Discussion

Incidence

Immune checkpoint inhibitors (ICIs) have been known to cause various skin reactions during or after treatment. The most common skin eruptions with ICIs are generally vitiligo, pruritus, and maculopapular rash. Common risk factors for developing an immune-related adverse event (irAE) would be treatment for melanoma, prior history of autoimmune skin conditions, and the type of ICI being used for treatment [7,8]. It is interesting to note that CTLA-4 inhibitors have been shown to have a dose-dependent reaction as compared to PD-1/PD-L1 inhibitors. There is no clear relationship between the dose of PD-1/PD-L1 inhibitors and the occurrence of irAEs that has been established [9]. LABD is considered a part of bullous disorders with an autoimmune etiology, the underlying mechanism of which is IgA directed against antigens within the basement membrane zone of the dermo-epidermal junction.

To date, fewer than 10 cases of LABD associated with ICI therapy have been reported in the published literature. The first was described by Jonna et al. in 2019 and included isolated gingival involvement in a patient treated with nivolumab [10]. Two cases of atezolizumab-induced LABD have since been published by Almutairi and Alessa and Aguilar-Duran et al. [11,12]. Momin et al. reported a case associated with combined anti-PD-1 and anti-CTLA-4 therapy in 2023 [13]. Most recently, Saeed et al. reported the only case to date of severe ocular involvement, including cicatricial keratoconjunctivitis and bilateral symblepharon, occurring in the setting of nivolumab therapy [14]. Notably, no prior case of pembrolizumab-induced LABD has been reported in the literature, underscoring the rarity and novelty of the present case.

A linear pattern noted on immunofluorescence with IgA deposits is pathognomonic. Linear IgA disease (LAD) has been shown to exhibit a bimodal age distribution, with cases first observed in children less than five years of age [15]. In their review of available studies, Fortuna and Marinkovich found no evidence of racial or ethnic clusters in LAD [16].

Pathogenesis

The underlying mechanism behind cutaneous irAE with ICIs is via T-cell activation. It is theorized that T cells target antigens at the dermo-epidermal junction because these antigens mimic tumor antigens [17]. LAD is thought to have a combination of humoral and cell-mediated immunity, typically CD4+ T cells that recognize the non-collagenous domain 16A (NC16A) of the BP180 antigen, similar to IgA. Sensitized T-helper cells proliferate and secrete both Th-1 and Th-2 cytokine profiles that, in combination with the IgA autoantibodies, lead to local tissue destruction in the basement membrane zone [18]. Since there is little data explaining the phenomenon of LABD as an irAE with ICI therapy, the underlying molecular basis is poorly understood. Dermatopathological investigations should always be carried out in cases of bullous eruptions for patients undergoing treatment with ICIs.

Clinical grading and management

Eruptions are graded according to body surface area (BSA) involvement as follows: grade 1 (<10% BSA), grade 2 (10-30% BSA), grade 3 (>30% BSA), and grade 4 (life-threatening eruptions requiring intensive care unit or burn unit admission). A multidisciplinary team comprising dermatology, oncology, and immunology specialists is recommended when considering interruption of ICI therapy. Management is based on BSA involvement - topical emollients and corticosteroids for BSA <10%, discontinuation of ICI therapy for BSA >10%, and oral corticosteroids for BSA 10-30%. For patients with BSA >30% requiring hospitalization, prompt initiation of systemic steroids and cessation of ICI therapy are advised [19].