A 23-year-old African American woman presents for a rash that has recurred on her arms for the last 2 years. The rash is not pruritic or painful. Initially, the rash was very red and became darker with time. The patient states that the rash occurs in the same spot every time. She is otherwise healthy. Her medications include an occasional ibuprofen for menstrual pain and a daily multivitamin. She has tried over-the-counter hydrocortisone with minimal improvement of the lesions.
A 19-year-old African American male presents with a 7-month history of a severely pruritic rash on his legs and arms. He is otherwise healthy and takes a daily multivitamin. He admits to taking long hot showers daily. He uses no moisturizer and washes with a deodorant soap. He has not tried any topical medications for the rash. He is currently taking diphenhydramine as needed for the pruritus, but it is not helping.
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Fixed drug eruption is a common cause of inflammatory skin pathology. Cutaneous reactions are the most common form of adverse drug reaction.
Fixed drug eruptions are one of the most common types of cutaneous drug eruption, along with morbilliform (maculopapular) drug reactions and urticaria/angioedema.1-4 Fixed drug eruptions are localized cutaneous responses to an offending medication. The adjective “fixed” indicates that the same cutaneous reaction occurs in the same location if the causative agent is ingested again.5
Fixed drug eruptions typically present as well-defined, circular or oval-shaped violaceous plaques with hyperpigmentation and edema. The lesion may be solitary or few in number, and they may be pruritic, burning, or painful; however, systemic complications are rare.2,5-7 Vesicles or bullae may form in an annular pattern, with potential for erosion or blistering in the middle of the lesion.6 The lesions are transient, fading over a few days to weeks, with residual hyperpigmentation indicative of the affected site that may last weeks to months.8 The original lesion or lesions may not leave residual hyperpigmentation, although this is less common.2,5,9 Although the lesions may occur in any location, common sites include the genitalia (especially the glans penis in males), dorsal area of the hands, feet, lips, perioral area of the face, and trunk.5,6,8
These localized skin reactions tend to occur 1 to 2 weeks after exposure to the drug, but subsequent reactions occur more rapidly, typically within a few hours or at least within 24 hours of exposure.2,5,10 Frequent causative agents of fixed drug eruption include sulfonamides (including trimethoprim-sulfamethoxazole), nonsteroidal anti-inflammatory drugs, salicylates, barbiturates, tetracyclines, oral contraceptives, quinine, and carbamazepine.5,6 Severe adverse drug reactions may be fatal or life threatening, especially in pediatric populations who have age-related differences in hepatic drug metabolism.11
The pathophysiology of fixed drug eruption is not well described, but it is thought that fixed drug eruption results from activated intraepidermal CD8+ T cells that elicit a stronger and more rapid response to re-exposure with the same drug, resulting in tissue damage in the lower portions of the epidermis involving keratinocytes and melanocytes.5,12
Histologically, fixed drug eruption may have a variety of presentations but is often characterized by vacuolar interface dermatitis at the dermoepidermal junction, with necrotic keratinocytes and eosinophilic and neutrophilic infiltrates. Lymphocytic infiltrate may be in the upper dermis.3,5 Damage to the basal cells of the epidermis and melanocytes results in melanin leaking into the papillary dermis, where pigment may be engulfed by macrophages.5 In chronic recurrent fixed drug eruption at the same site, significant fibrotic changes may be seen in the papillary dermis and dermal melanophages.3
Clinical diagnosis of fixed drug eruption is often missed because both physicians and patients may not recognize the localized skin reaction as a typical drug reaction pattern. Fixed drug eruption can usually be distinguished by history and physical examination, but punch biopsy or medication rechallenge can be useful tools when the diagnosis is uncertain.5 In a patient taking multiple medications, confirmation of the causative agent is accomplished by administering drugs individually to see which reproduces a reaction within a few hours at the same site.13 According to a recent study, patch testing may have diagnostic utility in cases of suspected fixed drug eruption caused by contrast medium or antiepileptic medications.14
The differential diagnosis of fixed drug eruption is extensive and includes recurrent herpes simplex infection, tinea infections, nummular eczema, post-inflammatory hyperpigmentation, acute urticaria, arthropod bite infections, pityriasis rosea, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and phytophotodermatitis, among others.
