Cutaneous manifestations associated with immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.

Keywords: CTLA-4; PD-1; PD-L1; cutaneous manifestation; epidemiology; immune checkpoint inhibitors; immune-related adverse events.

Figure 1

Common cutaneous irAEs. (A) Maculopapular rash. Erythematous macules and papules on the trunk. (B) Psoriasiform eruption. Scaly keratotic erythema plaques on the gluteal region and lower limbs. (C) Lichen planus-like eruption. Erythematous patches with scale and hyperkeratosis on the hands and lower limbs. (D) Vitiligo. Depigmented macules developing into plaques on the forearm. irAEs, immune-related cutaneous adverse events. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.

Figure 2

Bullous pemphigoid eruption. Multiple small tense bullae on extremities. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.

Figure 3

Alopecia areata. Circumscribed patches of hair loss on the parietal region. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.

Figure 4

Scleroderma. (A) Skin thickening and hardening causing the stiffness of the fingers and hands. (B) Skin thickening and hardening with pigmentation on the trunk. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.

Figure 5

Toxic epidermal necrolysis. (A) Erythematous macules, bullae, and erosions on the trunk. (B) Hemorrhagic erosion of the lip. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.

Figure 6

Time to onset of cutaneous immune-related cutaneous adverse events. MPR, Maculopapular rash; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysis; DIHS, Drug-induced hypersensitivity syndrome; DRESS, Drug reaction with eosinophilia and systemic symptoms; irAEs, immune-related cutaneous adverse events.