Mucocutaneous adverse events to immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for various solid and hematologic malignancies. The expanding use of ICIs in oncology underscores the need for diagnosis and treatment expertise in immune related adverse events (irAE). Cutaneous toxicities are the earliest and most common irAE in this class of therapy. In addition to the more frequent reactions including vitiligo, lichenoid dermatitis, psoriasiform dermatitis, other less common skin toxicities including bullous dermatoses, neutrophilic dermatoses, and autoimmune dermato-rheumatologic diseases have been reported. Even though less than 3% of cutaneous irAEs (irCAEs) are classified as grade 3 or higher events, irCAEs can greatly impact quality of life. Appropriate management of irCAEs is critical to avoid unwarranted interruptions or discontinuation of lifesaving immunotherapy.

Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors

“…Clinical presentations include pruritic faint erythematous macules and papules that coalesce into plaques. It primarily affects the trunk and the extensor side of the extremities, while the head, palms, and soles are usually unaffected [13,14]. Histopathological examinations reveal interface changes and perivascular or periadnexal lymphocytic infiltration, with or without eosinophils.…”

“…Psoriasiform eruptions are more frequently observed in patients receiving PD-1/PD-L1 inhibitors than in patients receiving CTLA-4 inhibitors. Approximately 3-12% of patients treated with PD-1 inhibitors may be affected [13,14,81,82]. These eruptions can be categorized into two types, including newly onset psoriasis (de novo psoriasis) and a flareup of pre-existing psoriasis (reactivated psoriasis).…”

“…These events usually develop within the first few weeks to months after initiating immunotherapy, but they can occur at any time, even after treatment discontinuation [12]. A wide range of clinical presentations, including morbilliform eruptions, pruritus, lichenoid eruptions, psoriasiform dermatitis, vitiligo, bullous disorders, alopecia, and severe cutaneous adverse reactions (SCARs), have been reported [8,10,11,13,14]. These adverse events can significantly impact patients' quality of life and may require the discontinuation of treatment.…”

Fever of unknown origin associated with immune checkpoint inhibitors

“…Immune-checkpoint inhibitors (ICIs), which reverse aforementioned tumor-mediated immune evasion by blocking immune checkpoints, have revolutionized the treatment of malignant tumors since the approval in 2014 ( 2 ). Currently, FDA-approved ICIs comprise monoclonal antibodies targeting the PD-1 - PD-L1 axis or CTLA-4 - CD28 axis ( 3 , 4 ) ( Table 1 ). Concomitant with the surge of ICIs usage, immune-related adverse events (irAEs) have garnered increasing attention.…”