Skin manifestations associated with checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are a relatively novel class of drugs whose administration has been approved for several malignancies. Adverse events are quite common, and the skin is the most frequently involved organ. In fact, regardless of the neoplasm being treated, more than 50% of patients receiving ICIs develop cutaneous immune-related adverse events (irAEs), with variable time to onset and severity. Potential pathogenetic mechanisms include drug-induced formation of neoantigens, unmasking of hidden selfantigens, and diffuse keratinocyte apoptosis induced by CD4+ and CD8+ T cell activation. Risk of cutaneous irAEs seems to be higher after anti-CTLA-4 rather than anti-PD-1/PD-L1 agent administration and rises in case of combination therapy. Furthermore, incidence of skin toxicity increases in the presence of specific malignancies (i.e., advanced melanoma) and pre-existing dermatoses or autoimmune diseases, while the possible role of ethnicity is still unclear. Aim of this review is to summarise the current knowledge of cutaneous irAEs and provide the clinician with a detailed clinical and histopathological description of the following types of skin toxicity: inflammatory dermatoses, immunobullous diseases, alterations of melanocytes, alterations of keratinocytes, hair abnormalities, oral and nail involvement. Particular attention is given to practical management of the different cutaneous irAEs, including detailed information about treatment regimens and necessity for ICI discontinuation. Patients should always receive multidisciplinary care, especially in severe or recalcitrant cases. The role of the dermatologists remains pivotal, particularly with regard to differential diagnosis and management of complex skin toxicity, as well as regular longterm follow-up of the patient's conditions.

Severe drug eruption after antibiotic administration in patients receiving immune checkpoint inhibitors: A monocentric case series

“…All the patients received antibiotics for UTI or IP during ICI therapy and experienced a fever after the resolution of the infection‐related symptoms during antibiotic administration. Because the fever preceded the skin rash, determining whether the fever was an irAE, ICI‐induced drug reaction with eosinophilia and systemic symptoms (DRESS), 10 caused by the antibiotics or caused by a recurrent infection was difficult.…”

“…The frequency and severity of drug eruptions increase after immune checkpoint inhibitor administration (ICIs). [1][2][3][4][5][6][7][8][9][10] Herein we present three cases of severe drug eruption with high fever, hypotension, and dyspnoea following tazobactam/piperacillin (TAZ/PIPC) administration in patients receiving ICI therapy.…”

The Cellular Stress and Cutaneous Manifestations in Renal Cell Carcinomas—A Narrative Review

“…Monotherapy with immune checkpoint inhibitors or immune-based combination therapies is associated with improved survival, regardless of performance status [28]. Drug-induced cutaneous adverse reactions encompass a wide spectrum of skin manifestations, ranging from mild or moderate events to severe and life-threatening conditions [121][122][123][124][125]. Cutaneous manifestations are one of the most common immune-related adverse events, presenting with a variety of manifestations: superficial perivascular dermatitis, interface dermatitis, psoriasis, acantholytic dermatitis, acute generalized exanthematous pustulosis, and erythema nodosum-like panniculitis [121,[123][124][125].…”

Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events

“…Dapsone is an anti-infective sulfone that is FDA-approved for the treatment of leprosy and dermatitis herpetiformis. It can also be used off-label for a number of inflammatory dermatoses and has been used successfully for the treatment of ircAEs, including Sweet syndrome and immunobullous eruptions [40,[75][76][77][78]. Common adverse effects include anorexia, nausea, vomiting, headache, dizziness, tachycardia, anxiety, insomnia, and skin disorders.…”

“…Anti-TNFa agents, including monoclonal antibodies infliximab, adalimumab, and golimumab and receptor fusion protein etanercept, are FDA-approved for a variety of inflammatory disorders, including ankylosing spondylitis, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and various forms of arthritis. These therapies can also be used off-label for a variety of indications and have shown success for the treatment of maculopapular, psoriasiform, and lichenoid ircAEs as well as hidradenitis suppurative and pyoderma gangrenosum, which can occur with ICI treatment [1,41,77,148,149]. The NCCN also recommends the use of etanercept and other biosimilar agents for the treatment of SJS [3].…”