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Case Report  |   January 2020
Topical Imiquimod and Subsequent Erythema Multiforme
Author Notes
  • From the Sampson Regional Medical Center/Campbell University (Drs Maxfield and and Hansen) in Clinton, North Carolina; the Dermatology & Laser Center, Medical Center Clinic and the Department of Dermatology at Florida State University College of Medicine in Pensacola (Dr Gaston); and the University of Tennessee College of Medicine in Memphis (Ms Peck). Dr Maxfield is a third-year resident. 
  • Address correspondence to Luke Maxfield, DO, Sampson Regional Medical Center/Campbell University, 607 Beaman St, Clinton, NC 28328-2603. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
Article Information
Cardiovascular Disorders
Case Report   |   January 2020
Topical Imiquimod and Subsequent Erythema Multiforme
The Journal of the American Osteopathic Association, January 2020, Vol. 120, 45-48. doi:https://doi.org/10.7556/jaoa.2020.010
The Journal of the American Osteopathic Association, January 2020, Vol. 120, 45-48. doi:https://doi.org/10.7556/jaoa.2020.010
Web of Science® Times Cited: 1
Abstract

Topical imiquimod is commonly used in the nonsurgical management of actinic keratosis and superficial basal cell carcinoma. Although adverse effects have been limited primarily to local irritation, another rare adverse reaction is erythema multiforme. We present a case of erythema multiforme involving the oral mucosa, trunk, and extremities that followed broad application of topical imiquimod for the management of suspected superficial basal cell skin cancers and actinic keratosis. The patient had used imiquimod previously without complication. Cessation of use and systemic corticosteroids resulted in prompt clearance.

Imiquimod is an immunomodulating drug that works through activation of Toll-like receptor-7 with downstream induction of multiple cytokines, including interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α). It demonstrates both antiviral and antitumoral effects and is approved by the US Food and Drug Administration for the treatment of warts, superficial and small (<2 cm) nonfacial basal cell carcinomas, and actinic keratosis within a contiguous area of 25 cm2.1,2 With topical therapy, the most common adverse events relate to local irritation, including erythema, ulceration, and pain.3 However, topical imiquimod has previously been associated with the onset of erythema multiforme (EM)4-9 and has been implicated as the inciting agent of Stevens-Johnson syndrome and toxic epidermal necrolysis.10 These rare but potentially serious adverse events are thought to be secondary to systemic absorption and directly related to the drug's mechanism of action with activation of pathologic cytokines.10-12 We present a case of a patient with mucosal and cutaneous EM after localized imiquimod application with subsequent resolution after removal of the drug and treatment with oral corticosteroids. This patient's case demonstrates the need for physician awareness and clear communication with patients about dosing limitations when prescribing topical therapies, including imiquimod. 
Report of Case
An 83-year-old man with prior nonmelanoma skin cancers was treated with topical imiquimod 5% cream twice weekly for 2 suspected superficial 4- to 5-mm basal cell carcinomas on his left shoulder and multiple 1- to 4-mm actinic keratoses on his left wrist and right dorsal hand. The patient stated that he noticed a “much more significant” reaction at the application sites immediately on initiating this round of treatment compared with previous applications for prior nonmelanoma cancers. On day 7, after 2 applications, pruritic, erythematous macules and erosions developed at the sites of imiquimod application, as well as multiple erythematous macules, patches, plaques, and targetoid lesions at sites distant to medication use, including all extremities and palms (Figure 1 and Figure 2) Also noted were erosions on his upper and lower lips (Figure 3) and some vesicles and bullae on the wrists and ankles. The patient discontinued topical therapy and, after 7 more days, presented to our dermatology office. Considering the characteristic targetoid lesions and oral involvement, EM was diagnosed. Given the temporal relationship to his recent imiquimod treatment, the cause was thought to be iatrogenic. He was prescribed 60 mg of prednisone daily for 5 days, with a decrease in dose by 10 mg every 5 days. He noted rapid improvement within 4 days, and clearance was observed at a 2-week follow-up. The patient declined any repeated applications of imiquimod. At the 1-month follow-up, after resolution of erosions and crusting, a reevaluation of the patient's skin cancers and precancerous lesions showed resolution and were considered successfully treated with the exuberant reaction to imiquimod. 
