Human & Experimental

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Toxicology

Nonsteroidal anti-inflammatory drugs-induced generalized fixed drug eruption: two cases

SG Bilgili, O Calka, AS Karadag, N Akdeniz and M Kosem
Hum Exp Toxicol 2012 31: 197 originally published online 15 June 2011
DOI: 10.1177/0960327111412804

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Case Report
Human and Experimental Toxicology
31(2) 197–200
Nonsteroidal anti-inflammatory ª The Author(s) 2011
Reprints and permission:
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drugs-induced generalized fixed drug DOI: 10.1177/0960327111412804
het.sagepub.com
eruption: two cases

SG Bilgili1, O Calka1, AS Karadag1, N Akdeniz2 and

M Kosem3

Abstract
Fixed drug eruption (FDE) is a drug-induced cutaneous reaction that occurs at the same site with each exposure
to a specific medication and usually manifests as round or oval, sharply demarcated erythematous or edematous
plaques. The exact mechanism is unknown. The most common causative agent is co-trimoxazole. Other major
categories of causative agents of FDE include antibiotics, antiepileptics, and nonsteroidal anti-inflammatory drugs
(NSAIDs). FDE usually causes localized eruptions and very rarely generalized lesions. We report two cases of
developing generalized FDEs after exposure to diclofenac and naproxen.

Keywords
fixed drug eruption; generalized; naproxen; nonsteroidal anti-inflammatory drug; diclofenac

Introduction
Fixed drug eruption (FDE) is a drug-induced cutaneous
reaction that occurs at the same site with each exposure
to a particular medication and usually manifests as
round or oval, sharply demarcated erythematous or ede-
matous plaques. Patients with FDE usually have 6
lesions; most of them usually have 1 lesion.1 If one has
more than one focus, it is defined as multifocal or
generalized FDE that is rarely seen.1-3 We report two
cases with generalized FDE.
Case 1
A 48-year-old male admitted to our clinic with com-
plaints of itching and erythematous lesions in his
body. He had diarrhea 5 days earlier. He received
diclofenac potassium and trimebutine, and developed
lesions all over the body 6 hours after exposure to
these medications.
Past medical history revealed that he had diabetes
mellitus and had similar lesions twice over the year and
a half after taking diclofenac potassium for joint pains.
There was no family history. Physical examination
showed increased bowel movements and abdominal
tenderness. Dermatological examination revealed mul-
tiple, round or oval, sharply demarcated, multiform,
violet-erythematous or edematous plaques on the
anterior and posterior body, both upper and lower limbs,
and genital region. The largest lesion was localized on
the lateral surface of the right thigh. In addition, a 1-
cm diameter eroded plaque was seen on the penis corpus
(Figures 1 and 2). Laboratory findings showed the fast-
ing glucose level was 348 mg/dl (normal range 70–110
mg/dl), hemoglobin A1c 10.7% (normal range 4.2–
5.7%), and C-reactive protein 11 mg/L (normal range
0–5 mg/L). The rest of the tests were unremarkable.
He was treated with oral prednisolone tablet 20 mg/day,
desloratadin tablet 10 mg /day, and topical halcinoid
cream. The lesions were healed in 1 month with residual
hyperpigmentation. The patch test was performed 2
weeks after the lesions resolved. The medication was
prepared by diclofenac potassium and 10% petrolatum
1
Department of Dermatology, Yuzuncu Yil University Faculty of
Medicine, Van, Turkey
2
Department of Dermatology, Atatürk University Faculty of
Medicine, Erzurum, Turkey
3
Department of Pathology, Yuzuncu Yil University Faculty of
Medicine, Van, Turkey
Corresponding author:
Serap Gunes Bilgili, Department of Dermatology, Yüzüncü Yıl
University Faculty of Medicine, Van, 65300, Turkey
Email: drserapgunes@yahoo.com

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198 Human and Experimental Toxicology 31(2)

Figure 2. Multiple, edematous, violet erythematous plaques

on trunk, extremities, and genital region.

Case 2
A 33-year-old male admitted to our clinic for red
lesions on his body and arms that started 2 hours after
taking naproxen. Family history was unremarkable.
The medical history shows he had similar reaction
after exposure to the same medication 1 year ago.
Dermatological examination revealed round or oval,
Figure 1. Multiple, edematous, violet erythematous plaques sharply demarcated, multiple, multiform (lesions’
on trunk and extremities. size ranged from 0.5 to 10 cm), violet-erythematous
plaques on the trunk, abdomen, and bilateral upper
and applied topically to previously involved skin. A and lower limbs (Figure 4). The histopathological
focal patch test (topical provocation test) on the examination was similar to Case 1.
affected area was negative. A 3-mm punch skin Although we recommended a patch test with
biopsy specimen was taken from a symptomatic naproxen for an accurate diagnosis, the patient refused
erythematous lesion and it was stained by hematoxy- the test. Based on clinical and histological findings, he
lin–eosin. The histopathological examination of the was diagnosed with FDE and the patient was success-
case showed hydrophic degenerations of the basal fully treated with an oral antihistamine, oral predniso-
membrane, necrotic keratinocytes in the epidermis, lone (40 mg/day), and a topical steroid (mometasone
pigment incontinence, and mixed-type inflammatory furoate). The patient’s lesions recovered after 3 weeks
cells and edema in the dermis (Figure 3). with residual hyperpigmentation.

