Vulvar Fixed Drug Eruption

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If the drug is ceased, the rash resolves over the next 2–3 weeks but it is also characteristic for postinflammatory hyperpigmentation to occur. With repeated ...
The Journal of Reproductive Medicine®

f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D Vulvar Fixed Drug Eruption A Report of 13 Cases

Gayle Fischer, M.B.B.S., F.A.C.D.

The fixed drug eruption (FDE) is an uncommon adverse drug reaction which characteristically presents as a well-demarcated, round or ovoid, erythematous plaque that occurs CASES: at the same site each time the offending drug is Genital FDE should be considered taken.1,2 The eruption with any acute or recurrent may be vesicular or bulCONCLUSION: lous. The rash appears vulvitis.... within minutes to 3 days of ingestion and is often heralded by itching and burning. If the drug is ceased, the rash resolves over (J Reprod Med 2006;51:0000–0000) the next 2–3 weeks but it is also characteristic for postinflammatory hyperpigmentation to occur. Keywords: vulvar diseases, drug eruptions, fixed With repeated ingestion, more and more lesions drug eruptions. may appear, so eventually multiple hyperpigmented macules are seen on the skin surface. Classic, acute FDE has characteristic and diagnostic histopathology similar to that of erythema multiforme, showing basal cell degeneration with pigmentary incontinence, evidenced by dermal melanophages.1 The list of drugs that cause FDE is very long, although certain groups, such as nonsteroidal antiinflammatory drugs, paracetamol and the antibiotic cotrimoxazole, do so more frequently than others.3 The “nonpigmenting FDE” described by Shelley BACKGROUND:

From the Department of Dermatology, Royal North Shore Hospital, St Leonard’s, Sydney, Australia.

Presented at the World Congress of the International Society for the Study of Vulvar Disease, Queenstown, New Zealand, February 2006. Address correspondence to: Gayle Fischer, M.B.B.S., F.A.C.D., Suite 9/60, Cecil Avenue, Castle Hill, NSW 2154, Australia ([email protected]). Financial Disclosure: The author has no connection to any companies or products mentioned in this article.

0024-7758/06/5100-0000/$15.00/0 © Journal of Reproductive Medicine®, Inc. The Journal of Reproductive Medicine®

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f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D Although FDE is well known to affect genital skin, the majority of reports in the literature focus on the male.8-11 It is accepted that genital FDE is of the nonpigmenting variety. Case Reports

Figure 1

Case 00. Typical nongenital, nonpigmenting FDE.

and Shelley in 19874 differs from classical FDE in that it is bilaterally symmetric, lacking postinflammatory hyperpigmentation and characteristic histopathologic features (Figure 1). The epidermis is typically normal, and the only abnormality is mild dermal edema with a mixed perivascular infiltrate. Shelley and Shelley hypothesized that the site of drug hypersensitivity in this type of FDE was dermal rather than epidermal. It has since become clear that nonpigmenting FDE may be asymmetric.5-7

Thirteen women aged 15–84 were seen over a 5year period from 2000 to 2005 with vulvitis related to drug ingestion (Table I). Two women, aged 34 and 54, presented with acute recurrent vulvitis related to ingestion of ibuprofen. Four women aged 15–84 presented with an acute episode from diverse medications, including ibuprofen, rofecoxib, cotrimoxazole and gliclazide. Seven women, aged 58–77, presented with chronic erosive vulvitis, nonspecific on biopsy and unresponsive to all therapeutic measures. Three of these patients’ vulvitis resolved when the HMG Co-A reductase inhibitors they were taking were ceased. Two others resolved when COX-2 inhibitors were ceased. One patient recovered when anastrozole was ceased and 1 when she ceased regularly using pseudoephedrine for hay fever. Five patients reacted to more than 1 drug, 3 to a related drug and 2 to an unrelated drug. All patients had in common bilaterally symmetric vulvitis, often extending to the inguinal crease, and in 9 of 13 cases, associated with erosive mucositis. In no case was biopsy typical of a classic fixed

Table I Case no.

Age (yr)

Reaction type

Drug(s) implicated

Clinically suspected

Cross-reaction, related drug

Cross-reaction, unrelated drug

1

15

A

Ibuprofen

No

No

No

2 3 4 5

34 35 46 54

AR C A AR

No No Yes No

No No No Yes

No No No No

6

58

C

Ibuprofen Pseudoephedrine Gliclazide Ibuprofen, aspirin, salicylates Celecoxib

No

No

No

7 8 9 10 11 12

63 65 69 72 73 77

C A C C C C

No No No No No No

Simvastatin No No No No Yes

No No Tamoxifen No No Yes

13

84

A

Atorvastatin Rofecoxib Anastrozole Simvastatin Rofecoxib Atorvastatin, telmisartan, aspirin, irbesartan Cotrimoxazole, hydrochlorthiazide, amiloride

No

Yes

No

A = acute, AR = acute recurrent, C = chronic.

