Are You Confident of the Diagnosis?
What you should be alert for in the history
Fixed drug eruption (FDE) is a distinctive drug eruption that is characterized by its unique morphology, namely a round shape. There may be pruritus, burning, or pain at involved sites. Dysuria may be experienced in periurethral cases. Systemic symptoms are rare, but fever and malaise have been reported.
Patients may recall a new drug; antimicrobials, analgesics, anticonvulsants, and sedatives are most commonly involved (for a comprehensive list, see “Etiology” below). New food or recent radiographic contrast media administration may also be factors.
FDE has occasionally been noted to have a predilection for sites of trauma, such as an old Bacillus Calmette-Guérin (BCG) scar. FDE may take days, or up to 2 weeks from initial drug exposure, to manifest. On rechallenge, symptoms and signs develop within minutes to hours.
Characteristic findings on physical examination
Reddish or dusky round macules, or erythematous edematous round plaques, appear on normal or previously involved skin (Figure 1, Figure 2). A more lightly erythematous ring may be seen at the periphery of the eruption. Bullae and erosions (especially in areas of trauma) may result.
Bullae may be prominent, and if so, the designation bullous FDE is given. After resolution of the acute phase, residual hyperpigmentation is characteristically seen. This is a more prominent finding in darker-skinned individuals.
FDE may occasionally be oval. This is usually seen in areas where the skin is more lax. The term “fixed” refers to the fact that sites of prior involvement are affected again on rechallenge with the offending drug. FDE may be single or multiple, and for the most part, more involved sites appear with each drug rechallenge. Occasionally, FDE may be so widespread and bullous as to simulate toxic epidermal necrolysis (TEN).
Mucous membrane involvement is not rare. Genital skin, including the glans penis; lips; and intraoral sites, including the tongue, may be affected.
A nonpigmenting variant of FDE was described in the 1980s. Large tender well-circumscribed edematous and erythematous plaques that may be symmetrical occur after drug ingestion and fade completely within 2 to 3 weeks. Recurrence in the same sites occurs on rechallenge. Other variants, such as linear, urticarial, eczematous, or erythema-dyschromicum-perstans-like fixed drug eruption, have been reported.
A propensity for certain body sites has been reported with different drugs. Glans penis lesions are usually caused by sulphonamides or tetracyclines, while nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen and the oxicams have been noted to cause lip lesions. The reason for this is unclear.
Expected results of diagnostic studies
The diagnosis is usually a clinical one, based on the classical examination findings. In unusual (for example, nonpigmenting) or widespread cases, histopathologic examination will help to clinch the diagnosis.
Histopathologic findings include a vacuolar interface dermatitis with pigment incontinence and melanophages in the dermis. Individual necrotic keratinocytes are also seen in the epidermis. In the dermis, upper dermal edema and a mixed inflammatory infiltrate, often with prominent eosinophils, are seen. The infiltrate occurs in the superficial and mid-dermis. In bullous cases, a subepidermal bulla is seen. In widespread cases, histopathologic examination will help to clinch the diagnosis.
In cases where the offending agent is in doubt, topical or oral provocation tests may be performed . The following differential diagnoses need to be borne in mind:
The early active phase of erythema dyschromicum perstans (EDP), during which gray-to-violaceous, round-to-oval macules have an active red rim at their periphery, may resemble active FDE. EDP is asymptomatic.
Nonpigmenting FDE may resemble the non-annular plaque of Lyme disease, dermal hypersensitivity reaction, Wells’ cellulitis, urticarial vasculitis, Sweet’s syndrome, or the urticarial phase of bullous pemphigoid.
Generalized bullous FDE may resemble TEN. In these cases, a history of previous, more typical, FDE lesions may be helpful. Also, the borders of coalescing FDE plaques or bullae will be round or scalloped, as opposed to those of TEN, which will look irregular and jagged. This clinical feature may narrow the diagnosis.
FDE may resemble other bullous diseases. A case of FDE mimicking localized bullous pemphigoid has been reported.