Figure 1.
Elderly patient with topical imiquimod–induced erythema multiforme. Left hand with edema, superficial ulceration, and scattered small erythematous targetoid lesions in the area of previously-applied imiquimod.
Figure 1.
Elderly patient with topical imiquimod–induced erythema multiforme. Left hand with edema, superficial ulceration, and scattered small erythematous targetoid lesions in the area of previously-applied imiquimod.
Figure 2.
Multiple erythematous, targetoid lesions on the palmar surface of the hand.
Figure 2.
Multiple erythematous, targetoid lesions on the palmar surface of the hand.
Figure 3.
Scattered erosions, ulcers, and crusts involving the mucosal surface and vermillion border of the lower lip.
Figure 3.
Scattered erosions, ulcers, and crusts involving the mucosal surface and vermillion border of the lower lip.
Discussion
This report demonstrates a case of EM with mucosal involvement suspected to be secondary to topical imiquimod use. Imiquimod is approved by the US Food and Drug Administration for both actinic keratosis and superficial (<2 cm) nonfacial basal cell carcinomas. Notably, studies assessing efficacy and safety when treating patients with actinic keratosis limit the treatment area to a 25-cm2 contiguous area.1,2 Absorption and serum levels of imiquimod have been shown to increase when larger surface areas (eg, hands and arms) were treated for extragenital warts.1 Additionally, more frequent dosing—as seen with this 5-times-weekly application for superficial basal cell skin cancer—has also been shown to correlate with increased serum levels of imiquimod.1 
Imiquimod, as an activator of Toll-like receptor 7 and 8, induces multiple cytokines attributable to both Th1 and Th2 CD4 T-cells. Many Th1 cytokines are increased, including IFN-γ, IFN-α, and multiple interleukins, such as interleukin 6 (IL-6) and IL-12 and the Th2 cytokine, TNF-α.13,14 Direct consequences of imiquimod's individual cytokine activation are well documented and exemplified by the inadvertent worsening and induction of psoriasis and psoriasiform lesions attributed to an increase in IL-12.14 As herpes-associated EM has been shown to signal through the Th1 cytokine IFN-γ and drug-induced EM through the Th2 signal TNF-α,11 it is notable that both cytokines are directly upregulated by imiquimod. 
Diagnosis of EM is usually clinical, although histopathologic analysis and direct immunofluorescence can help distinguish it from other dermatoses.12 Management of drug-induced EM begins by stopping the offending agent and avoiding reexposure. Treatment for suspected drug-induced EM is often supportive, with topical corticosteroids and antihistamines given for symptomatic relief. Systemic corticosteroid use is controversial and, although efficacy has not been studied, it is still reported as a treatment option and given as therapy, especially for extensive involvement.12,15 
Conclusion
Topical imiquimod usually has limited local adverse effects, and systemic absorption is considered minimal. However, with a disrupted skin barrier, extensive application, or more frequent dosing, it may rarely induce more significant reactions, including EM. In the current case and other similar case reports, the initial local reaction from imiquimod was noted to be more erosive, to cover a larger area than previous applications, and to involve areas distant from application sites. Anecdotally, it is our observation that often during topical treatment of skin cancer, imiquimod is inadvertently applied diffusely to areas of actinic damage as well as directly over multiple precancerous or cancerous lesions. The osteopathic tenet of using treatment based on an understanding of the body unit and the interrelationship of structure and function is well exemplified when considering the suspected pathophysiology of diseases and the mechanism of medications, including imiquimod. For the physician prescribing these medications, it is important to present clear instructions for application to patients, as well as to understand risk factors for systemic absorption. 
