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

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.

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 edematous 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 complaints 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 multiple, 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 fasting 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 and applied topically to previously involved skin. A focal patch test (topical provocation test) on the affected area was negative. A 3-mm punch skin biopsy specimen was taken from a symptomatic erythematous lesion and it was stained by hematoxylin–eosin. The histopathological examination of the case showed hydrophic degenerations of the basal membrane, necrotic keratinocytes in the epidermis, pigment incontinence, and mixed-type inflammatory cells and edema in the dermis (Figure 3).

Figure 1.

Multiple, edematous, violet erythematous plaques on trunk and extremities.

Figure 2.

Multiple, edematous, violet erythematous plaques on trunk, extremities, and genital region.

Figure 3.

Hydrophic degenerations of the basal membrane, necrotic keratinocytes in the epidermis, pigment incontinence (H&E, ×200).

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, sharply demarcated, multiple, multiform (lesions' size ranged from 0.5 to 10 cm), violet-erythematous plaques on the trunk, abdomen, and bilateral upper and lower limbs (Figure 4). The histopathological examination was similar to Case 1.

Figure 4.

Multiple, edematous, violet erythematous plaques on trunk and extremities.

Although we recommended a patch test with naproxen for an accurate diagnosis, the patient refused the test. Based on clinical and histological findings, he was diagnosed with FDE and the patient was successfully treated with an oral antihistamine, oral prednisolone (40 mg/day), and a topical steroid (mometasone furoate). The patient’s lesions recovered after 3 weeks with residual hyperpigmentation.

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 CD8+ cells in the epidermis may play a major role in the pathogenesis. Severe epidermal damage in FDE lesions may be related to intraepidermal CD8+ T cells, which rapidly produce a large amount of interferon γ. ⁴

The common FDE causative agents are usually intermittently used medications. ¹ The most common categories of the causative agents are antibiotics, antiepileptics, hypnotics, and analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs), including phenylbutazone, 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, however more commonly on the trunk, extremities, lips, and genital region.^1,3 FDE usually recovers with residual pigmentation after interrupting treatment with the causative agents. At the beginning, there is one 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, keratinocyte 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 epidermal necrolysis. On the other hand, erythema dyschromicum perstans, lichen planus pigmentosus, urticaria pigmentosa should be considered in differential diagnosis during the postinflammatory hyperpigmentation phase. In addition, FDE can also be confused with postinflammatory hyperpigmentation 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 medication. 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 Negative 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 generalized manifestations. In Case 1, the most suspicious agent was diclofenac, however the skin patch test for diclofenac was negative. Getting negative test results despite testing 2 weeks after disappearance 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 careful physical examination and a histopathological assessment are essential in the diagnosis.