Hemidesmosomal Reactivity and Treatment Recommendations in Immune Checkpoint Inhibitor-Induced Bullous Pemphigoid-A Retrospective, Monocentric Study

Abstract

Immune checkpoint inhibitors (ICI) induce T-cell-mediated antitumour responses. While ICI were initially successfully applied in metastasized melanoma, they are now approved for several tumour entities. Numerous autoimmune disorders have been reported to occur as adverse events of the treatment, among them bullous pemphigoid (BP), with less than 1% of the patients experiencing ICI-induced BP. This number is higher than the estimated prevalence of autoimmune bullous diseases in the general population of Germany, which lies around 0.05%. We here describe our cohort of eight patients, who developed a bullous pemphigoid under or shortly after ICI treatment. Half of them had a severe subtype (as shown by BPDAI >57) and showed a median onset of ICI-BP after 10 months of ICI initiation. Six patients had a palmar and/or plantar involvement, while oral involvement occurred in one case. All patients had linear epidermal IgG depositions in split skin in the indirect immunofluorescence. In four out of five biopsies available for direct immunofluorescence, linear IgG and C3 depositions were detected at the basement membrane, while one patient showed linear IgM staining. Moderate to high levels of FLBP180 autoantibodies were found in seven of eight cases. The disease can still be active after ICI discontinuation, while rituximab might be required for remission. Finally, four tumour samples were stained histochemically for collagen XVII (BP180), but no enhanced expression was found.

Keywords: autoimmune bullous disorders; collagen XVII; immunosuppression; melanoma; skin fragility.

Figure 1

Immunohistochemistry staining for collagen XVII (BP180) in malignant tumours of the skin. Using a rabbit monoclonal antibody (Abcam, clone: EPR14758) to collagen XVII (BP180), we stained formalin-fixed paraffin-embedded tissue sections of normal skin and tumour tissue available from a subgroup of our patient cohort. Upper line shows H&E stainings. Lower line shows staining for collagen XVII (BP180). Staining for collagen XVII in normal skin shows a physiological intercellular distribution in the basal layers of epidermal keratinocytes and following the adnexal structures into the deeper dermis. Nearly all tumour cells of the cutaneous squamous cells carcinoma (cSCC) showed strong positive staining for collagen XVII (patient #7). No positive staining was seen in melanoma cells of the nodal metastasis of patient #4 or in the Merkel cell carcinoma (MCC) cells of patient #6. In the latter, positive staining could only be detected in regions of physiological epidermis. Finally, weakly positive staining was found in melanoma cells of a subcutaneous metastasis of patient #3. Scale bar = 100 µm; insert scale bar = 25 µm.

Figure 2

Clinical presentation of selected patients of the cohort, #1 shows excoriated, haemorrhagic erosions on erythematous ground on the back, #2 shows urticarial plaques with tense blisters on the abdomen, #3 presents with tense and eroded blisters on erythematous ground on the dorsum of the feet and lower leg, #6 shows periungual tense, dyshidrosiform blisters of the digitus I, IV and V and #8 shows tense, dyshidrosiform blisters on the palms of the hands and erosions on the right buccal mucosa.

Figure 3

Clinical presentation and BP progression of patient #1. Upper left picture (Nov 2017): eroded, haemorrhagic crusts on erythematous ground, which changed to urticarial plaques in June 2018 (upper right picture), when BP180 NC16A ELISA became positive. Direct immunofluorescence (lower left picture) with linear IgM n-serrated deposition at DEJZ of patient #1. Serological course of patient #1: initial positivity of BP230, followed by FLBP180 and BP180 NC16A in the course of time. Serological remission after therapy with rituximab in February 2019.

Figure 4

Clinical course of patient #1: Disease onset of melanoma in 2013, axillary lymph node macrometastasis in 2015, pembrolizumab initiation in 2016 because of cerebral metastasis, onset of pruritic exanthema in the end of 2017 and diagnosis of BP in 2018.