Introduction
Persistent erythema multiforme (EM) is a rare form of EM, characterized by targetoid mucocutaneous lesions that persist for months or years [1]. The triggering factors of this condition remain unclear, and, together with the limited number of reported cases, the evidence regarding therapeutic options is scarce. On the other hand, apremilast has recently shown efficacy in isolated reports of other forms of EM [2], suggesting a potential role in difficult-to-treat cases.
However, there is no published evidence regarding its use in persistent EM. We report a case of refractory EM with prolonged persistent mucocutaneous activity who achieved sustained remission with apremilast, together with a brief review of the published literature. This case report was prepared in accordance with the CARE guidelines, and the completed CARE checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/cde/abvag024).
Case Presentation
A 45-year-old woman developed in 2012 recurrent flares of acral bullous targetoid lesions associated with painful oral ulcers. A skin biopsy confirmed EM, supported by negative direct immunofluorescence and autoimmune studies. Herpes simplex virus (HSV) serology was positive (IgG), with a history of oral herpes.
Following an initially acceptable response to daily valacyclovir, the patient developed a prolonged mucocutaneous flare in 2019 (Fig. 1), which subsequently evolved into continuously active disease. EM became refractory to antiviral therapy and high-dose oral prednisone, with significant impairment of oral intake.
Multiple subsequent treatments, including colchicine, dapsone, hydroxychloroquine, azathioprine, adalimumab, and infliximab, were discontinued due to lack of efficacy or intolerance. The patient consequently remained corticosteroid-dependent, with persistent oral involvement and significant functional limitation.
During the course of this persistent phase, multiple biopsies, including repeatedly negative direct immunofluorescence studies, consistently showed histopathological findings compatible with EM (Fig. 2). Thoracoabdominopelvic computed tomography revealed no evidence of malignancy or pathological lymphadenopathy.
Together with the clinical presentation and repeated compatible histopathological findings, these investigations supported the diagnosis of EM and did not identify an underlying systemic condition. Given the persistence of clinical activity and refractoriness to multiple therapeutic lines, treatment with apremilast (30 mg twice daily) was initiated in March 2025.
Within 3 months, the patient experienced progressive improvement with reduction of acral lesions and complete resolution of oral involvement. After 1 year of follow-up under apremilast treatment, she remains in sustained remission, with good tolerability and no significant adverse effects.
Discussion
EM is typically an acute and self-limited dermatosis; however, recurrent forms are well recognized, particularly in association with HSV [1, 3]. Prolonged or persistent mucocutaneous activity is uncommon and is not clearly defined as a distinct clinical entity. Only a limited number of cases have been reported, and it has been associated with malignancies, inflammatory bowel disease, Epstein-Barr virus infection, and HSV, although many cases remain idiopathic [3, 4].
The clinical course of our patient was noteworthy. She initially presented with recurrent flares associated with a history of oral herpes but later evolved into a persistent form lasting 6 years. During the persistent phase, HSV IgG remained positive, consistent with previous exposure, but there was no evidence of active HSV reactivation.
Thus, although previous HSV exposure was documented, a role for HSV as a trigger of the persistent disease could not be established, and no underlying systemic disease was identified.
First-line therapy for EM includes antiviral agents such as valacyclovir or famciclovir, even in the absence of a clear HSV trigger as HSV DNA has been detected in up to 44% of idiopathic cases [1, 3]. In refractory disease, multiple immunosuppressive and immunomodulatory agents have been used with variable success, including azathioprine, mycophenolate mofetil, intravenous immunoglobulins, hydroxychloroquine, and rituximab [3].
In the few reported cases of persistent EM, treatments such as dapsone, azathioprine, and thalidomide (62% remission rate at 6 months of treatment) [1] have shown responses in selected reports, albeit with potentially significant adverse effects [4, 5]. More recently, JAK inhibitors such as tofacitinib and upadacitinib have demonstrated potential benefit, likely related to inhibition of IFN-γ and IL-15 pathways [6, 7]. Nevertheless, therapeutic options and supporting evidence remain scarce in this subtype of EM.
Our patient was refractory or intolerant to multiple previously described therapeutic options, leading to the decision to initiate apremilast, given its favorable safety profile and emerging evidence in isolated cases of recurrent EM. Apremilast acts as a phosphodiesterase 4 (PDE4) inhibitor, increasing intracellular cyclic AMP levels. This rise in cAMP suppresses the production of key proinflammatory mediators, including IL-12, IL-23, TNF-α, and IFN-γ, and specifically counteracts the Th1 immune response, which plays a central role in the pathogenesis of EM [2, 8, 9].
To date, only five cases of EM treated with apremilast have been reported [8, 9] (Table 1). Among these, four correspond to EM major with oral involvement, half of them associated with HSV infection, and all presented with recurrent flares despite multiple lines of antiviral and immunosuppressive therapy, including intravenous immunoglobulins, anti-TNF agents, and rituximab. In all cases, initiation of apremilast led to rapid and complete resolution of lesions, typically within less than 2 weeks, without significant adverse effects.
However, in one case, treatment was discontinued due to suicidal ideation following a stressful life event [9]. One patient received treatment for only 2 weeks, with no documented recurrences thereafter. The case of a 6-year-old child with EM major reported by Chen et al. [9] further highlights the potential utility of apremilast in pediatric patients, with similarly rapid onset of action.
As with any single case report, several limitations should be acknowledged. The single-patient nature of this report precludes definitive conclusions regarding the efficacy of apremilast. Although the sustained clinical improvement following treatment initiation may suggest a therapeutic effect, spontaneous disease fluctuations and delayed effects of previous therapies cannot be completely excluded.
In addition, further cases and longer follow-up are needed to better assess the durability of response and long-term safety.
Conclusion
This case adds to the limited evidence supporting the potential use of apremilast in difficult-to-treat EM with prolonged mucocutaneous activity. Although the rapid and sustained response observed in our patient with apremilast at the standard dose of 30 mg twice daily is encouraging, further studies are needed to determine its efficacy, optimal treatment duration, and long-term safety in this setting.
Statement of Ethics
This study was performed in accordance with the Declaration of Helsinki. Ethical approval was not received for this human study because Ethical approval is not required for this study in accordance with local or national guidelines. All adult participants provided written informed consent to participate in this study.
Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study received no specific funding.
Author Contributions
Pedro José Fernández Esparcia contributed to the conception and design of the study, data collection, analysis and interpretation of clinical data, and drafting of the manuscript. Andrés González García, Daniela Baracaldo Santamaría, Carmen Moreno García del Real, and María Asunción Ballester Martínez contributed to data collection, clinical management of the patient, and critical revision of the manuscript. All authors approved the final version of the manuscript.