Dermatology Online Journal

Fixed drug eruption related to ibuprofen presenting as giant bullae on the posterior thigh
Misha Vladislavovich Koshelev¹ PhD, Kristy F Fleming² MD, Sarah J Grekin³ MD, Carina A Wasko⁴ MD
Dermatology Online Journal 18 (11): 10

1. MSTP Program, Baylor College of Medicine, Houston, Texas
2. Department of Dermatology, UCLA Medical Center, Santa Monica, California
3. Department of Dermatology, University of Texas Health Science Center, Houston, Texas
4. Department of Dermatology, Baylor College of Medicine, Houston, Texas

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Abstract

Fixed drug eruptions (FDEs), first described by Bourns in 1889, are solitary or multiple, sharply demarcated, round to oval, edematous and erythematous patches that arise after exposure to a specific medication. They can be pink to dark red to brown and can be larger than 10 cm in size. In almost a third of patients in some case series, these lesions have been reported to progress to vesicles or bullae. Fixed drug eruptions have been associated in up to 40 percent of cases with non-steroidal inflammatory drugs, including ibuprofen. We describe an interesting case of a biopsy-confirmed FDE that presented as large bullae on the posterior thigh after ibuprofen use.

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Case report

Figure 1	Figure 2
Figure 1. Skin findings: a ~4 cm erythematous plaque on the medial thigh with flaccid bullae on the inferior aspect, a ~2 cm flaccid bulla on the medial aspect, numerous vesicles, and superficial desquamation. Figure 2. Close-up view of the posterior aspect of the patient’s left thigh at presentation.

A 47-year-old man presented with a 2-day history of increasingly tender “fluid filled sacs” on his posterior thigh, which caused pain with sitting. The patient was otherwise healthy, but reported he started taking ibuprofen for a toothache approximately one and a half months ago. His last dose was 4 weeks prior to presentation. He denied illicit drug use and he denied taking any other oral medications except cetirizine that he continued to take after symptom resolution without further eruptions. Physical examination revealed a 4 cm erythematous patch with an overlying flaccid bulla on the inferior aspect, a 2 cm flaccid bulla on the medial aspect, numerous vesicles, and superficial desquamation (Figures 1 and 2).

Figure 3	Figure 4
Figure 3. Low power view (10X) of a 4-mm punch biopsy taken on the day of presentation. Figure 4. High power view (40X) of a 4-mm punch biopsy taken on the day of presentation.

Figure 5
Figure 5. The patient’s skin findings 2 weeks after initial presentation: a faint erythematous patch with no vesicles or bullae on the left posterior thigh extending to the medial thigh.

A 4 mm punch biopsy was obtained from the lateral edge of the lesion. Histological examination revealed skin with a sub-epidermal bulla and necrosis of the epidermis, with necrotic keratinocytes (Figures 3 and 4) with a lymphocytic infiltrate. A varicella-zoster immunohistochemical study was negative. Bulla fluid was cultured and grew 1+ coagulase negative Staphylococci.

The patient was instructed to avoid ibuprofen and was prescribed topical mupirocin 2 percent to apply to his lesion three times a day. He returned to clinic 2 weeks later, with an asymptomatic faintly erythematous patch with no vesicles or bullae (Figure 5). The patient has remained off ibuprofen and has no further recurrences in the last 2 months.

Discussion

Bourns described the first case of a fixed drug eruption (FDE) in 1889 [1]. The term, “éruption érythémato-pigmentée fixe,” was coined by Brocq in reference to a fixed, erythematous, and pigmented rash caused by antipyrine [2]. Classically, a FDE occurs 1-2 weeks after initial exposure to a medication [3]. An initial FDE may also occur a few weeks to several years after a person starts taking a particular medication [4, 5]. Subsequent exposures to the offending agent will typically cause an eruption 30 minutes to 48 hours after ingestion [6, 7], with a mean time to appearance of approximately 2 hours [8]. Specifically, one or several sharply defined, round and/or oval erythematous macules appear on the skin or mucous membranes. These macules, which can be greater than 10 cm [9], may rapidly progress to edematous plaques [8]. In some cases, as many as 30 percent in one report, such plaques will form vesicles or blisters [10]. These lesions can be located on the abdomen, medial aspect of the limbs, and palms and soles, in addition to the lips, tongue, oral mucosa, and glans penis [11]. Characteristically, FDEs will recur in the same location if a person is re-exposed to the offending agent [12]. Some FDE lesions initially appear at sites of recent herpes simplex virus and herpes zoster lesions [13].