Recurrent herpes simplex infection, particularly in the genital region, can be differentiated from fixed drug eruption through skin biopsy detecting herpes simplex virus DNA by means of polymerase chain reaction.15,16 Clinically, herpes simplex virus has grouped vesicles on an erythematous base, with more pain than pruritus.5 Histologically, herpes simplex virus involves margination of nuclear chromatin, multinuclear giant cells, ballooning degeneration, and nuclear viral inclusions, none of which are present in fixed drug eruption.5
Tinea infections present as annular lesions, usually with multiple erythematous scaly papules or plaques that may increase in size and spread centrifugally. Furthermore, the typical distribution differs from that of fixed drug eruption, involving the trunk and extremities but excluding the groin, palms and soles, and nails.6
Nummular eczema may be differentiated from fixed drug eruption by typical location. Fixed drug eruption lesions are common on the hands, feet, genitalia, lips, and face, and nummular eczema lesions are more common on extensor surface, although location varies by age.1 Lesions of nummular eczema involve intense pruritus and are chronic, relapsing lesions, whereas lesions in fixed drug eruption may not be pruritic and may fade over a few days to weeks, resulting in hyperpigmentation in the area of the lesion.6
Postinflammatory hyperpigmentation may mimic residual hyperpigmentation following the initial lesion in fixed drug eruption but can be differentiated based on an associated prior inflammatory skin infection such as acne vulgaris, atopic dermatitis, or impetigo.17
Acute urticaria from drug exposure develops rapidly and lesions resolve within 1 day; however, lesions in fixed drug eruption may last for a few days and ultimately disappear, with subsequent hyperpigmentation.18,19 The lesions in urticaria are raised, erythematous, pruritic wheals and may be diffuse and not well demarcated like those in fixed drug eruption.
Arthropod bite infections may be differentiated from fixed drug eruption by location, as they tend to occur on the extremities and do not resolve with hyperpigmentation.19,20
Pityriasis rosea in initial stages with a herald patch may mimic fixed drug eruption but will be followed by small, salmon-colored raised lesions across the trunk, often in a Christmas-tree type pattern rather than hyperpigmentation.21
Erythema multiforme can also result from drug exposure. However, it presents as a characteristic target lesion with an erythematous center surrounded by a pale inner ring with an additional erythematous outer ring, unlike the sharply demarcated pigmented vesicles or bullae in fixed drug eruption.
Stevens-Johnson syndrome and toxic epidermal necrolysis are extreme forms of erythema multiforme and may be differentiated from fixed drug eruption by the presence of a fever and involvement of the oral mucosa in addition to the conjunctiva and genitourinary regions, with erosions and hemorrhagic crusts that are not present in fixed drug eruption.22
Phytophotodermatitis also involves residual hyperpigmentation, with erythematous and edematous bullae and vesicles similar to those seen in fixed drug eruption, but rather than well-demarcated ring-like lesions, phytophotodermatitis is distributed in streak-like or artificial patterns.5
The treatment of fixed drug eruption begins by identifying and discontinuing the offending drug immediately. If treatment of an underlying condition is still necessary, a different medication should be prescribed. Medium- or high-potency topical steroids may be provided for symptomatic relief in severe cases, and antihistamines may help relieve associated pruritus. For persistent hyperpigmentation, hydroquinone 4% cream may be applied to decrease the pigmented appearance.5
For the patient in our case, biopsy of the lesion was consistent with fixed drug eruption. Ibuprofen was determined to be the likely culprit, and the patient was advised to discontinue that medication. After discontinuing ibuprofen, there was no recurrence of the lesions.
Nummular eczema, also known as nummular dermatitis or discoid eczema, is a common morphologic subtype of eczematous dermatitis.22
The prevalence of nummular eczema has been reported at 2 cases per 1000 people.23 The Greek word eczema means “to boil over” and nummular means “coin shaped,” and both of these words accurately describe the lesions of nummular eczema, which are numerous, well-defined, coin-shaped or discoid, erythematous, oozing, and crusted skin plaques that derive from the confluence of papules and papulovesicles.1,22
If the lesions have a bacterial origin such as Staphylococcus, they are more likely to involve honey-crusted vesicles.24 Scratch marks or excoriations will often be seen in the lesions as a result of the intense pruritus, and the lesions are often lichenified and hyperkeratotic.8,23 The lesions tend to measure one to a few centimeters in diameter.8,25 Nummular eczema has a predilection for extremities, and lesions tend to be located on the lower limbs (thighs and legs) in men and on the forearms and hand dorsa in women. Lesions are not typically seen on the face or scalp.8,24
Patients often have severe pruritus, a chronic relapsing course, and may have a personal or family history of atopic diseases, such as food allergies, asthma, or allergic rhinitis.3 Nummular eczema affects males more frequently than females, and it tends to present in males at an older age (>50 years, rather than <30 years in females). Although atopic dermatitis is prominent in children, nummular eczema is not common at a young age.8,23,25
The etiology of nummular eczema has not been precisely defined, and factors such as nutrition, infection (bacterial colonization), psychiatric/emotional issues, alcohol intake, and dry skin (especially in the elderly) have all been implicated in its pathogenesis.25-27 The course of eczema oscillates, increasing in colder months, likely as a result of increased contact with hot water, soaps, and detergents, and decreasing in summer months.1,27 In older patients, dry skin leads to cracking and fissuring in the stratum corneum, especially in winter months, which in turn leads to worsening pruritus and dryness, which are common features in nummular eczema.25 With an already damaged skin barrier, allergens may enter the skin and exacerbate the eczema.25 In addition to xerosis, nummular dermatitis is also associated with contact dermatitis and venous hypertension.8,25
The diagnosis of eczema is primarily based on history and physical examination alone, as there are no distinct diagnostic modalities for eczema. Early histologic examination will show epidermal spongiosis and dermal edema with lymphocytic infiltrate and microvesicle formation, whereas later histologic examination will show hyperkeratosis, parakeratosis, and progressive acanthosis with a thickened granular layer.22,24 Because contact allergy occurs commonly with nummular eczema, patch testing is recommended in those with persistent or recurrent discoid eczema to distinguish allergen-related causes.26 If the lesions are complicated by bacterial infection, swabs for bacterial culture may be taken, and skin scrapings may be performed with a potassium hydroxide preparation to rule out fungal infection.
