Author:
David F Butler, MD; Chief Editor: Dirk M Elston, MD
Background
Adverse
reactions to medications are common and often manifest as a cutaneous eruption. Drug-induced
cutaneous disorders frequently display a characteristic clinical morphology
such as morbilliform exanthem, urticaria, hypersensitivity syndrome,
pseudolymphoma, photosensitivity, pigmentary changes, acute generalized
exanthematous pustulosis, lichenoid dermatitis, vasculitis, Stevens-Johnson
syndrome, or fixed drug eruption (FDE). The term fixed drug eruption describes
the development of one or more annular or oval erythematous patches as a result
of systemic exposure to a drug; these reactions normally resolve with
hyperpigmentation and may recur at the same site with reexposure to the drug.
Repeated exposure to the offending drug may cause new lesions to develop in
addition to "lighting up" the older hyperpigmented lesions.
Several
variants of fixed drug eruption have been described, based on their clinical
features and the distribution of the lesions.[1,
2, 3, 4, 5, 6] These include the following:
- Pigmenting fixed drug eruption
- Generalized or multiple fixed drug eruption
- Linear fixed drug eruption
- Wandering fixed drug eruption
- Nonpigmenting fixed drug eruption
- Bullous fixed drug eruption
- Eczematous fixed drug eruption
- Urticarial fixed drug eruption
- Erythema dyschromicum perstans–like fixed drug eruption
- Vulvitis
- Oral
- Psoriasiform
- Cellulitislike eruption[7]
Pathophysiology
Although
the exact mechanism is unknown, recent research suggests a cell-mediated
process that initiates both the active and quiescent lesions. The process may
involve an antibody-dependent, cell-mediated cytotoxic response.[8]
CD8+ effector/memory T cells play an important role
in reactivation of lesions with re-exposure to the offending drug.[9,
10]
The
offending drug is thought to function as a hapten that preferentially binds to
basal keratinocytes, leading to an inflammatory response.[11]
Through liberation of cytokines such as tumor necrosis
factor-alpha, keratinocytes may locally up-regulate expression of the
intercellular adhesion molecule-1 (ICAM1).[12]
The up-regulated ICAM1 has been shown to help T cells (CD4 and
CD8) migrate to the site of an insult.[13,
14]
The
newly arriving and residential CD8 cells likely perpetuate tissue damage by
their production of the inflammatory cytokines interferon-gamma and tumor
necrosis factor-alpha. CD8 cells isolated from active lesions have also been
shown to express alpha E beta 7, a ligand for E-cadherin, which may further
contribute to the lymphocyte’s ability to localize to the epidermis. Other cell
surface molecules, such as CLA/alpha4beta1/CD4a, that bind E-selectin/vascular
cellular adhesion molecule-2/ICAM1 help to further attract CD8 cells to the
area.[8]
Changes
in cell surface markers allow vascular endothelium to select CD4 cells for
migration into active lesions. These regulatory CD4 cells likely produce
interleukin 10, which has been shown to help suppress immune function,
resulting in a resting lesion.[8]
As the inflammatory response dissipates, interleukin 15
expression from keratinocytes is thought to help ensure the survival of CD8
cells, helping them fulfill their effector memory phenotypes. Thus, when
reexposure to the drug occurs, a more rapid response develops in the exact
location of any prior lesions.[8]
Epidemiology
Frequency
United States
The
prevalence of drug eruptions has been reported to range from 2-5% for
inpatients and greater than 1% for outpatients.[15]
Fixed drug eruptions may account for as much as 16-21% of all
cutaneous drug eruptions. The actual frequency may be higher than current
estimates, owing to the availability of a variety of over-the-counter
medications and nutritional supplements that are known to elicit fixed drug
eruptions.
International
The
international prevalence is variable but is likely similar to that in the
United States. Most studies report fixed drug eruptions to be the second or
third most common skin manifestation of adverse drug events.[16]
Mortality/Morbidity
No
deaths have been attributed to fixed drug eruptions. Widespread lesions may
initially mimic toxic epidermal necrolysis, but they have a benign clinical
course.[17] Localized hyperpigmentation is a
common complication, but pain, infection, and, rarely, hypopigmentation, also
may occur.[1]
Race
Fixed
drug eruptions have no known racial predilection. A genetic susceptibility to
developing a fixed drug eruption with an increased incidence of HLA-B22 is
possible.[18, 19]
Sex
One
large study of 450 patients revealed a male-to-female ratio of 1:1.1 for fixed
drug eruptions.[1]
Age
Fixed
drug eruptions have been reported in patients as young as 1.5 years and as old
as 87 years. The mean age at presentation is 30.4 years in males and 31.3 years
in females.[1]
History
The
initial eruption is often solitary and frequently located on the lip or
genitalia. Rarely, the eruption may be intraoral. Other common locations of the
initial lesion are the hip, lower back/sacrum, or proximal extremity. With the
initial fixed drug eruption attack, a delay of up to 2 weeks may occur from the
initial exposure to the drug to the development of the skin lesion.[20]
Skin lesions develop over a period of hours but require days
to become necrotic. Lesions may persist from days to weeks and then fade slowly
to residual oval hyperpigmented patches.
