Lichen Planus Pemphigoides Induced by Camrelizumab in Combination With Lenvatinib

To the Editor: Camrelizumab is emerging as a novel programmed cell death-1 (PD-1) inhibitor for the treatment of various malignancies. However, recipients of PD-1 inhibitors frequently experience dermatological adverse events, including lichenoid and bullous pemphigoid–like eruptions.1 Notably, lichen planus pemphigoides (LPP), a rare subepidermal blistering disease associated with lichenoid skin changes, occasionally occurs in association with immunotherapy. Currently, cases of LPP associated with PD-1 inhibitors include pembrolizumab, nivolumab, atezolizumab, and tislelizumab.2 Here, we present a case of a patient with esophageal cancer who developed LPP following treatment with a combination of camrelizumab and lenvatinib, a tyrosine kinase receptor inhibitor (TKI). A 53-year-old woman was diagnosed with esophageal cancer and was treated with camrelizumab, 200 mg intravenously every 3 weeks, and lenvatinib 12 mg orally once daily. Approximately 6 months into the camrelizumab regimen, she presented with sporadic pink to violaceous plaques on her abdomen and extremities, clinically resembling lichen planus without biopsy confirmation. Two months later, a significant worsening of skin lesions was observed, characterized by an increased number of lesions, scaling, and the appearance of vesicles on certain plaques (Fig. 1).FIGURE 1.: Widespread pink to violaceous plaques with scaling and blistering on the abdomen and extremities.A biopsy from the left upper extremity demonstrated hyperkeratosis, acanthosis, and lichenoid interface dermatitis with dyskeratotic keratinocytes at the lower epidermis (Fig. 2A). A follow-up biopsy of the lesion on the left lower extremity 10 days later revealed hyperkeratosis, hypergranulosis, a sawtooth-like alteration of the dermal–epidermal junction, and focal subepidermal clefting. In addition, superficial to deep perivascular and interstitial inflammation with lymphocytes and occasional eosinophils within the dermis was also observed (Fig. 2B). These 2 studies demonstrated the dynamic nature of the disease. Direct immunofluorescence showed a linear deposition of C3 along the basement membrane zone (Fig. 2C). These findings supported the diagnosis of LPP. After discontinuation of camrelizumab and lenvatinib, the patient showed an improvement in response to oral corticosteroid therapy.FIGURE 2.: A, H&E sections demonstrated hyperkeratosis, acanthosis, and lichenoid interface dermatitis with dyskeratotic keratinocytes at the lower epidermis (H&E, ×40). B, The follow-up biopsy revealed focal subepidermal clefting, accompanied by hyperkeratosis, hypergranulosis, and a sawtooth-like alteration of the dermal–epidermal junction. In addition, superficial to deep perivascular and interstitial inflammation with lymphocytes and occasional eosinophils within the dermis was observed (H&E, ×100). C, Biopsy of perilesional skin showed linear C3 deposition along the basement membrane zone by direct immunofluorescence.Immunotherapy stands out as a widely acknowledged and potent approach in treating cancer. Tumor cells can avoid immune detection by developing immunological tolerance through various pathways, including the upregulation of checkpoint molecules such as programmed cell death ligand 1 (PD-L1). Blocking the PD-1/PD-L1 pathway can revive cytotoxic -cells and restore immune function against cancer cells. Camrelizumab, a novel PD-1 inhibitor, can be combined with TKI for cancer treatment.3,4 Although PD-1 inhibitors are effective in activating the immune system, they can cause immune-related adverse events, with skin toxicity being a common problem. Conditions, such as bullous pemphigoid-like eruptions, vitiligo-like depigmentation, and psoriasiform dermatitis, are commonly associated with PD-1/PD-L1 inhibitors.1 Reactive cutaneous capillary endothelial proliferation (RCCEPs) appears to be unique to patients treated with camrelizumab.3 A rare manifestation is LPP, initially thought to be a variant of bullous pemphigoid or lichen planus. However, recent evidence suggests that LPP is a distinct condition associated with autoantibodies to type XVII collagen (BP180).5 Some theories suggest that cytotoxic CD8+ T cells induce widespread apoptosis of the basal epidermis in lichen planus. This process exposes various antigens of the dermal–epidermal junction to autoreactive T cells, leading to the formation of pathogenic autoantibodies.6 This results in the development of characteristic subepidermal vesicles. In addition, the presence of complement factor C3 deposition at the dermal–epidermal junction indicates the involvement of complement in the pathogenesis. This complex interplay of immune mechanisms may contribute to the development of LPP. After 6 months of combined immunotherapy, our patient developed lichenoid skin lesions. Initially, there was little concern. However, 2 months later, the condition progressed rapidly vesicles appeared on the plaques. Lichenoid lesions associated with immune checkpoint inhibitors typically manifest as multiple reddish purple papules and plaques primarily on the chest and back, with rare involvement of the limbs and palmoplantar surfaces.1 By contrast, LPP lesions, typically localized on the extremities, were also observed on the limbs in our case. Clinically, simple lichenoid eruptions have been reported in 0.5%–6% of patients, making them a relatively common adverse event associated with anti–PD-1 therapy.1 Notably, the onset of initial papulosquamous eruptions often precedes the appearance of blisters in LPP by several months. It is important to emphasize the rarity of blistering in this context because lichenoid lesions may show dynamic changes suggestive of LPP. There are no documented cases of bullous lichenoid reactions associated with tyrosine kinase inhibitors, which precludes speculation on the role of lenvatinib in disease progression. If vesicles do occur, prompt discontinuation of treatment is essential to prevent the escalation of more severe consequences. A high index of suspicion and immunohistochemical and immunologic tests to confirm an autoimmune origin are essential for a definitive diagnosis. There is currently no specific and effective treatment for this condition. However, discontinuation of immunotherapy with concomitant steroids appears to result in gradual improvement in skin lesions. Our patient is at present being followed up.