	fever, widespread nonfollicular sterile pustules, large areas of oedematous erythema usually starts on the face or axillae marked neutrophilia acute generalised exanthematous pustulosis photos
typical onset after drug exposure [NB1] [NB2]	hours to 2 weeks
some commonly implicated drugs	terbinafine, antibacterials (beta lactams, macrolides, quinolones), calcium channel blockers, antimalarials, pholcodine, paracetamol
Note: ACEIs = angiotensin converting enzyme inhibitors; NSAIDs = nonsteroidal anti-inflammatory drugs NB1: Typical onset time after drug exposure is based on reported data and expert opinion. NB2: Typical onset time is presented as a range, but most skin reactions occur during the first prolonged exposure to the drug. NB3: Amiodarone can cause slate-blue discoloration of sun-exposed skin. NB4: Stevens–Johnson syndrome and toxic epidermal necrolysis are the same disorders of different severity.

Figure 4. Stevens-Johnson syndrome (SJS)

Figure 5. Toxic epidermal necrolysis (TEN)

Figure 6. Acute generalised exanthematous pustulosis (AGEP)

Reactions may be confined to the skin or be part of a systemic reaction (eg fever, sore throat, arthralgia, other systemic symptoms)—systemic features can precede the cutaneous reaction by several days.

Severe cutaneous drug reactions require hospital assessment and treatment. Some signs and symptoms of severe delayed hypersensitivity cutaneous drug reactions includeBalakirski, 2017:

widespread confluent erythema
skin pain, blistering, purpura or necrosis
desquamation of skin when lateral pressure is applied (positive Nikolsky sign)
rapid progression of skin signs
mucous membrane involvement (eg eyes [such as conjunctival irritation and photophobia], mouth, genitals [dysuria])
facial or neck swelling
headache or neck stiffness
sore throat
lymphadenopathy
fever
abnormal full blood examination, liver or kidney dysfunction.

Also see Types of cutaneous drug reactions, their time courses, and some commonly implicated drugs for specific signs and symptoms of severe cutaneous adverse reactions (eg acute generalised exanthematic pustulosis [AGEP], Stevens–Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], drug rash with eosinophilia and systemic symptoms [DRESS]).

Transfer a patient with a suspected severe cutaneous drug reaction to the nearest hospital emergency department for assessment and management; see Management of severe cutaneous drug reactions. See also Drugs commonly implicated in severe cutaneous drug reactions for a list of drugs commonly implicated in severe cutaneous drug reactions.

Otherwise, patients with a suspected less severe cutaneous drug reaction can be managed in primary care; see Management of less severe cutaneous drug reactions.

Figure 7. Drugs commonly implicated in severe cutaneous drug reactions

allopurinol

antiepileptics (eg phenytoin, carbamazepine, oxcarbazepine, phenobarbital [phenobarbitone], lamotrigine)

nonsteroidal anti-inflammatory drugs (NSAIDs)

sulfonamide antibacterials

penicillins

cephalosporins

antiretrovirals (eg abacavir, nevirapine)

proton pump inhibitors (PPIs) [NB1]Casciaro, 2019 Lombardo, 2015 Salloum, 2021

Note:

NB1: Proton pump inhibitors are not as commonly implicated as other listed drugs; however, they are widely prescribed.