Subsequent
reexposure to the medication results in a reactivation of the site, with
inflammation occurring within 30 minutes to 16 hours.[21]
The reactivation of old lesions also may be associated with
the development of new lesions at other sites.
Patients
may not be cognizant that a drug, nutritional supplement, over-the-counter
medication, or, rarely, food (eg, fruits, nuts) triggered the skin problem.
They may be convinced that an insect, particularly a spider, may be the
culprit. A careful history is required to elicit the fact that a drug has been
taken and is temporally related to the onset of the eruption. Medications taken
episodically, such as pain relievers, antibiotics, or laxatives, are often to
blame. When able to be identified, patients often report ingestion of one the
following types of medications[22]
:
- Analgesics
- Muscle relaxants
- Sedatives
- Anticonvulsants
- Antibiotics
Local
symptoms may include pruritus, burning, and pain.[1]
Systemic symptoms are uncommon, but fever, malaise, nausea,
diarrhea, abdominal cramps, anorexia, and dysuria have been reported.[21,
22]
Further
questioning may reveal prior episodes of fixed drug eruption, atopic disease,
or other past drug reactions. Family history may render a history of atopy,
drug reactions, or diabetes mellitus.[1]
Several
cases of fixed drug eruption on the genitalia have been reported in patients
who were not ingesting the drug but whose sexual partner was taking the
offending drug and the patient was exposed to the drug through sexual contact.[23,
24, 25]
Physical
The
most common clinical manifestation is the pigmenting fixed drug eruption, which
usually manifests as round or oval, sharply demarcated erythematous/edematous
plaques located on the lip, hip, sacrum, or genitalia.[2]
These erythematous patches or plaques gradually fade with
residual hyperpigmentation (see images below). The center of the patch may
blister or become necrotic. Other less common variants may manifest as lesions
resembling erythema multiforme, toxic epidermal necrolysis, eczema, urticaria,
a linear pattern following Blaschko lines, bullous lesions, a migrating
eruption, or a nonpigmenting form with no postinflammatory hyperpigmentation.[3]
Targetoid fixed drug eruption on the
abdomen of a child. 
Hyperpigmented fixed drug eruption
on the hip of an adult. 
Vesicular fixed drug eruption on the
glans penis. 
Multiple hyperpigmented fixed drug
eruptions on the trunk. 
Hyperpigmented fixed drug eruption
on the right side of the upper lip.
Initially,
a single lesion or a few lesions develop, but, with reexposure, additional
lesions occur. The vast majority of patients present with 1-30 lesions, ranging
in size of 0.5-5 cm, but reports of lesions greater than 10 cm have been
published. Lesions may be generalized. The most common reported site is the
lips, and these may be seen in up to half of all cases.[1]
Medications
may also follow a site-specific eruption pattern. For example,
trimethoprim-sulfamethoxazole (Bactrim) has been shown to favor the genital
region (especially in males) and naproxen and the oxicams involve the lips.[2]
Resting/inactive
lesions tend to appear as round or oval, gray, hyperpigmented macules.
Upon
reexposure, the resting hyperpigmented macules activate, developing a
violaceous center encircled by concentric rings of erythema. Re-administration
of the medication poses the risk of increased pigmentation, size, and number of
lesions.
Individuals
with darker pigmentation may develop postinflammatory hypopigmented macules
once the lesions have resolved.[11]
Causes
The
major categories of causative agents of fixed drug eruption include
antibiotics, antiepileptics, nonsteroidal anti-inflammatory agents, and
phenothiazines, although numerous other agents and certain foods such as
cashews and licorice have also been reported as causative agents. Ingestion of
the causative agent may occur via any route, including oral, rectal, or
intravenous.[22]
Differential Diagnoses
- Bullous Pemphigoid
- Cellulitis
- Drug Eruptions
- Drug-Induced Bullous Disorders
- Eczema
- Erythema Annulare Centrifugum
- Erythema Dyschromicum Perstans
- Erythema Multiforme
- Herpes Simplex
- Insect Bites
- Lichen Planus
- Lichen Planus Actinicus
- Lupus Erythematosus, Discoid
- Melasma
- Pemphigus Vulgaris
- Pemphigus, Drug-Induced
- Pityriasis Rosea
- Postinflammatory Hyperpigmentation
- Psoriasis
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Urticaria, Acute
Laboratory Studies
Blood
studies are not useful for the diagnosis of fixed drug eruption (FDE), although
eosinophilia is common with drug eruptions.
