Treatment of Recurrent Erythema Multiforme in an Immunosuppressed Patient

Erythema multiforme (EM) is an immune-mediated, self-limited reaction secondary to medications, immunizations, and infections that involves the skin and often the oral mucosa. It presents clinically as a rash originating as macules and papules, which develop into distinctive, erythematous, targetoid lesions 2 to 3 days after onset of the rash. Often distributed symmetrically, starting on the back of the hands and feet and spreading proximally to potentially cover the whole body, EM is a reaction to a cause and can be a solitary or recurrent condition, with outbreaks occurring an average of 6 times per year. The cause for recurrent EM is most often herpes simplex virus (HSV).^1,2 EM typically resolves with treatment of the underlying condition or discontinuation of a causative medication. The treatment recommendation for recurrent EM is continuous prophylactic antiviral therapy.¹

In this article, we present a recurrent case of EM refractory to standard treatment, which developed on the arms, legs, and oral mucosa. 

Case Report 

A 36-year-old man presented to the dermatology clinic with multiple polymorphous and target-like erythematous patches and plaques distributed in the oral mucosa and bilaterally on the upper and lower extremities (Figure). There was no truncal involvement. Medical history included the use of IV infliximab for the past 9 years for management of ulcerative colitis. At this dermatology visit, he was clinically diagnosed with EM; due to oral involvement, a prednisone taper (20 mg once a day for 7 days, 10 mg once a day for 7 days, and 10 mg every other day for 14 days) and famciclovir (500 mg once a day) were prescribed. At a 3-week follow-up, the patient had 80% resolution of the lesions on the extremities and oral mucosa. The patient was advised to continue 500 mg famciclovir once daily to prevent outbreak recurrence. 

Although the patient reported adhering to the standard famciclovir 500 mg daily regimen, he only had moderate symptom improvement.³ Outbreaks recurred roughly every 3 months, requiring systemic prednisone treatments for the next 2 years. At his next follow-up visit when the EM had cleared after prednisone, the famciclovir dosage was doubled to 1000 mg daily. Since starting the increased dose of famciclovir, the patient has been in remission for 6 months. 

Discussion

Recurrent EM is the repeated occurrence of EM over a period of years. A retrospective review of 48 cases of recurrent EM revealed a mean disease duration between 6 and 10 years. Patients who fall into this subgroup experience an average of 6 EM episodes per year.^3,4 As recurrent EM is often a response to recurrent subclinical HSV outbreaks, the most effective treatment is continuous antiviral therapy for at least 6 months.⁴ Treatment recommendations include acyclovir (400 mg twice daily), valacyclovir (500 mg twice daily), and famciclovir (250 mg twice daily).³ The goal of treatment is to minimize the number and severity of outbreaks and eventually induce remission of symptoms. Due to high rates of recurrence, patients who respond to antiviral therapy should be kept on medication for 1 to 2 years before discontinuing therapy.³ 

This case presents a unique challenge because the patient was prescribed the tumor necrosis factor (TNF)-alpha inhibitor infliximab for his ulcerative colitis. Although there is a reported association between infliximab use and EM in multiple case reports, reactions usually occur within 45 days of treatment.⁵ Another possible etiology for this patient’s recurrent EM is that the infliximab caused more frequent and severe HSV reactivation. However, there is no clinical evidence that anti-TNF therapy is a major risk factor for HSV reactivation in humans.⁶ The repeated outbreaks could also be a consequence of poor adherence to the initial recommended treatment strategy. 

Current alternative treatments for recurrent EM refractory to standard antiviral therapy include immunosuppressive medications that are poorly supported by evidence. Five of 10 patients treated with dapsone (≤ 200 mg daily) achieved partial or complete remission.⁴ Mycophenolate mofetil (≤ 2 g daily) achieved partial or complete remission in 6 of 8 patients treated.^3,4 Several systemic agents were effective in small numbers of patients.^1,4 There are also more reported adverse reactions associated with immunosuppressants compared to antiviral medications.¹ Common adverse reactions of taking 1000 mg famciclovir daily include nausea, headaches, and dizziness. The most severe adverse effects include hepatotoxicity and Stevens-Johnson syndrome.⁷ The patient in our case has had no adverse effects after his prescribed famciclovir dosage was doubled and is in complete remission. The patient reported strict adherence to the 1000 mg daily dose of famciclovir at 2 follow-up visits in the last 6 months. 

Conclusion 

This case suggests that doubling the standard dose of famciclovir in a patient with recurrent EM on a TNF-alpha inhibitor may be an effective therapy to prevent repeated outbreaks. 

References 

1. Trayes KP, Love G, Studdiford JS. Erythema multiforme: recognition and management. Am Fam Physician. 2019;100(2):82-88. 

2. 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 

3. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902. doi:10.1111/j.1365-4632.2011.05348.x 

4. Wetter DA, Davis MDP. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. doi:10.1016/j. jaad.2009.06.046 

5. Edwards D, Boritz E, Cowen EW, Brown RS. Erythema multiforme major following treatment with infliximab. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(2):e36-40. doi:10.1016/j.oooo.2012.08.001 

6. Asthana A, Lubel J. Reactivation of latent viruses after treatment with biological therapies. Virus Adaptation Treatment. 2014;6:1-10. doi:10.2147/VAAT.S64290 

7. Semaan JR, Parmar M. Famciclovir. In: StatPearls [Internet]. StatPearls Publishing; 2022. 

Disclosures

Dr Feldman has received research, speaking, and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Ortho Dermatology, Menlo, Merck & Co, Qurient, Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Teladoc, BMS, Ono, Micreos, Eurofins, Informa, UpToDate, and the National Psoriasis Foundation. He is founder and part owner of Causa Research and holds stock in Sensal Health. 

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