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f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D drug eruption. All patients were tested for Candida albicans infection and those with acute erosions for herpes simplex. All but 1 were negative, and 1 patient positive for C albicans did not respond to antifungal treatment. No patient responded to any therapeutic measure other than cessation of the offending medication; that resulted in an improvement within 2 weeks. Of the 13 patients, only 1 with an acute reaction to gliclazide suspected that there was a connection between the drug and reaction. In no other case was it suspected by patients or their physicians. Discussion

The classic cutaneous pattern of FDE, characterized by asymmetric, erythematous patches that progressively turn brown, differs significantly from the typical vulvar FDE.1,2 The latter has much more in common with the nonpigmenting variant of FDE in that it is bilaterally symmetric, does not undergo color change or exhibit postinflammatory hyperpigmentation or have characteristic histopathology.4 In the male, the typical genital FDE is an itchy, erythematous plaque that may become bullous, edematous or eroded. The most common site is the glans, but the penile shaft and scrotum may also be affected.8 Previous studies attempted to relate specific site

Figure 2

Positive challenge performed

Case 00. Acute, eczematous, genital FDE.

Clinical appearance

Biopsy

Bacteriology

No

Herpes Candida negative

Yes Yes Yes Yes

Ulceration, erosive mucositis, edema Erosive vulvitis, nonvulvar lesions Erosive vulvitis Erosive vulvitis Erosive vulvitis, dusky

No Spongiosis No Superficial dermal inflammation

Herpes Candida negative Herpes Candida negative Candida negative Candida negative

No

Nonspecific dermatitis

No

No No Yes Yes No Yes

Erosive vulvitis Acute, nonspecific vulvitis Erosive vulvitis Nonspecific vulvitis Nonspecific vulvitis, dusky Erosive vulvitis, skin lesions

No

Erosive vulvitis

No No Nonspecific dermal inflammation Spongiosis, perivascular inflammation Spongiosis, perivascular inflammation Spongiosis, eosinophil, perivascular inflammation No

C albicans (no response to treatment) Candida negative Candida negative Candida negative Candida negative Candida negative Candida negative

No

Candida negative

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f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D Figure 3

Case 00. Acute, erosive, genital FDE.

involvement to certain drugs, and these papers have nominated cotrimoxazole and tetracycline as the most common cause of genital FDE. However, those cases involved males.11 In this series, case 13 did react to cotrimoxazole and also to a related drug, hydrochlorthiazide. Case 4 reacted to gliclazide, a hypoglycemic agent related to sulfa drugs. In this series, the most common clinical presentation was bilaterally symmetric erythematous vulvitis involving the labia minora and majora and perineum and extending in some cases to the inner thighs and perianal area (Figures 2–4). In 9 of 13 patients there was also erosive mucositis (Figure 5) that progressed to frank ulceration, healing with scarring in 1 patient. The incidence of vulvar FDE is unknown, but it probably is very uncommon. Previous series of genital FDE have focused almost completely on the male. The list of drugs that have been reported to cause genital fixed eruption is long and diverse, including antibiotics, analgesics and antihistamines. It is important to understand that it is not only prescription drugs that may cause pigmented and nonpigmented FDE, as patients may not mention them when asked for a drug history. In this study, some of the patients’ reactions were caused by over-thecounter analgesics and decongestants.3,4,7,12-14 The most common drugs implicated in this series are ibuprofen (3 cases), COX-2 inhibitors (3 cases) and HMG-CoA reductase inhibitors (3 cases). Nonste-

roidal inflammatory drugs are well known to cause fixed drug eruption,3,15 and celecoxib has been implicated.16 FDE from atorvastatin and simvastatin has not been previously reported; these cases were site specific to the vulvar area. The pathogenesis of FDE and why it recurs on localized areas are unknown. It is possible to reproduce the eruption by patch testing on lesional, but not nonlesional, skin, indicating a delayed type of hypersensitivity occurring in specific areas.17 One previous study of genital FDE in male children reported a positive migration inhibiting factor assay in 91.6% of subjects.9 This test is also thought to correlate with cell-mediated immunity. FDE in an individual patient may be the result of ingestion of only 1 medication, but cross-reactivity with related drugs is well described.18 This was seen in cases 5, 7, 12 and 13. Less common but also observed are patients who exhibit FDE from multiple, unrelated drugs.19,20 This was seen in cases 9 and 12. Two patients, cases 2 and 12, had concurrent cutaneous as well as vulvar lesions.

Figure 4

Case 00. Chronic FDE.

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f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D sponse, and sudden improvement within 2–3 weeks of stopping a drug is an acceptable and kinder way to make the diagnosis. Genital FDE should be considered with any acute or recurrent vulvitis, particularly, but not necessarily, when there is an erosive element, nonspecific biopsy, negative bacteriology and resistance to treatment. A drug history is essential in any case of refractory vulvitis. References

1. Commens C: Fixed drug eruption. Australas J Dermatol 1983;24:1–8

Figure 5

Case 00. Erosive mucositis in chronic FDE.

