Clinical Associations and Classification of Immune Checkpoint Inhibitor-Induced Cutaneous Toxicities

A Multicentre Study From the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients

Vasiliki A. Nikolaou; Zoe Apalla; Cristina Carrera; Davide Fattore; Pietro Sollena; Julia Riganti; Sonia Segura; Azael Freites-Martinez; Konstantinos Lallas; Maria Concetta Romano; Chrysa Oikonomou; Michela Starace; Meletios A. Dimopoulos; Athanassios Kyrgidis; Elizabeth Lazaridou; Priscila Giavedoni; Maria Carmela Annunziata; Ketty Peris; Maria Echeverría; Emilio Lopez-Tujillo; Konstandinos Syrigos; Chryssoula Papageorgiou; Sebastian Podlipnik; Gabriella Fabbrocini; Ana C. Torre; Christina Kemanetzi; Lorena Villa-Crespo; Aimilios Lallas; Alexander J. Stratigos; Vincent Sibaud


The British Journal of Dermatology. 2022;187(6):962-969. 

In This Article

Abstract and Introduction


Background: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs).

Objectives: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies.

Methods: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models.

Results: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01–0·76] and vitiligo (OR 0·07, 95% CI 0·006–0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02–0·31), lichenoid reactions (OR 0·15, 95% CI 0·03–0·77) and eczematous reactions (OR 0·24, 95% CI 0·07–0·78), all compared with pruritic rash.

Conclusions: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome.


Immune checkpoint inhibitors (ICIs) have been approved for the treatment of various types of cancer, including non-small cell lung cancer (NSCLC), renal cell carcinoma, melanoma and nonmelanoma skin cancers. They have become a significant part of the therapeutic options for late-stage cancer therapies. They are characterized by a unique pattern of action that aims to enhance the host's immune response against cancer. However, these same properties of ICIs are responsible for a novel group of adverse events, known as immune-related adverse events (irAEs). Approximately 60% of patients receiving immunotherapy will experience at least one irAE during or even after their course of treatment, mainly involving diarrhoea, colitis, hepatitis, mucosal–cutaneous reactions and thyroid dysfunction.[1] Considering that these agents have been approved as a first-line treatment for a wide range of malignancies, irAEs attributed to ICI management have turned into a growing challenge of great clinical importance.

Cutaneous toxicities are among the most common irAEs in patients treated with ICIs.[2] Although cutaneous life-threatening reactions remain exceptional, they may lead to treatment interruption or even discontinuation and may have a significant negative impact on patients' quality of life.[3] Lichenoid dermatitis, eczematous reaction, maculopapular rash, pruritus, vitiligo, bullous pemphigoid and psoriasis are the most frequently reported cutaneous toxicities.[4] However, a remarkably wide range of uncommon skin reactions has also been reported. In this large, multicentre study conducted by the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients, we aimed to identify the clinical characteristics and the overall incidence of each skin toxicity among patients with cancer with cutaneous irAEs and to identify clinical associations for each toxicity.