Recurrent Round Brown to Gray Spots

Fixed drug eruption is a common, self-limited type IV hypersensitivity reaction due to sensitization to a specific drug. It is characterized by cutaneous lesions recurring at the same “fixed” site with re-administration of offending medication.1 Individuals of any race and...

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Fixed drug eruption is a common, self-limited type IV hypersensitivity reaction due to sensitization to a specific drug. It is characterized by cutaneous lesions recurring at the same “fixed” site with re-administration of offending medication.¹ Individuals of any race and age may be affected, with fixed drug eruption representing 14% to 22% of all cutaneous drug reactions.²

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics, specifically sulfonamides, tetracyclines, and fluoroquinolones, are the most common causative agents.^1,2 The required sensitization period is highly variable for each patient, ranging from weeks to years, with sensitization occurring more rapidly with intermittent rather than continuous administration. Once sensitized, lesions typically appear within 30 minutes to 8 hours after drug intake, with the average time to onset of symptoms being 2 hours.³

Fixed drug eruption most commonly presents as 1 or multiple well-circumscribed, round or oval-shaped erythematous macules and patches with dusky-gray centers. Variations in presentation include edematous plaques with violaceous target-like centers and localized or generalized bullae.² A burning sensation often precedes cutaneous presentation.³ Lesions commonly cover 1% to 2% of the body surface area and usually recur in the same locations from previous eruptions.¹ Initial lesions may present anywhere on the skin or mucosa, with certain drugs causing lesions in preferential sites.

Major categories of fixed drug eruption are determined by clinical morphology such as localized pigmenting, localized bullous, mucosal, non-pigmenting, generalized, and generalized bullous,² with the most common being localized pigmenting. Mucosal fixed drug eruption presents with bullous or erosive lesions and does not exhibit postinflammatory hyperpigmentation. Non-pigmenting fixed drug eruption, classically caused by pseudoephedrine, lacks residual hyperpigmentation after resolution due to lack of pigment incontinence.² Generalized bullous fixed drug eruption is a rare subtype presenting with more widespread cutaneous vesicles and bullae. Although this variant generally lacks systemic involvement, a study of elderly patients reports a mortality of 22%, only slightly lower than Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).⁴

The differential diagnosis for fixed drug eruption includes erythema multiforme, SJS or TEN, contact dermatitis, cellulitis, and herpes simplex infection.² Fixed drug eruption and erythema multiforme have similar clinical and histopathologic presentations, however, fixed drug eruption may be distinguished by its more localized, oval-shaped patch appearance rather than characteristic targetoid lesions found in erythema multiforme. On histopathology, fixed drug eruption exhibits more prominent dermal melanophages than erythema multiforme.² Generalized bullous fixed drug eruption must be distinguished from SJS and TEN. The former lacks or has very mild mucosal and visceral involvement, onset is much faster, within hours of exposure to the causative medication, and histopathologic exam reveals more inflammation and pigment incontinence.⁴

Fixed drug eruption is diagnosed clinically by its characteristic hyperpigmented oval-shaped lesions that recur in the same sites after recent drug exposure.¹ As part of diagnosis, it is crucial to obtain a detailed history of medication use to prevent future recurrence. In cases where clinical findings are inconclusive, alternate diagnostic methods include oral challenge and patch testing. In the oral challenge, a subtherapeutic dose of the drug in question is administered and the patient is assessed for a reaction in an inactive hyperpigmented lesion within 8 hours.^2,5 Although previously considered the gold standard for diagnosis, oral challenge is now generally avoided because of the risk of widespread drug reaction.² Patch testing, considered a safer option, is performed on a hyperpigmented inactive site of fixed drug eruption, with normal skin used as a control. Patch testing relies on memory CD8+ T cells that reside in hyperpigmented lesions and is more sensitive to NSAIDs than to antibiotics.²

In unclear cases of fixed drug eruption, a biopsy may be diagnostic. Additional indications for biopsy include systemic symptoms such as fever, malaise, and arthralgias.² Histopathology reveals a vacuolar interface dermatitis, scattered dyskeratotic keratinocytes, lymphocytic and eosinophilic perivascular dermatitis, and abundant dermal melanophages.^2,5 When the diagnosis is still unclear, less common methods such as the lymphocyte transformation test, which measures a sensitized T-cell reaction in response to the in vitro addition of a drug, have been tried. However, it is not commonly used as it has a sensitivity of 60% to 70% and has not been documented to be an effective confirmatory test.⁶

Fixed drug eruption resolves with hyperpigmentation after discontinuation of the causative agent. Symptomatic relief may be achieved with systemic antihistamines and topical corticosteroids. Generalized fixed drug eruption is sometimes treated with systemic corticosteroids, though they have not been proven effective.^2,5 Successful lightening of residual hyperpigmentation has been reported with consistent sunscreen use, hydroquinone cream, and Q-switched laser treatment.^5,7

To prevent future recurrence, patients should avoid the causative drug and chemically related drugs, as cross-reactivity may occur. If future treatment with the causative drug is required and there is no substitute, successful desensitization has been rarely documented.⁸

The patient in this case was diagnosed clinically with fixed drug eruption due to ibuprofen. She was advised to avoid NSAIDs to prevent recurrences. Diligent sun protection was recommended to improve hyperpigmentation.

Morgan Hammack is a fourth-year medical student at Baylor College of Medicine. Talia Noorily, MD, is a dermatology resident at Baylor College of Medicine.

References

1. Ben Fadhel N, Chaabane A, Ammar H, et al. Clinical features, culprit drugs, and allergology workup in 41 cases of fixed drug eruption. Contact Dermatitis. 2019;81(5):336-340. doi:10.1111/cod.13351
2. Patel S, John AM, Handler MZ, Schwartz RA. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21(3):393-399. doi:10.1007/s40257-020-00505-3
3. Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9(4):316-321. doi:10.1097/ACI.0b013e32832cda4c
4. Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168(4):726-732. doi:10.1111/bjd.12133
5. Flowers H, Brodell R, Brents M, Wyatt JP. Fixed drug eruptions: presentation, diagnosis, and management. South Med J. 2014;107(11):724-727. doi:10.14423/SMJ.0000000000000195
6. Kim MH, Shim EJ, Jung JW, Sohn SW, Kang HR. A case of allopurinol-induced fixed drug eruption confirmed with a lymphocyte transformation test. Allergy Asthma Immunol Res. 2012;4(5):309-310. doi:10.4168/aair.2012.4.5.309
7. Zhao F, Li Y, Meng Z. Successful treatment of hyperpigmentation from fixed drug eruption with a low-dose and large-spot Q-switched 1064 nm Nd:YAG laser. J Cosmet Dermatol. 2023;22(7):2128-2130. doi:10.1111/jocd.15665
8. Umpiérrez A, Cuesta-Herranz J, Heras MDL, Lluch-Bernal M, Figueredo E, Sastre J. Successful desensitization of a fixed drug eruption caused by allopurinol. J Allergy Clin Immunol. 1998;101(2 Pt 1):286-287. doi:10.1016/S0091-6749(98)70396-3