2. Korkij W, Keyoumars S: Fixed drug eruption: A brief review. Arch Dermatol 1984;120:520–524

3. Mahboob A, Haron TS: Drugs causing fixed eruptions: A study of 450 cases. Int J Dermatol 1998;37:833–838

The differential diagnosis of chronic vulvar FDE includes any cause of chronic or erosive vulvitis, including lichen planus, desquamative inflammatory vulvovaginitis, contact dermatitis, psoriasis and chronic vulvovaginal candidiasis. In acute FDE, the clinical history, recurrence on rechallenge and resolution after stopping the offending drug are all that is needed to make the diagnosis. However, chronic vulvar FDE is a much more challenging condition. Patients are commonly over 60; on complex drug regimens; may have other, concurrent vulvar skin conditions, such as lichen sclerous; and may be taking over-the-counter medications that they have not mentioned to their physicians. Patients and their physicians rarely make the connection between vulvitis and drug ingestion. The rarity of the condition, its nonspecific histopathology and its dissimilarity to classic FDE make it unlikely that it will be readily diagnosed. It is necessary in such patients to systematically stop all medications 1 by 1; that may take many weeks. Although various attempts have been made to confirm the diagnosis by in vitro and patch testing, the gold standard is resolution once the drug is stopped and, if the patient is willing, recurrence on rechallenge.17 Genital FDE is an uncommon and frequently confusing event. The eruption itself is uncomfortable, often painful and frustrating but readily resolves when the drug is ceased. It is not serious, and its very nature is that it does not generalize, making rechallenge a realistic option. However, patients with chronic FDE have usually been subjected to every possible therapeutic intervention without re-

4. Shelley WB, Shelley ED: Non-pigmenting fixed drug eruption as a distinctive reaction pattern: Examples caused by sensitivity to pseudoephedrine hydrocholoride tetrahydrozoline. J Am Acad Dermatol 1987;17:403–407

5. Matsumoto K, Mikoshiba H, Saida T: Nonpigmenting solitary fixed drug eruption caused by a Chinese traditional herbal medicine, ma huang (Ephedra Hebra), mainly containing pseudoephedrine and ephedrine. J Am Acad Dermatol 2003;48:628–630 6. Krivda SJ, Bensone PM: Nonpigmenting fixed drug eruption. J Am Acad Dermatol 1994;31:291–292

7. Hindioglu U, Sahin S: Nonpigmenting solitary fixed drug eruption caused pseuoephedrine hydrochloride. J Am Acad Dermatol 1998;38:499–500 8. Sehgal VH, Gangwani OP: Genital fixed drug eruption. Genitourin Med 1986;62:57–58 9. Nussinovitch M, Prais D, Ben-Amitai D, et al: Fixed drug eruption in the genital area in 15 boys. Pediatr Dermatol 2002;19:216–219

10. Gaffoor PMA, George WM: Fixed drug eruptions occurring on the male genitals. Cutis 1990;45:242–244 11. Ozaya-Bayazit E: Specific site involvement in fixed drug eruption. J Am Acad Dermatol 2003;49:1003–1007

12. Vidal C, Prieto A, Perez-Carral C, et al: Nonpigmenting fixed drug eruption due to pseudoephedrine. Ann Allergy Asthma Immunol 1998; 80:309–310 13. Alanko K, Kanerva L, Mohell-Talolahti B, et al: Nonpigmenting fixed drug eruption from pseudoephedrine. J Am Acad Dermatol 1996;35:647–648 14. Hayashi H, Shimizu T, Shimizu H: Multiple fixed drug eruption caused by acetaminophen. Clin Exp Dermatol 2003;28: 455–456

15. Gonzalo MA, Alvarado MI, Fernandez L, et al: Fixed drug eruption due to narproxen: Lack of cross sensitivity to other prionic acid derivatives. Br J Dermatol 2001;144:1291–1292 16. Bandyopadhyay D: Celcoxib-induced fixed drug eruption. Clin Exp Dermatol 2003;28:452–453

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f e o t o a r c P i l e p g u a D P T f O e o t N o a r o c P i l D e p g u a P TD f O o N o r o c P i l D e p g u a P TD O N o D 17. Zedlitz S, Lindzbzch L, Kaufman R, et al: Reproducible identification of the causative drug of a fixed drug eruption by oral provocation and lesional patch testing. Contact Dermatitis 2002;46:352–353

19. Ozkaya-Bayazit E: Independent lesions of fixed drug eruption caused by trimethoprim-sulfamethoxazole and tenoxicam in the same patient: A rare case of polysensitivity. J Am Acad Dermatol (suppl 2) 2004;51:S102–S104

18. Correia O, Delgado L, Polonia J: Genital fixed drug eruption: Cross reactivity between doxycycline and minocycline. Clin Exp Dermatol 1999;24:137–138

20. Chan HL, Tan KC: Fixed drug eruption to three anticonvulsant drugs: An unusual case of polysensitivity. J Am Acad Dermatol 1997;36:259