Background

These lesions characteristically occur as round to oval, dusky erythematous macules which are occasionally painful, develop hours after administration of the offending drug. It characteristically recurs at the same site with each subsequent exposure. Bullous changes may occur. If the drug is discontinued, a hyperpigmented macule is left though occasionally, non-pigmented lesions may be seen. The distribution of some of the lesions may be dependent upon the drug. For example, tetracycline usually produces lesions on the penis while pyrazolones mainly affect the lips and mucosa.

Numerous drugs have been implicated but the vast majority are antibiotics. Of these, sulfonamides are the chief offenders. Other important and common drugs include acetaminophen and NSAIDs.

The histopathology is a lichenoid dermatitis. Unlike erythema multiforme, the accompanying inflammatory cell infiltrate is a superficial and deep perivascular infiltrate. There are also neutrophils and melanophages, indicative of repeat injury at the dermoepidermal junction. However, occasionally, early lesions may show epidermal spongiosis, dermal edema, neutrophilic microabscesses, and dermal eosinophils.

The drug acts as a hapten, a foreign antigen, that binds to the keratinocytes and melanocytes. This stimulates cytotoxic T lymphocytes which attack these altered cells. Altered keratinocytes may express ICAM-1 which promotes adherence with suppressor T lymphocytes, which preserves the memory of the reaction. Genetic susceptibility may be present in HLA-B22 patients.

OUTLINE

Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS	CHARACTERIZATION
Drugs causing fixed eruptions: a study of 450 cases. Mahboob A, Haroon TS. Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore, Pakistan..	Int J Dermatol 1998 Nov;37(11):833-8 Abstract quote BACKGROUND: Drug eruptions are among the most common cutaneous disorders encountered by the dermatologist. Some drug eruptions, although trivial, may cause cosmetic embarrassment and fixed drug eruption (FDE) is one of them. The diagnostic hallmark is its recurrence at previously affected sites. OBJECTIVE: We evaluated 450 FDE patients to determine the causative drugs. RESULTS: The ratio of men to women was 1:1.1. The main presentation of FDE was circular hyperpigmented lesion. Less commonly FDE presented as: nonpigmenting erythema, urticaria, dermatitis, periorbital or generalized hypermelanosis. Occasionally FDE mimicked lichen planus, erythema multiforme, Stevens-Johnson syndrome, paronychia, cheilitis, psoriasis, housewife's dermatitis, melasma, lichen planus actinicus, discoid lupus erythematosus, erythema annulare centrifugum, pemphigus vulgaris, chilblains, pityriasis rosea and vulval or perianal hypermelanosis. Cotrimoxazole was the most common cause of FDE. Other drugs incriminated were tetracycline, metamizole, phenylbutazone, paracetamol, acetylsalicylic acid, mefenamic acid, metronidazole, tinidazole, chlormezanone, amoxycillin, ampicillin, erythromycin, belladonna, griseofulvin, phenobarbitone, diclofenac sodium, indomethacin, ibuprofen, diflunisal, pyrantel pamoate, clindamycin, allopurinol, orphenadrine, and albendazole. CONCLUSIONS: Cotrimoxazole was the most common cause of FDE, whereas FDE with diclofenac sodium, pyrantel pamoate, clindamycin, and albendazole were reported for the first time. FDE may have multiform presentations.
Fixed drug eruption induced by trimethoprim-sulfamethoxazole: Evidence for a link to HLA-A30 B13 Cw6 haplotype Esen Özkaya-Bayazit, MD Uur Akar, MD Istanbul, Turkey	J Am Acad Dermatol 2001;45:712-7 Abstract quote Background: Recent reports indicated a significant association between fixed drug eruption (FDE) and HLA class I antigens. A strong correlation was found between B22 antigen and feprazone-induced FDE. Objective: Our aim was to investigate the association between HLA class I antigens and FDE in Turkey, a country where feprazone is not on the market and trimethoprim-sulfamethoxazole is most often the offending drug. Methods: HLA class I typing was performed by lymphocytotoxicity assay in 67 unrelated patients with FDE, all established by oral provocation. The frequencies are compared with those of 2378 control subjects. Results: Significantly higher (P < .001) frequencies of the A30 antigen and A30 B13 Cw6 haplotype were found in 42 patients with FDE induced by trimethoprim-sulfamethoxazole. HLA-B55 (split of B22) was present exclusively in trimethoprim-sulfamethoxazole-induced FDE, and in higher frequency than in control subjects. Conclusion: To our knowledge, ours is the first report indicating a link between A30 B13 Cw6 haplotype and trimethoprim-sulfamethoxazole-induced FDE. In addition, HLA-B22 was increased in patients with FDE caused by a drug other than feprazone.

