Abstract
Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by an autoimmune response to type XVII collagen (BP180). The generation of anti-BP180-NC16A IgG autoantibodies is considered to be central to the pathogenesis of BP, in part due to the close correlation between serum concentration and disease activity. However, ~60% of BP patients also generate IgG autoantibodies against LAD-1, the soluble 120 kDa ectodomain of BP180. Whilst the pathogenic significance of anti-LAD-1 IgG remains unclear, it may be sufficient to precipitate the development of BP, even in the absence of anti-BP180-NC16A IgG, based on several case reports in Japanese patients. There is increasing recognition that immune-checkpoint inhibitors may trigger and/or exacerbate BP as an immune-related adverse event (irAE). Until now, all of these cases have been associated with the induction of anti-BP180-NC16A IgG. Here, we report the case of a female Caucasian patient who developed BP during treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab. Intriguingly, the patient exclusively generated anti-LAD-1 IgG, suggesting that anti-LAD-1 IgG was responsible for the development of her autoimmune blistering dermatosis. This is the first such case documented in a non-Japanese patient, thus, lending further support to the pathogenic relevance of anti-LAD-1 IgG in BP.
Highlights
Nivolumab, an immune checkpoint inhibitor, is an IgG4 antibody which antagonizes the programmed cell death protein 1 (PD-1) receptor [1] and was licensed by the FDA in 2014 for the treatment of metastatic melanoma [1]
There is increasing evidence that checkpoint inhibition can result, in rare cases, in the development of blistering skin diseases; clinically and immunopathologically indistinguishable from bullous pemphigoid (BP) [5,6,7,8,9,10,11,12,13,14] and associated with the development of tense blisters and erosions on erythematous skin. These lesions are characterized by subepidermal clefts and immunofluorescence reveals linear deposition of IgG and C3 at the dermal-epidermal junction (DEJ)
Our case suggests that in addition to increasing T-lymphocyte activation, the use of checkpoint inhibitors may be associated with the development of highly specific, B cell-driven autoimmune responses
Summary
An immune checkpoint inhibitor, is an IgG4 antibody which antagonizes the programmed cell death protein 1 (PD-1) receptor [1] and was licensed by the FDA in 2014 for the treatment of metastatic melanoma [1]. In most cases, circulating IgG autoantibodies, directed to the NC16A domain of the hemidesmosomal protein BP180 (type XVII collagen), are detectable in the serum The presence of these antibodies supports the clinical observation that checkpoint inhibitors can trigger BP. We present a case of BP which developed during treatment with nivolumab, in which anti-LAD-1 IgG antibodies alone were detectable. There was no deposition of IgA autoantibodies In line with these findings, serum IgG antibodies were detected by indirect IF microscopy on both monkey esophagus and human salt-split skin (Figure 3A). The patient continued to suffer from severe pruritus, on the feet, and developed vitiligo
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