The appearance of a FDE is often accompanied by a sensation of burning [13], such as that experienced by our patient. Although uncommon, concomitant fever, diarrhea, anorexia, malaise, and abdominal complaints have also been reported [11]. Healing of a FDE characteristically occurs with hyperpigmentation that can persist for months. However, a non-pigmenting FDE can also occur. Systemic signs are often present and large, almost symmetric, well-demarcated erythematous plaques can be seen [13].

Fixed drug eruptions are traditionally described to be most common in 20 to 40 year old patients [4]. However, FDEs can occur in any age range [12] and several recent case series report that patients with these eruptions have a median age between 52 and 58 [12, 14, 15]. These lesions are most commonly seen after oral medication intake [13]. Less frequently, FDEs can occur after intramuscular, intravenous, or topical application. In rare cases, FDEs may occur after sexual contact with a partner who has taken the eliciting agent [16]. The incidence of FDE caused by a particular medication depends on the frequency of its use, and thus varies between reports [12]. Antibiotics, antifungal medications, analgesics, anticonvulsants, barbiturates, and antiphlogistics are commonly responsible for FDEs [4, 9].

FDEs have been reported in association with non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen [8, 14, 17, 18]. In fact, in a retrospective analysis of clinically diagnosed FDEs in a 20-year period submitted to patch testing in one center, NSAIDs were clearly responsible for almost 40 percent of FDEs [15]. The authors suggest that when presented with a FDE of unknown origin, NSAIDs should be ruled out as being the causative agent. Our patient’s fixed drug reaction occurred 4 weeks after his last dose of ibuprofen, which is somewhat longer than the classic 1-2 week delay for an FDE after first exposure to a medication [3]. However, the patient denied illicit drug use and any other medication intake except cetirizine that he continued to take without further eruptions. Further, the time course of our patient’s FDE is well within the “refractory period” of a few weeks to several years between medication exposure and first FDE occurrence that has been reported in the literature [4, 5]. Finally, in support of the etiology of his dermatologic findings as an FDE to ibuprofen, the patient has not had a recurrence of his symptoms since avoiding ibuprofen intake.

Topical provocation by patch testing on residual pigmented lesions can be used to identify the responsible medication [15]. Infiltrated erythema or more intense reactions on pigmented lesions without a reaction on non-lesional skin suggest the patient had a FDE to the agent being tested. However, even patients with a negative patch test to a medication can have a FDE to the substance. In one retrospective study of 52 patients patch-tested for FDE based on clinical suspicion, 60 percent of patients did not have a reactive patch test. Oral re-challenge with the medication allowed drug identification in 5 of 7 patients tested, but 4 of the 5 reactive patients required oral or topical steroids after re-challenge. Oral administration of the offending medication has also been associated with generalized bullous lesions [19]. Thus, patch testing can be of limited utility in FDEs when clinical suspicion for the offending agent is high. Additionally, oral re-challenge, although it is the gold standard, carries risks that patients may not want to accept. Our patient had biopsy findings and clinical history that were characteristic for FDE. Given the severity of his initial reaction, we chose not to perform patch testing or oral re-challenge to avoid a significant reaction on ibuprofen re-administration.

By definition, a FDE recurs at the same site after exposure to a responsible medication. The mechanism of this site-specificity is not completely known. However, it is thought that αβTCR+ CD8+ T cells in the epidermis, which function similarly to effector memory T cells, are primarily responsible for the damage to the epidermis seen in a FDE [8, 13]. These T cells can remain in the epidermis for years, and can be reactivated after new exposure to the drug of interest, potentially through a TNF-α-dependent up-regulation of the expression of ICAM-1 on keratinocytes [17].