Very few conditions give rise to plaques that are completely round. Nummular eczema and pityriasis rotunda may need to be considered, depending on the clinical features.
Who is at Risk for Developing this Disease?
Fixed drug eruptions accounted for 3% of ninety-seven cases of drug eruptions seen in hospitalized patients in one study. Most patients with FDE are adults between the ages of 20 and 40 years, but children, and even infants, have been reported to develop it. There is a trend toward male predominance. FDE has been linked to the presence of HLA B-22 and HLA-Cw1.
What is the Cause of the Disease?
The usual culprits are analgesics (acetaminophen, paracetamol, NSAIDs, codeine), antimicrobials (tetracycline family, sulfamethoxazole/trimethoprim, penicillins, rifampin, fluoroquinolones, metronidazole, the imidazoles, terbinafine), anticonvulsants (phenytoin, barbiturates, carbamazepine), and sedatives (benzodiazepines).
Cotrimoxazole was the most common cause of FDE in a series of sixty-four cases from Turkey, whereas paracetamol (followed by NSAIDs) was the most common culprit in a series of fifty-nine cases from France. A wide range of other medications, such as phenolphthalein (a laxative), omeprazole, and cyproterone acetate (an anti-androgenic progestogen), have also been reported to cause FDE. These medications have been administered orally, parenterally, or topically.
Cases of genital FDE have occurred secondary to exposure to a drug that the patient’s sexual partner was taking. Foods, such as strawberries, licorice, and cashew nuts are also implicated (the so-called “fixed food eruption”). Food additives (sodium benzoate, tartrazine), iodinated radiographic contrast media, and herbal products have also been implicated.
Paracetamol, piroxicam, pseudoephedrine, cimetidine, and more recently, the multikinase inhibitor sorafenib, have been noted to cause nonpigmenting FDE. Rifampin, paracetamol, metronidazole, paclitaxel, erythromycin, and ibuprofen have all been reported to cause bullous FDE.
It is thought that the inciting agent binds to basal keratinocytes, or occasionally melanocytes, as a hapten. Intercellular adhesion molecule-1 (ICAM1) is released, which upregulates CD8+T lymphocytes. CD8+ T cells are subsequently activated and give rise to a cellular cytotoxic response. The Fas ligand (FasL) pathway has been shown to play a major role in the resultant apoptosis of keratinocytes.
Cytokines, such as interferon-gamma and tumor necrosis factor-alpha, augment the tissue damage. Interleukin-15 expression from keratinocytes acts in the formation of drug-specific CD8+ memory T cells, so that when drug reexposure occurs, a more rapid and localized response develops.
CD4+ T lymphocytes also play a role in that they produce interleukin-10, which assists in a damping down of the CD8+– initiated response at the time of resolution of the lesions.
Systemic Implications and Complications
FDE does not affect internal organs. Rarely, fever and malaise have been reported; however, patients are usually systemically well.
Stop offending agent
Potent topical steroids
Optimal Therapeutic Approach for this Disease
The most important first step is to identify and discontinue the offending drug. Localized cases may not warrant treatment at all, especially if asymptomatic.
For symptomatic cases, a potent or ultrapotent topical steroid cream (such as betamethasone diproprionate 0.05% or equivalent, or clobetasol 0.05% or equivalent), with or without oral antihistamines, can be given. Topical steroids may help to decrease the intensity of the inflammatory reaction, and therefore, the degree of postinflammatory hyperpigmentation seen.
For erosive cases, wet compresses, followed by hydrated petrolatum or Vaseline gauze, may be used to aid in healing. For widespread cases in which the diagnosis is not immediately apparent, hospital admission and close monitoring until the diagnosis has been established, is recommended. In these cases, topical steroid ointments and topical occlusive dressings, such as Vaseline gauze or a silver-based dressing, can be used. Oral prednisone in a dose of 0.5mg/kg/day may be given.