The differential diagnosis of nummular eczema includes tinea infections, contact dermatitis, fixed drug eruption, cutaneous T-cell lymphoma, granuloma annulare, pityriasis rosea, secondary syphilis, lichen simplex chronicus, and plaque psoriasis.
Clinically, tinea infections have a central clearing, with a surrounding and advancing red, scaly, elevated border, but not the crusting, scaling, or lack of central clearing seen in nummular eczema.28 Furthermore, patients with tinea infections may not have a history of eczema and may only have 1 or 2 asymptomatic lesions with affected contacts, especially in humid climates.28 Definitive diagnosis of tinea may be distinguished by skin scrapings with potassium hydroxide preparation demonstrating dermatophytes.
Nummular eczema may be distinguished from contact dermatitis by the characteristic coin-shaped morphology in nummular eczema, although this is often associated with contact dermatitis. Patch testing may be useful in persistent cases to rule out contact allergy.26
The annular lesions of fixed drug eruption appear similar to those of nummular eczema, with central vesicles or bullae, but they tend to occur more often on the hands and feet, genitalia, and lips and face. Lesions in fixed drug eruption are not always pruritic and are more transient than the chronic relapsing lesions of nummular eczema, as fixed drug eruption may fade over a few days, resulting in hyperpigmentation in the area of the lesion.6
In cutaneous T-cell lymphoma, neoplastic T cells cause erythematous scaling, but cutaneous T-cell lymphoma may be differentiated by specific biomarkers or biopsy, depending on the stage of disease. The lesions of cutaneous T-cell lymphoma do not follow developmental boundaries and have a predilection for the bathing trunk region, unlike the extremities, as in nummular eczema.29
Granuloma annulare involves erythematous or flesh-colored papules that are not scaly, but there are no associated vesicles or scaling involved as there is in nummular eczema.6
In its early stages with a herald patch, pityriasis rosea may mimic and be indistinguishable from nummular eczema, but a few days to weeks later, pityriasis rosea will present with small salmon-colored raised lesions across the trunk, often in a Christmas-tree pattern.21 If similar lesions occur on the palms and soles, it is important to rule out secondary syphilis with rapid plasma reagin or Venereal Disease Research Laboratory (VDRL) testing.
Lichen simplex chronicus results from lichenification caused by repetitive scratching and itching and is more common in patients with anxiety or obsessive-compulsive disorders. Lesions of lichen simplex chronicus may appear anywhere but are more commonly seen on the head and neck in women and on the perineum and scrotum in men, as opposed to the extremities in nummular eczema.8
Plaque psoriasis presents with a larger, thick, and silvery scale that is not present in nummular eczema. Plaque psoriasis is typically found on the extensor surfaces of the knees and elbows, often with additional involvement on the scalp and positive Koebner phenomenon, whereas nummular eczema tends to be seen on the extremities and does not exhibit Koebner phenomenon.8
Topical corticosteroids, such as hydrocortisone cream 1%, are the initial treatment for nummular eczema, and more potent steroids may be used in refractory cases.27 Antihistamines may provide symptomatic relief of pruritus.27 Furthermore, emollients like petrolatum help maintain skin moisture, thereby helping prevent excessive dryness and pruritus. In severe cases, topical immunomodulators, such as tacrolimus and pimecrolimus, may be used. Phototherapy may also be used to clear the lesions.8 Recent studies have demonstrated that methotrexate may be used to treat pediatric nummular eczema without significant adverse effects in eczema that is refractory to conventional treatment.30,31
For the patient in our case, biopsy of the lesions was consistent with nummular eczema. Treatment with a topical clobetasol ointment applied twice daily to the lesions was initiated. The patient was advised to use a gentle cleanser, shorten his showers to less than 10 minutes, and use moisturizer several times a day. After a few weeks of this regimen, the patient had dramatic clearance of many of the lesions.
