Recalcitrant Erythema Multiforme Minor Successfully Treated With Apremilast—A Novel Insight

Erythema multiforme (EM) is an acute, self-limited or recurrent dermatosis characterised by erythematous, targetoid lesions, primarily affecting the acral areas of the body. EM minor involves no mucosal surfaces, in contrast to EM major [1]. Common triggers include herpes simplex virus (HSV), Mycoplasma pneumoniae, other infectious agents and certain drugs and systemic diseases [1]. There are no standardised treatment guidelines for EM [1]. First-line treatment generally consists of antiviral agents like acyclovir or famciclovir. Refractory or non-herpetic cases may respond to agents like thalidomide, dapsone, methotrexate, antimalarials or rituximab, often with limited success. We present a 45-year-old woman with a 10-year history of recurring erythematous-oedematous targetoid acral papules, affecting both palms and soles. Some lesions exhibited central, tense vesiculation. Episodes recurred every 1–2 months and typically lasted around 2 weeks. She reported a score of 10/10 on the Visual Analog Scale (VAS) for pruritus, indicating severe quality of life impact. Lesions affected only the acral region. She had no oral mucosal or chilblain-type lesion, no photosensitivity and was otherwise asymptomatic (Figure 1A–D). Serology for HSV was positive (IgG+, cualitative result). Multiple skin biopsies revealed a superficial perivascular dermatitis with hydropic basal degeneration, dyskeratotic keratinocytes and focal epidermal necrosis. Severe spongiosis was noted (Figure 2). Direct immunofluorescence in perilesional skin was negative. Autoimmune testing was negative as well, except for a single instance of low-titre ANA positivity (1:40) with negative ENA (extractable nuclear antigen) panel, including SSA/Ro, SSB/La, Sm, RNP, Scl-70 and Jo-1. The patient was treated with acyclovir (400 mg twice daily for 5 months) without any improvement. Hydroxychloroquine (400 mg daily for 2 years) provided minimal benefit and was later discontinued after the development of bull's-eye maculopathy. Additional topical retinoids (tretinoin), quinacrine, methotrexate, acitretin and dapsone did not lead to any clinical response. Pruritus was unresponsive to gabapentin and sertraline. The condition was only partially controlled with high-potency topical and systemic corticosteroids. Given the limited success, treatment with apremilast (30 mg every 12 h) was initiated. It led to significant pruritus improvement (VAS for pruritus 2/10) and complete resolution of flare-ups. After 4 months, the patient developed suicidal ideation following a stressful life event, which prompted the discontinuation of apremilast. Skin lesions and pruritus recurred 4 weeks after withdrawal (Figure 1E). Erythema multiforme is thought to be a Th1-mediated immune response [2] triggered by autoantigens exposed by damaged keratinocytes, typically in the presence of viral antigens [1, 2]. Elevated serum levels of IFN-γ and IL-12 [3] have been observed in EM, contributing to an inflammatory cascade that results in predominant intradermal inflammation, perivascular infiltration, dyskeratotic keratinocytes and necrosis [1]. Apremilast, an oral PDE4 inhibitor [4], is approved for plaque psoriasis, psoriatic arthritis and, in some regions such as Europe and the United States, for Behçet's disease [4]. It has shown benefit in other aphthous conditions and recently in Hailey–Hailey disease [3]. By downregulating pro-inflammatory cytokines (IL-17, TNF-α, IL-12/23, IL-10 and IFN-γ) it targets some crucial pathways in EM pathogenesis [2, 4]. To our knowledge, Chen et al. [5] reported the only previously documented cases of recalcitrant erythema multiforme major successfully treated with apremilast. Our case is the first to report its efficacy in EM minor. Common adverse effects include gastrointestinal disturbance (such as diarrhoea), headache and rarely suicidal ideation. In our case, external factors likely contributed as the suicidal thoughts persisted after discontinuation of apremilast. Our patient is currently being treated with mycophenolate mofetil (750 mg twice daily) without clinical response and is now being transitioned to upadacitinib (15 mg daily). As a selective JAK 1 inhibitor, upadacitinib also targets IFN-y, which, as we said before, plays a key role in EM pathogenesis. Recent case series have demonstrated the efficacy of JAK inhibitors in persistent EM [6]. Apremilast and upadacitinib may represent a promising treatment for EM, particularly in unresponsive cases. Further studies are needed to evaluate their efficacy, safety and long-term outcomes. Each one of the authors has reviewed the manuscript thoroughly and given their complete approval. We declare that this is an original and not previously published paper. Patients informed consent was provided. The authors declare no conflicts of interest. The authors have nothing to report.