An in-depth history is required in some cases in order to elicit the offending drug or food. Patients need to be made aware that avoidance of this substance is vital in the prevention of further such eruptions, and that the eruption may become more widespread if it recurs.
The patient can be reassured that spontaneous resolution is expected, but that hyperpigmentation may result. Potent topical steroids can be offered for symptom control and to decrease the intensity of the inflammatory reaction and the resultant pigmentation.
In cases of doubt, the following maneuvers may be offered to the patient:
This is noted to be the gold standard by certain authors; however, this method should not be used in widespread or generalized cases, or in children. The optimal waiting period is not defined, but it is recommended that there is at least a 4-week window before testing, so as to avoid false-negatives from this refractory period.
A subtherapeutic initial dose, such as 1/8 of a tablet, is recommended. If no response occurs, this is increased every 12 to 24 hours until reaching the dose of a whole tablet of the putative offending drug. A flare in an old FDE site is expected with this testing method. This may occur as soon as 10 to 30 minutes after ingestion, or up to 10 to 18 hours thereafter.
Topical provocation with patch testing is an alternative. Unfortunately, lack of standardization in the way patch testing is performed has led to varying results being reported in the literature.
It is recommended that patch testing be performed on lesional skin, that it be an open test, and that the commercial product be compounded in white petrolatum at a concentration of 1% to 10%. Higher concentrations and other vehicles (ethanol or dimethyl sulfoxide [DMSO]) may be needed if reactions are negative. Single or repeated applications may be performed every 12 hours (up to four times).
A positive test is defined as erythema in lesional skin that starts within 24 hours and lasts at least 6 hours. The literature on the methodology for patch testing for various drugs was recently reviewed. For trimethoprim/sulfamethoxazole, a 93% sensitivity was achieved with open repeated patch tests in DMSO, starting at a 10% concentration, and increasing to 20% and then 50%, if negative. For naproxen, the same conditions lead to a 60% positivity in five patients.
Unusual Clinical Scenarios to Consider in Patient Management
In the less common scenario of a generalized bullous fixed drug eruption, a short course of oral corticosteroids (such as oral prednisone in a dose of 0.5mg/kg/day) may be given to assist with resolution, depending on the severity of the eruption and the patient’s underlying co-morbidities.
What is the Evidence?
Brahimi, N, Routier, E, Raison-Peyron, N, Tronquoy, AF, Pouget-Jasson, C, Amarger, S. “A three-year-analysis of fixed drug eruptions in hospital settings in France”. Eur J Dermatol. vol. 20. 2010. pp. 461-4. (A large clinical series detailing the features of fifty-nine cases of FDE.)
Ozkaya, E. “Fixed drug eruption: state of the art”. J Dtsch Dermatol Ges. vol. 6. 2008. pp. 181-8. (An excellent review with general guidelines for topical and systemic provocation tests.)
Pellicano, R, Ciavarella, G, Lomuto, M, Di Giorgio, G. “Genetic susceptibility to fixed drug eruption: evidence for a link with HLA-B22”. J Am Acad Dermatol. vol. 30. 1994. pp. 52-4. (HLA class I and II typing in thirty-six patients was performed, revealing a significantly higher frequency of HLA-B22 and HLA-Cw1.)
Sehgal, VN, Srivastava, G. “Fixed drug eruption (FDE): changing scenario of incriminating drugs”. Int J Dermatol. vol. 45. 2006. pp. 897-908. (An outstanding review on the subject.)
Tanabe, K, Amoh, Y, Mii, S, Eto, H, Iwamura, M, Katsuoka, K. “Non-pigmenting fixed drug eruption induced by sorafenib”. Acta Derm Venereol. vol. 90. 2010;May. pp. 307(The first case of a nonpigmenting FDE from sorafinib.)
Weedon, D, Weedon, D. “The lichenoid reaction pattern (“interface dermatitis”)”. Weedon’s Skin Pathology. 2010. pp. 35-70. (An excellent text on the histopathologic findings of the lichenoid dermatoses.)
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