On histopathology, necrotic keratinocytes are seen within the lesion in association with a superficial and deep dermal and perivascular infiltrate of lymphocytes, eosinophils, and, sometimes, neutrophils [6]. Dermal melanophages – macrophages pigmented with melanin – can be an important clue to the diagnosis. Sequential biopsies of lesions after re-challenge with the offending agent have been described [13]. Prior to re-challenge by the causative agent, the basal layer of the epidermis contains an increased number of lymphocytes compared to that in uninvolved, adjacent skin. Otherwise, there is a normal-appearing epidermis with minimal lymphocytic infiltrates around blood vessels. When slight erythema or irritation appears at the lesion site approximately 2-3 hours after re-challenge, lymphoid cells reach the lower half of the epidermis, with a significant change in the number or distribution of dermal infiltrates. Twenty-four hours after re-challenge, an extensive exocytosis of dermal lymphoid cells into the epidermis, known as “epidermotropism,” and hydropic degeneration of the basal layer classically associated with a FDE can be seen. On days 3-4 after re-challenge, a psoriasiform lichenoid pattern with slight focal spongiosis is encountered.

The prognosis of a fixed drug reaction is usually excellent. In fact, in most patients, the lesions will resolve over several days after drug discontinuation [8]. The only remaining mark of the lesion in these individuals will be hyperpigmentation, except when a non-pigmenting FDE has occurred. Further, in a typical FDE, the shade of hyperpigmentation will become darker after repeated medication administration. There are, however, cases in which the lesions of a FDE continue to increase in number and size several days after discontinuation of the responsible agent.

References

1. Bourns D. Unusual effects of antipyrine. Br Med J. 1889;2:218-20.

2. Brocq L. Erutpion érythémato-pigmentée fixe due à l'antipyrine. Ann Dermatol Vénéréol. 1894;5:308-13.

3. Revuz J, Valeyrie-Allanore L. Drug Reactions. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. London, Great Britain: Saunders; 2012. p. 335-56.

4. Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006 Aug;45(8):897-908. [PubMed]

5. Browne SG. Fixed Eruption in Deeply Pigmented Subjects: Clinical Observations on 350 Patients. Br Med J. 1964 Oct 24;2(5416):1041-4. [PubMed]

6. Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail and hair disorders. Drug Saf. 2007;30(11):1011-30. [PubMed]

7. Duarte AF, Correia O, Azevedo R, do Carmo Palmares M, Delgado L. Bullous fixed drug eruption to etoricoxib--further evidence of intraepidermal CD8+ T cell involvement. Eur J Dermatol. 2010 Mar-Apr;20(2):236-8. [PubMed]

8. Mizukawa Y, Shiohara T. Fixed drug eruption: a prototypic disorder mediated by effector memory T cells. Curr Allergy Asthma Rep. 2009 Jan;9(1):71-7. [PubMed]

9. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998 Nov;37(11):833-8. [PubMed]

10. Lisi P, Stingeni L. Fixed drug eruption: bullous form. Clin Dermatol. 1993 Oct-Dec;11(4):461-6. [PubMed]

11. Handisurya A, Moritz KB, Riedl E, Reinisch C, Stingl G, Wohrl S. Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms. J Dtsch Dermatol Ges. 2011 May;9(5):374-8. [PubMed]

12. Lee C-H, Chen Y-C, Cho Y-T, Chang C-Y, Chu C-Y. Fixed-drug eruption: A retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012 Mar;30(1):11-5.

13. Shiohara T, Mizukawa Y. Fixed drug eruption: a disease mediated by self-inflicted responses of intraepidermal T cells. Eur J Dermatol. 2007 May-Jun;17(3):201-8. [PubMed]

14. Brahimi N, Routier E, Raison-Peyron N, Tronquoy AF, Pouget-Jasson C, Amarger S, et al. A three-year-analysis of fixed drug eruptions in hospital settings in France. Eur J Dermatol. 2010 Jul-Aug;20(4):461-4. [PubMed]

15. Andrade P, Brinca A, Goncalo M. Patch testing in fixed drug eruptions--a 20-year review. Contact Dermatitis. 2011 Oct;65(4):195-201. [PubMed]

16. Gruber F, Stasic A, Lenkovic M, Brajac I. Postcoital fixed drug eruption in a man sensitive to trimethoprim-sulphamethoxazole. Clin Exp Dermatol. 1997 May;22(3):144-5. [PubMed]

17. Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008 Jun;158(6):1230-8. [PubMed]

18. Kasemsarn P, Kulthanan K, Tuchinda P, Dhana N, Jongjarearnprasert K. Cutaneous reactions to non-steroidal anti-inflammatory drugs. J Drugs Dermatol. 2011 Oct;10(10):1160-7. [PubMed]

19. Gendernalik SB, Galeckas KJ. Fixed drug eruptions: a case report and review of the literature. Cutis. 2009 Oct;84(4):215-9. [PubMed]

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