immediately and established interventions instituted. Interventions are stepwise based on cirAE severity and offered alongside grade-based recommendations for discontinuation or interruption of immunotherapy. Treatment recommendations for each cirAE class will be expanded upon below.
Type of Cancers Treated With Immune Checkpoint Inhibitors
ICIs can be classified based on the proteins they inhibit: cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Except for the novel LAG-3 inhibitor, multiple drugs exist within each class with various oncologic indications (Table 2).
Immune Checkpoint Inhibitors and Associated Cutaneous Adverse Events
While the heightened immune response activated by ICIs has meaningful anti-cancer effects, the ensuing immunologic commotion can idiosyncratically confront any host organ system including the skin. Cutaneous immune-related adverse events (cirAEs) develop in up to 60% of ICI-treated cancer patients, with the highest rate in those receiving combination immunotherapy (59-72%) followed by anti-CTLA-4 (44-59%), anti-PD1 (34-42%), and anti-PD-L1 (~20%) monotherapies.5,25-27 The median time to onset of cirAEs is 4 weeks, often presenting as the first treatment-related toxicity; however, a broad temporal range has been reported from time of onset to years later, including beyond treatment discontinuation.5,12
Inflammatory dermatoses including maculopapular, eczematous, bullous, lichenoid, and psoriasiform eruptions predominate the cirAEs, as well as pruritus. Less common manifestations include granulomatous eruptions, keratinocyte carcinomas, alopecia, rheumatologic dermatoses, severe cutaneous adverse reactions, and others.25 ICI-induced pigmentary changes are also important to recognize, particularly the development of vitiligo-like depigmentation in the setting of melanoma which is associated with improved response to treatment. While some patients with pre-existing dermatologic conditions may have ICI-induced exacerbation of their chronic skin disease, it is impossible to predict which patients will develop cirAEs and which type they will develop. According to CTCAE (v.5) categorization, cirAEs are generally mild to moderate with severe toxicity (grade 3-4) occurring in <5% of those receiving combination immunotherapy and <3% in monotherapy. Treatment discontinuation because of a cirAE is likewise approximately 5%.27 Importantly, ICI anti-cancer efficacy has been correlated with the extent of immune activation, and an association between the development of cirAEs and clinical benefit (ie, progression-free survival) has been shown.28,29 Therefore, treatment of cirAEs, when safe and appropriate, can limit ICI-