Other Tests
Rechallenging
the patient to the suspected offending drug is the only known test to possibly
discern the causative agent. Patch testing of the suspected drug to lesional
and non-lesional skin has been helpful in a few instances. The exact protocol
of patch testing has varied.
Patch
testing and oral provocation have been used to identify the suspected agent and
check for cross-sensitivities to medications.[37,
38] A refractory period has been reported in fixed drug
eruption; therefore, a delay before and between patch testing and oral
provocation is recommended. One study used an 8-week time window after lesion
resolution and between tests, which yielded positive results.[39]
Patch testing must be performed on a previously involved site;
otherwise, a false-negative result is likely.[38]
Some locations may be inappropriate for patch testing; thus,
clinical discretion is advised. Once patch testing is complete, oral
provocation should follow, with the least likely culprits and the negative
patch test agents first, followed by more likely causes. Oral provocation is
thought to be the only reliable way to diagnose fixed drug eruption.
Patch
testing is particularly efficacious in identifying a putative cause of the
reaction when nonsteroidal anti-inflammatory agents are suspected, but patch
testing is not helpful in discerning reactions to antibiotics and allopurinol.[40]
Procedures
Skin
biopsy is the diagnostic procedure of choice
Histologic Findings
Histological
examination of inflammatory/acute lesions shows an interface dermatitis with
vacuolar change and Civatte bodies[11]
(see the image below).
Acute
interface dermatitis with prominent vacuolar change and individual necrotic
keratinocytes within the epidermis (X10).
The
overall pattern may mimic that seen in erythema multiforme. Dyskeratosis and
individual necrotic keratinocytes within the epidermis may be a prominent
feature (see the image below).
Interface
dermatitis, vacuolar change, necrotic keratinocytes, and incontinent pigment in
the dermis (X40).
On
occasion, the lymphocytic infiltrate can be prominent enough to obscure the
dermoepidermal junction. Spongiosis, dermal edema, eosinophils, and occasional
neutrophils may be present. Pigmentary incontinence within the papillary dermis
is a characteristic feature and may be the only feature seen in older,
noninflamed lesions. Chronic or inactive lesions may also show mild acanthosis,
hyperkeratosis, and relatively few inflammatory cells.
Medical Care
The
main goal of treatment is to identify the causative agent and avoid it.
Treatment for fixed drug eruptions (FDEs) otherwise is symptomatic. Systemic
antihistamines and topical corticosteroids may be all that are required. In
cases in which infection is suspected, antibiotics and proper wound care are
advised. Desensitization to medications has been reported in the literature,
but this should be avoided unless no substitutes exist.[41]
Consultations
Consultation
with a dermatologist is warranted if the diagnosis is in doubt. If patch
testing is needed to determine which drug may be involved, a dermatologist with
such experience may be required. If Stevens-Johnson syndrome or toxic epidermal necrolysis
is suspected, hospitalization and possible referral to the intensive care unit
or burn unit may be appropriate.
Diet
A
regular diet is usually acceptable. However, food may be an exacerbating
factor; reactivation has been reported with cashews, liquorice, lentils, and
strawberries.[11, 33, 36]
Activity
Generally,
no limits on activities are imposed. Multiple studies have sited male genital
lesions occurring following intercourse with female partners taking
trimethoprim-sulfamethoxazole.[42]
Therefore, patients may consider avoiding sexual activity
while a partner is taking a medication that has resulted in a prior fixed drug
eruption. If open lesions are present, general wound care precautions are
recommended.
Medication Summary
Lesions
of fixed drug eruption resolve spontaneously with avoidance of the inciting
drug. Additional medications should be used to relieve symptoms associated with
the condition. Generally, an oral antihistamine (eg, hydroxyzine) and a topical
corticosteroid may be sufficient. The use of corticosteroids may interfere with
later diagnostic provocation testing. Hyperpigmentation may take many months to
resolve. Incontinent pigment in the dermis responds poorly to topical bleaching
agents such as hydroquinones.
Deterrence/Prevention
Avoid
the offending drug. Patch testing may be used to help identify agents that pose
a risk of cross-sensitivity.[43]
Complications
Hyperpigmentation
is the most likely complication of a fixed drug eruption (FDE). The potential
for infection exists in the setting of multiple, eroded lesions. Generalized
eruptions have been reported following topical and oral provocation testing.[22,
44]
Prognosis
The
prognosis is very good, and an uneventful recovery should be expected. No
deaths due to fixed drug eruption have been reported. Residual
hyperpigmentation is very common, but this is less likely with the
nonpigmenting variant.
Patient Education
Patients should be counseled on medication avoidance and
possible cross-reactions of similar medications. Patients should notify their
physicians of all drug allergies they have experienced.