References
ALDARA (imiquimod) cream, 5%. United States Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20723s016lbl.pdf Accessed February 18, 2019.
Korman N, Moy R, Ling M, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of 2 phase-3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol. 2005;141(4):467-473. [CrossRef] [PubMed]
Sheth P, Landis M. Topical and intralesional antiviral agents. In: Wolverton S, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. New York, NY: Saunders/Elsevier; 2013:476-488.
Yanes DA, Kaffenberger JA, Carr DR. Erythema multiforme as a reaction to imiquimod 5% cream. Dermatol Online J. 2017;23(2).
Ballester I, Guijarro J, Silvestre JF, Niveiro M. Erythema multiforme induced by imiquimod 5% cream. Int J Dermatol. 2014;53(7):e347-e348. doi: 10.1111/ijd.12265 [CrossRef] [PubMed]
Pena-Lopez S, Suarez-Magdalena O, Monteagudo B, et al. Erythema multiforme caused by treatment with topical imiquimod 5% in a patient with Gorlin syndrome. Actas Dermosifiliogr. 2018;109(3):277-227. doi: 10.1016/j.ad.2017.08.007 [CrossRef] [PubMed]
García-Arpa M, Rodríguez-Vázquez M, Delgado Portela M, et al. Erythema multiforme due to 5% imiquimod cream [in Spanish]. Actas Dermosifiliogr. 2010;101(6):551-552. [CrossRef] [PubMed]
Chan MYL, Kennedy J, Oakley A. Erythema multiforme triggered by imiquimod 5% cream. Australas J Dermatol. 2017;58(4):e257-e258. doi: 10.1111/ajd.12578 [CrossRef] [PubMed]
Kumar B, Narang T. Local and systemic adverse effects to topical imiquimod due to systemic immune stimulation. Sex Transm Infect. 2011;87:432. doi: 10.1136/sextrans-2011-050025
Leitner C. Topical imiquimod—be aware of the unexpected. J Am Acad Dermatol. 2016;74(5):AB223. doi:: 10.1016/j.jaad.2016.02.877
Kokuba H, Aurelian L, Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions. J Invest Dermatol. 1999;113(5):808-815. [CrossRef] [PubMed]
Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current perspectives on erythema multiforme. Clin Rev Allergy Immunol. 2018;54(1):177-184. doi: 10.1007/s12016-017-8667-7 [CrossRef] [PubMed]
Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557-1569. doi: 10.1182/blood-2008-05-078154 [CrossRef] [PubMed]
Grine L, Dejager L, Libert C, Vandenbroucke RE. Dual inhibition of TNFR1 and IFNAR1 in imiquimod-induced psoriasiform skin inflammation in mice. J Immunol. 2015;194(11):5094-5102. doi: 10.4049/jimmunol.1403015 [CrossRef] [PubMed]
Michaels B. The role of systemic corticosteroid therapy in erythema multiforme major and Stevens-Johnson syndrome: a review of past and current opinions. J Clin Aesthet Dermatol. 2009;2(3):51-55. [PubMed]
Figure 1.
Elderly patient with topical imiquimod–induced erythema multiforme. Left hand with edema, superficial ulceration, and scattered small erythematous targetoid lesions in the area of previously-applied imiquimod.
Figure 1.
Elderly patient with topical imiquimod–induced erythema multiforme. Left hand with edema, superficial ulceration, and scattered small erythematous targetoid lesions in the area of previously-applied imiquimod.
Figure 2.
Multiple erythematous, targetoid lesions on the palmar surface of the hand.
Figure 2.
Multiple erythematous, targetoid lesions on the palmar surface of the hand.
Figure 3.
Scattered erosions, ulcers, and crusts involving the mucosal surface and vermillion border of the lower lip.
Figure 3.
Scattered erosions, ulcers, and crusts involving the mucosal surface and vermillion border of the lower lip.