Sachin Allahabadi is a medical student and Rana Mays, MD, is a dermatology resident at Baylor College of Medicine in Houston.
- Pugliarello S, Cozzi A, Gisondi P, Girolomoni G. Phenotypes of atopic dermatitis. J Dtsch Dermatol Ges. 2011;9(1):12-20.
- Farshchian M, Ansar A, Zamanian A, Rahmatpour-Rokni G, Kimyai-Asadi A, Farshchian M. Drug-induced skin reactions: a 2-year study. Clin Cosmet Investig Dermatol. 2015;8:53-56.
- Weyers W, Metze D. Histopathology of drug eruptions—general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept. 2011;1(1):33-47.
- Akpinar F, Dervis E. Drug eruptions: an 8-year study including 106 inpatients at a dermatology clinic in Turkey. Indian J Dermatol. 2012;57(3):194-198.
- Flowers H, Brodell R, Brents M, Wyatt JP. Fixed drug eruptions: presentation, diagnosis, and management. South Med J. 2014;107(11):724-727.
- Alarkhia M. Annular papules: making the right diagnosis. UWOMJ. 2008;77(1):34-36.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37(11):833-838.
- Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. Philadelphia, PA: Mosby; 2003.
- Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol. 2000;1(5):277-285.
- Gaiser CA. Sabatino D. Fluconazole-induced fixed drug eruption. J Clin Aesthet Dermatol. 2013;6(3):44-45.
- Dilek N, Özkol HU, Akbaş A, et al. Cutaneous drug reactions in children: a multicentric study. Postepy Dermatol Allergol. 2014;31(6):368-371.
- Shiohara T, Mizukawa Y, Teraki Y. Pathophysiology of fixed drug eruption: the role of skin-resident T cells. Curr Opin Allergy Clin Immunol. 2002;2(4):317-323.
- Ashton R, Leppard B. Differential Diagnosis in Dermatology. 3rd ed. London, UK: Radcliffe Publishing; 2005.
- Ohtoshi S, Kitami Y, Sueki H, Nakada T. Utility of patch testing for patients with drug eruption. Clin Exp Dermatol. 2014;39(3):279-283.
- Gürkan A, Sarikaya E, Oğuz O, Demirkesen C, Yilmaz G, Midilli K. The overlap of fixed drug eruption and human herpes virus type II associated erythema multiforme. J Turk Acad Dermatol. 2007;1(1):3.
- Sonnex C. Sorting out genital ulceration. Trends in Urology Gynaecology & Sexual Health. 2007;12(1)25-29.
- Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20-31.
- Lee A, Thomson J. Drug-induced skin reactions. In: Lee A, ed. Adverse Drug Reactions. 2nd ed. London, UK: Pharmaceutial Press; 2005.
- Burkhart CN, Morrell DS, Goldsmith LA, et al., eds. VisualDx: Essential Pediatric Dermatology. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
- Juckett G. Arthropod bites. Am Fam Physician. 2013;88(12):841-847.
- Stulberg DL, Wolfrey J. Pityriasis rosea. Am Fam Physician. 2004;69(1):87-91.
- Lazar AJF, Murphy GF. The skin. In: Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier Saunders; 2010:1165-1204.
- Burgin S. Nummular eczema, lichen simplex chronicus, and prurigo nodularis. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw Medical; 2012.
- [[Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier Saunders; 2010:1165-1204.]] Nummular Eczema. Google eBook, 2013.
- Bobonich M, Nolen M. Dermatology for Advanced Practice Clinicians. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.
- Bonamonte D, Foti C, Vestita M, Ranieri LD, Angelini G. Nummular eczema and contact allergy: a retrospective study. Dermatitis. 2012;23(4):153-157.
- Halberg M. Nummular eczema. J Emerg Med. 2012;43(5):e327-e328.
- Noble SL, Forbes RC, Stamm PL. Diagnosis and management of common tinea infections. Am Fam Physician. 1998;58(1):163-174.
- Wong HK. Novel biomarkers, dysregulated epigenetics, and therapy in cutaneous T-cell lymphoma. Discov Med. 2013;16(87):71-78.
- Roberts H, Orchard D. Methotrexate is a safe and effective treatment for paediatric discoid (nummular) eczema: a case series of 25 children. Australas J Dermatol. 2010;51(2):128-130.
- Deo M, Yung A, Hill S, Rademaker M. Methotrexate for treatment of atopic dermatitis in children and adolescents. Int J Dermatol. 2014;53(8):1037-1041.