The editors of JCAD are pleased to present this biannual column as a means to recognize select medical students, PhD candidates, and other young investigators in the field of dermatology for their efforts in scientific writing. We hope that the publication of their work encourages these and other emerging authors to continue their efforts in seeking new and better methods of diagnosis and treatments for patients in dermatology.
J Clin Aesthet Dermatol. 2019;12(6):58–59
by Selena R. Pasadyn, BA and Robert Cain, MD
Ms. Pasadyn and Dr. Cain are with the Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio.
FUNDING: No funding was provided for this study.
DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.
ABSTRACT: Imiquimod can be used to treat superficial basal cell carcinoma, actinic keratosis, genital warts, and other skin conditions. The adverse events associated with this topical agent commonly include application site irritation, primarily erythema, as well as headache, myalgia, and fatigue. There are usually minimal systemic symptoms. We report the case of a patient who used topical imiquimod 5% cream on nine basal cell carcinoma lesions daily for three days and developed severe muscle weakness and the inability to walk. He fell twice, went to the emergency department, and was given 125mg injection of methylprednisolone. The imiquimod was then discontinued and he recovered almost back to baseline in 48 hours. We hypothesize the patient’s reaction to the imiquimod was due to an immune etiology, potentially involving TLR7 and NF-kappaB as precipitators of this myopathy. Overall, this report demonstrates a potential severe and rapid adverse reaction to topical imiquimod administration not previously reported in the literature
KEYWORDS: Carcinoma, basal cell, imiquimod, myalgia
Imiquimod is a topical agent that can be used in the treatment of a variety of skin conditions, such as superficial basal cell carcinoma, actinic keratosis, and genital warts. Its mechanism is through stimulation of the immune system, primarily by way of its agonistic effects on Toll-like receptors (TLR) 7 and 8, along with its activation of nuclear factor kappa B (NF-kappaB).1 Imiquimod also promotes the release of cytokines, including interferon-a, interferon-g, and interleukin-12, and provokes a primarily TH1 response in order to induce apoptosis.2,3
Imiquimod has been associated with local skin reactions, primarily erythema, upon application.4 Safety trials have reported that application site reactions, such as itching, can occur in 16 to 62 percent of all imiquimod-treated patients.4 Additionally, headache (29%) and upper respiratory tract infection (14%) are common adverse events observed in other trials.5 In a safety trial where imiquimod was used in 800 patients with actinic keratosis, the most commonly reported systemic symptoms were headache (6.0%), myalgia (2.4%), and fatigue (2.3%).6 We report the case of a patient who developed myalagias and the inability to walk after a three-day course of treatment with imiquimod.
An 88-year-old Caucasian man with a past medical history of atrial fibrillation, cerebrovascular accident, diabetes, hypercholesterolemia, hypertension, and pacemaker implantation presented to the emergency department with myalgias, labored breathing, wheezing with a cough and chills, and generalized weakness leading to the inability to walk. He had fallen twice in his home in the hours before arriving at the emergency department. His blood pressure was 132/61, pulse was 77, oral temperature was 99.2F, and his respirations were 20 per minute. A work-up was completed for influenza and cardiac causes. A computed tomography of the head showed no acute findings. The patient showed no signs of a stroke, although a National Institutes of Health Stroke Scale evaluation was not performed. The patient was continued on aspirin and dipyridamole-aspirin. All other physical exam and laboratory findings were unremarkable.
The patient’s medications included imiquimod, atorvastatin, ferrous sulfate, docusate sodium, sertraline, tamsulosin, lisinopril, metformin, pantoprazole, and bisoprolol-hydrochlorothiazide. Three days prior to admittance to the emergency department, the patient began using topical imiquimod 0.625mg for eight basal cell carcinoma lesions on his chest and one on his forehead. On the third day of application, the patient began to experience myalgias, labored breathing, and generalized weakness, which progressively worsened. After four hours, the patient’s wife attempted to wipe off the cream when he began to feel like a “limp rag” and was unable to lift his arms and walk. After falling twice, the patient went to the emergency department, where he was given ipratropium bromide/abuterol sulfate inhalation aerosol and a 125-mg injection of methylprednisolone for his exertional shortness of breath and wheezing. The imiquimod was discontinued. It was hypothesized that the sudden muscle weakness and inability to walk was related to the topical imiquimod. Because of the patient’s compromised ambulation and weakness, it was determined that he should be admitted to the hospital inpatient service for observation. The patient recovered over the next two days and was discharged. The incident exacerbated his underlying gait and balance deficiencies, so he remained in physical therapy for three weeks with an ultimate return to his baseline functioning.