 

PATHOGENESIS	CHARACTERIZATION
HLA
Genetic susceptibility to fixed drug eruption: evidence for a link with HLA-B22. Pellicano R, Ciavarella G, Lomuto M, Di Giorgio G. Department of Dermatology, IRCCS, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.	Am Acad Dermatol 1994 Jan;30(1):52-4 Abstract quote BACKGROUND: Our observation of familial cases of fixed drug eruption (FDE) prompted us to consider a genetic predisposition to this disease. OBJECTIVE: Our purpose was to determine whether there is any association between FDE and any of the major histocompatibility complex class I or II alleles. METHODS: HLA class I and II typing was performed by lymphocytotoxicity assay in 36 unrelated patients with FDE. RESULTS: Significantly higher (p < 0.0001) frequencies of the B22 and Cw1 antigens were found in the 36 patients with FDE. CONCLUSION: Our data are the first to suggest a genetic predisposition to FDE.
Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. Ozkaya-Bayazit E, Akar U. Department of Dermatology, Istanbul Medical Faculty, Istanbul University, 34750 Istanbul, Turkey.	J Am Acad Dermatol 2001 Nov;45(5):712-7 Abstract quote BACKGROUND: Recent reports indicated a significant association between fixed drug eruption (FDE) and HLA class I antigens. A strong correlation was found between B22 antigen and feprazone-induced FDE. OBJECTIVE: Our aim was to investigate the association between HLA class I antigens and FDE in Turkey, a country where feprazone is not on the market and trimethoprim-sulfamethoxazole is most often the offending drug. METHODS: HLA class I typing was performed by lymphocytotoxicity assay in 67 unrelated patients with FDE, all established by oral provocation. The frequencies are compared with those of 2378 control subjects. RESULTS: Significantly higher (P <.001) frequencies of the A30 antigen and A30 B13 Cw6 haplotype were found in 42 patients with FDE induced by trimethoprim-sulfamethoxazole. HLA-B55 (split of B22) was present exclusively in trimethoprim-sulfamethoxazole-induced FDE, and in higher frequency than in control subjects. CONCLUSION: To our knowledge, ours is the first report indicating a link between A30 B13 Cw6 haplotype and trimethoprim-sulfamethoxazole-induced FDE. In addition, HLA-B22 was increased in patients with FDE caused by a drug other than feprazone.

 

LABORATORY/RADIOLOGY	CHARACTERIZATION
TOPICAL PROVOCATION
Topical provocation of fixed drug eruption. A study of 30 patients. Alanko K. Department of Dermatology, Helsinki University Central Hospital, Finland.	Contact Dermatitis 1994 Jul;31(1):25-7 Abstract quote Topical provocation with the causative agent was performed in 30 patients with fixed drug eruption (FDE). The epicutaneous open test method was used on inactive sites of old FDE lesions. Drugs at 10% in the vehicles petrolatum, alcohol and dimethylsulfoxide (DMSO) were used as test preparations. Positive reactions were always seen with phenazone salicylate (16 patients) and carbamazepine patients (3 patients), and in an individual case from chlormezanone. Both positive and negative reactions were seen with trimethoprim (3 and 2, respectively), doxycycline (2 and 1) and sulfadiazine (1 and 1). Control tests on unaffected skin with drug preparations and pure vehicles remained negative. The present results confirm our previous observation that topical provocation is a reliable test method in FDE caused by phenazone salicylate. The present study also shows that topical provocation may be useful in FDE caused by carbamazepine. In FDE caused by trimethoprim, doxycycline and sulfonamides, a positive, but not a negative, skin reaction is informative.

 

CLINICAL VARIANTS	CHARACTERIZATION
LIPS
Specific site involvement in fixed drug eruption. Ozkaya-Bayazit E. Department of Dermatology, Istanbul Medical Faculty, Istanbul University, 34390 Capa, Istanbul, Turkey.	J Am Acad Dermatol. 2003 Dec;49(6):1003-7. Abstract quote   A total of 105 patients with established fixed drug eruption (FDE) by oral provocation were evaluated with regard to a drug-related site involvement. Cotrimoxazole was the leading causative agent (63.8%), followed by naproxen sodium (23.8%), dipyrone (5.7%), oxicams (4.8%) and other rare causes (1.9%). Cotrimoxazole most frequently induced lesions on genital mucosa; naproxen and oxicams on lips; and dipyrone on trunk and extremities. Isolated FDE on male genitalia (n = 16) was exclusively because of cotrimoxazole. A highly significant association could be established between naproxen and FDE on lips (chi-square = 28.3; corrected P =.000002). As this study represents the largest series of patients with naproxen-induced FDE, we would suggest that naproxen should be considered as an important potential cause of FDE on lips.
PEDIATRIC
Fixed drug eruptions in children. Morelli JG, Tay YK, Rogers M, Halbert A, Krafchik B, Weston WL. Department of Dermatology, University of Colorado School of Medicine, Denver, Colorado 80262, USA.	Pediatr 1999 Mar;134(3):365-7 Abstract quote To determine the anatomic location and offending drug in fixed drug eruptions (FDE) in children, we performed a 5-year retrospective analysis. Thirty-five children with FDE were evaluated. The most common cause of FDE was the combination drug trimethoprim-sulfamethoxazole.
PENIS
Fixed drug eruptions on male genitalia: clinical and etiologic study. Pandhi RK, Kumar AS, Satish DA, Bhutani LK.	Sex Transm Dis 1984 Jul-Sep;11(3):164-6 Abstract quote Fixed drug eruptions exclusively involving the genitalia of 60 male patients were investigated. Forty-two of the 60 patients completed tests designed to identify the causative drug. Tetracycline, aspirin, metamizole, and trimethoprim-sulfamethoxazole were found to be common etiologic agents. The sites affected were the glans penis, coronal sulcus, and preputial skin. Superficial ulceration or pigmented areas surrounded by an erythematous halo were the main clinical findings at the time of presentation.

Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

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