Search

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.