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Joining the bullae pulpit: PD-1 inhibitors

DII small banner By Warren R. Heymann, MD
Aug. 25, 2016

As the use of immune checkpoint inhibitors has increased, so have the number of severe immunotherapy-related adverse events (irAEs). Although discontinuation of therapy may result in resolution of these untoward reactions, long-term sequelae and death have been reported. In a recently published systematic review encompassing 191publications reporting on 251 cases, the following were noted:

Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab (1).

Autoimmune bullous dermatoses, notably bullous pemphigoid may now be added to the list. Jour et al, reported 5 patients with vesiculobullous disease while receiving either nivolumab or pembrolizumab. Four of the 5 were proven to have bullous pemphigoid (BP); one case was bullous erythema multiforme. The onset of BP following the administration of anti-PD-1 inhibitor therapy was an average of 78 days. All patients had a partial or complete resolution of the skin lesions with administration of systemic steroids and discontinuation of checkpoint blockade (2).

According to Spain et al, ipilimumab is a fully human monoclonal antibody against CTLA-4 binding of which leads to deactivation of the inhibitory signal of the T-cell. PD-1 is expressed on T-cells and binds to its ligands PD-L1 and PD-L2 that are expressed on cancer cells and other immune cells. Antibodies against PD-1, such as nivolumab, pembrolizumab and pidilizumab, or PD-L1, such as MEDI4736 and MPDL3280A increase the anti-tumor T-cell response by blocking the interaction of PD1 and PD-L1 to prevent T-cell inactivation. The anti-PD-1 antibodies have a different toxicity profile from ipilimumab, with fewer high-grade events (3).

Given the mechanism of these agents, it is no surprise that autoimmune bullous diseases have now been reported as irAEs. Early recognition is vital; by establishing rapid control of the blistering disease, perhaps it will be possible to maintain utilizaton of PD-1 inhibitors for further prolongation of life.

1. Abdel-Wahab N, et al. Adverse events associated with immune checkpoint blockade in patients with cancer: A systematic review of case reports. PLoS One 2016; Jul 29; 11 (7).
2. Jour G, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: A report on bullous skin eruptions. J Cutan Pathol 2016; 43: 688-96.
3. Spain L, et al. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016; 44: 51-60.

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