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Bilgili S G et al.
Figure 3. Hydrophic degenerations of the basal membrane,
necrotic keratinocytes in the epidermis, pigment inconti-
nence (H&E, 200).
Discussion
FDE occurs at the same site with each exposure to a
particular medication. However, more areas may be
involved with repeated attacks.3 The pathogenesis is
not clear, but cytotoxic memory CD8þ cells in the
epidermis may play a major role in the pathogenesis.
Severe epidermal damage in FDE lesions may be
related to intraepidermal CD8þ T cells, which rapidly
produce a large amount of interferon g.4
The common FDE causative agents are usually
intermittently used medications.1 The most common
categories of the causative agents are antibiotics, anti-
epileptics, hypnotics, and analgesics. Nonsteroidal
anti-inflammatory drugs (NSAIDs), including phe-
nylbutazone, ibuprofen, naproxen, piroxicam, and
celecoxib, may cause FDE as well.4
The lesions usually occur within 1 hour and up to 1
day after exposure to a specific medication. The
lesions may be localized anywhere in the body, how-
ever more commonly on the trunk, extremities, lips,
and genital region.1,3 FDE usually recovers with resi-
dual pigmentation after interrupting treatment with
the causative agents. At the beginning, there is one
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199
Figure 4. Multiple, edematous, violet erythematous plaques
on trunk and extremities.
lesion; the count and the size of lesions increases with
recurrent attacks.3 In both cases, widespread lesions
were seen on the trunk and extremities. In Case 1, the
genital region was involved as well. In addition, the
severity of the attack and the number of lesions were
increased when compared to the previous attacks in
both cases.
The histopathological assessment of FDE shows
intraepidermal and subepidermal vesicules, keratino-
cyte necrosis, pigment incontinence, and interphase
dermatitis presenting superficial and deep infiltrations
of neutrophils, eosinophils, and mononuclear cells.1
The histopathological findings in both cases were
consistent with FDE.
Generalized FDE can be confused with erythema
multiform, Stevens-Johnson syndrome, and toxic epi-
dermal necrolysis. On the other hand, erythema dys-
chromicum perstans, lichen planus pigmentosus,
urticaria pigmentosa should be considered in differen-
tial diagnosis during the postinflammatory hyperpig-
mentation phase. In addition, FDE can also be
confused with postinflammatory hyperpigmentation
200
caused by inflammatory dermatoses such as nummular
eczema and pityriasis rosea.2,5
The finding of the causative agents for FDE is
challenging when one receives more than one med-
ication. The rechallenge test seems to be the most
reliable method to identify the causative agents
even though it is not always accurate and probably
risky.6 The results of the skin patch tests on the
healthy side or on the lesion side can vary. It was
shown that the skin patch test on the affected side
was positive in up to 43% of the patients.7 Nega-
tive test results may be due to testing time, testing
in an uninvolved area, or low concentration of
drugs used in patch test. Also the patient might not
have been sensitive to the original medication but
rather to its metabolites. However, negative test
results do not rule out FDE.5 We did not apply oral
provocation test in our cases because of their gen-
eralized manifestations. In Case 1, the most suspi-
cious agent was diclofenac, however the skin patch
test for diclofenac was negative. Getting negative
test results despite testing 2 weeks after disappear-
ance of lesions might be due to the use of multiple
medications by the patient or sensitivity of the
patient to metabolites of medication rather than the
drug itself. Case 2 did not accept the skin patch
test.
An early diagnosis and treatment of generalized
FDE may be very important. Oral provocation tests
are not always safe, and skin patch tests are not
always accurate. Therefore, a detailed history, a care-
ful physical examination and a histopathological
assessment are essential in the diagnosis.
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Human and Experimental Toxicology 31(2)
Declaration of conflicting interests
The authors declared no conflicts of interest.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
References
1. James WD, Berger TG, and Elston DM. Contact der-
matitis and drug eruptions. Andrews’ diseases of the
skin clinical dermatology. 10th ed. Saunders: Elsevier,
2006, pp.91–138.
2. Rallis E, Rigopoulos D, Anyfantakis V, Kalogirou O,
Christophidou E, Papadakis P, et al. ‘Dalmatian
dog’-like skin eruption (two cases of multifocal fixed
drug eruption induced by mefenamic acid). J Eur Acad
Dermatol Venereol 2005; 19: 753–755.
3. Mahboob A and Haroon TS. Drugs causing fixed erup-
tions: a study of 450 cases. Int J Dermatol 1998; 37:
833–888.
4. Rho YK, Yoo KH, Kim BJ, Kim MN, and Song KY. A
case of generalized fixed drug eruption due to a pirox-
icam. Clin Exp Dermatol 2010; 35: 204–205.
5. Shiohara T. Fixed drug eruption:pathogenesis and
diagnostic tests. Curr Opin Allergy Clin Immunol
2009; 9: 316–321.
6. Puavilai S, Chunharas A, and Kamtavee S. Drug erup-
tions: the value of oral rechallenge test and patch test.
J Med Assoc Thai 2002; 85: 263–269.
7. Rallis E, Stavropoulou E, and Paraskevopoulos I.
Nimesulide-induced, multifocal, urticarial fixed drug
eruption confirmed by oral provocation test. Indian
J Dermatol Venereol Leprol 2008; 74: 403–404.