Other case reports of serious adverse events with topical imiquimod usage have been reported. A 78-year-old man using topical imiquimod 5% cream daily for six weeks for a basal cell carcinoma lost 7kg of weight and developed postural hypotension.7 A 69-year-old woman developed dizziness, nausea, and severe postural hypotension upon a second course of imiquimod treatment, four months following the first course.8 Three cases of patients using imiquimod for anogenital warts reported a range of side effects, including flu-like symptoms and rash exacerbations, with one patient progressing to intense headache, fatigue, lumbar pain, generalized myalgia, and locomotor difficulties during the third week of imiquimod treatment.9 Finally, a 67-year-old man developed fever, myalgias, fatigue, and exacerbation of pityriasis rubra pilaris after using imiquimod three times per week for two weeks on his scalp and cheek.10
While the symptoms experienced by our patient (e.g., muscle weakness, myalgia, inability to walk) were consistent with previously reported reactions, our patient’s reaction was more severe with a more rapid onset. Prior patients developed symptoms after several weeks of using imiquimod, whereas our patient experienced a severe systemic reaction after three days.
Given these cases, along with imiquimod’s role in exacerbating autoimmune conditions, an immune etiology is suspected.11,12 NF-kappaB has been shown to play a role in inflammatory myopathies, modulating the immune response, myogenesis, and muscle repair.13 Additionally, TLR-7 has demonstrated involvement in inflammatory responses in myositis and has been expressed in inflammatory myopathic tissues.14 Thus, it is possible that imiquimod, which stimulates rapid synthesis and release of cytokines, such as TLR7 and NF-kappaB, could potentially be precipitating this inflammatory myopathy. Potentially, the steroid received at the hospital on the first night our patient arrived could have ameliorated the exaggerated immune response, leading to his myopathy.
Finally, it has been shown that a high-fat diet exacerbates imiquimod-induced reactions in mice and that hyperlipidemia can contribute to inflammation.15 Given that our patient had hypercholesterolemia, history of cerebrovascular accident, a body mass index of 27.44kg/m2, and diabetes, he might have had underlying inflammation, making him more susceptible to such a reaction. Regardless, this clinical picture illustrates a significant and immediate systemic reaction to topical imiquimod not previously described. Clinicians prescribing imiquimod should be aware of this potential immune response.
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- Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Brit J Dermatol. 2000;143(4):843–845.
- Kumar B, Narang T. Local and systemic adverse effects to topical imiquimod due to systemic immune stimulation. Sex Transm Infect. 2011;87(5):432–432.
- Ryu J, Yang, C. A review of topical imiquimod in the management of basal cell carcinoma, actinic keratoses, and other skin lesions. Clin Med Ther. 2009:CMT-S1969.
- Beutner KR, Tyring SK, Trofatter KF Jr., et al. Imiquimod, a patientapplied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother. 1998;42(4): 789–794.
- Stockfleth E, Sterry W, Carey-Yard M, Bichel J. Multicentre, open-label study using imiquimod 5% cream in one or two 4-week courses of treatment for multiple actinic keratoses on the head. Br J Dermatol. 2007;157(Suppl 2):41–46.
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- Tournadre A, Lenief V, and Miossec P. Expression of toll-like receptor 3 and toll-like receptor 7 in muscle is characteristic of inflammatory myopathy and is differentially regulated by Th1 and Th17 cytokines. Arthritis Rheum. 2010;62(7): 2144–2151.
- Higashi Y, Yamakuchi M, Fukushige T, et al. High-fat diet exacerbates imiquimod-induced, psoriasis-like dermatitis in mice. Exp Dermatol. 27(2):178–184.