Clinical characterization and treatment outcomes of follicular cutaneous immune-related adverse events caused by immune checkpoint inhibitors: A multicenter retrospective study.

To the Editor: Acneiform rash, rosacea, folliculitis, and hidradenitis suppurativa related to immune checkpoint inhibitors (ICIs) have been limited to anecdotal reports,1Bousquet E. Zarbo A. Tournier E. et al.Development of papulopustular rosacea during nivolumab therapy for metastatic cancer.Acta Derm Venereol. 2017; 97: 539-540Crossref PubMed Scopus (11) Google Scholar,2Apalla Z. Nikolaou V. Fattore D. et al.European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force 'dermatology for cancer patients' position statement.J Eur Acad Dermatol Venereol. 2022; 36: 332-350Crossref PubMed Scopus (16) Google Scholar hindering the identification of clinical features for an accurate diagnosis and limiting therapeutic strategies. Herein, we characterize these follicular cutaneous immune–related adverse events (cirAEs), describe their management, and analyze the outcomes of dermatologic treatments. Following the ethics regulatory rules, a retrospective multicenter case-series study over a 5-year period between January 2016 and July 2021 was conducted by the European Academy of Dermatology and Venereology Task Force of dermatology for cancer patients. A total of 762 medical records of cancer patients treated with ICIs were reviewed from databases held by 11 oncodermatology units to identify patients who were diagnosed with follicular cirAEs. Diagnosis was based on the most representative clinical manifestations of each follicular cirAE, also considering the therapy timeline and temporal association with the ICI therapy (available Supplementary Tables I and II, available via Mendeley at https://doi.org/10.17632/rjvr5dkmm7.1). The dermatologic management and therapy outcome were assessed. Descriptive statistics and Chi-squared test were used. A total of 42 cancer patients with follicular cirAEs were included (Supplementary Table III, available via Mendeley at https://data.mendeley.com/datasets/rjvr5dkmm7/1). The median age was 63.5 years (53-70 years), 27 patients (64.3%) were men, and 17 patients (40.5%) had lung cancer. The most frequent follicular cirAEs were papulopustular rosacea in 21 patients (50%) and acneiform rash (35.7%). The face was the most affected area (35 [83.3%]). Almost all reactions (97.8%) were mild to moderate in severity. Bacteriologic reports were obtained for 11 patients; of which, 7 were negative (63.6%) for bacterial proliferation. Antiprogrammed cell death-1 therapy was the primary culprit in 27 patients (64.3%). The median time for development of follicular cirAE was 21 weeks (Supplementary Table III, available via Mendeley at https://data.mendeley.com/datasets/rjvr5dkmm7/1). Forty patients (95%) were treated with topical or systemic dermatologic therapy, with an overall complete or partial response in all cases. Topical antibiotics alone or in combination with topical corticosteroids were the preferred therapy in 28 patients (70%). Systemic dermatologic therapy was required to control the follicular cirAE in 42.5% patients, including doxycycline in 15 patients (37.5%) (Table I).Table IDermatologic management in 40 patients with rosacea, acneiform rash, folliculitis, and hidradenitis suppurativa related to immune checkpoint inhibitorsDermatologic managementTotal cases 40 (%)Rosacea 21 (%)Acneiform rash 15 (%)Folliculitis 3 (%)Topical dermatologic therapy Betamethasone + fusidic acid13 (32.5)2 (9.5)8 (53.3)2 (67.7) Metronidazol11 (27.5)11 (52.3)00 Ivermectine4 (10)4 (19)00 Clindamycine4 (10)02 (13.3)1 (33.3) Benzoyl peroxide2 (5)02 (13.3)0 Betamethasone1 (2.5)1 (4.8)00 Pimecrolimus + Benzoyl peroxide1 (2.5)1 (4.8)00No topical therapy4 (10)2 (9.5)2 (13.3)0Systemic dermatologic therapy Doxycycline 100-200 mg daily15 (37.5)8 (38.1)5 (33.3)1 (33.3) Oral prednisone1 (2.5)000 Antihistamines (cetirizine 10 mg)1 (2.5)1 (5)00Biopsy performed5 (12.5)1 (4.8)3 (20)1 (33.3)Available bacteriologic results11 (27.5)1 (4.8)7 (46.7)3 (100)Negative7 (63.6)1 (100)5 (71.4)1 (33.3)Positive4 (36.4)0 (0)2 (28.6)2 (66.6)Hidradenitis suppurativa was controlled in 1 case with betamethasone + fusidic acid, topical clindamycine, doxycycline 200 mg daily and oral prednisone. Open table in a new tab Hidradenitis suppurativa was controlled in 1 case with betamethasone + fusidic acid, topical clindamycine, doxycycline 200 mg daily and oral prednisone. Follicular cirAE in cancer patients involving particularly the face (observed in 83.3% in this group) may cause relevant psychosocial impact.3Orion E. Wolf R. Psychologic consequences of facial dermatoses.Clin Dermatol. 2014; 32: 767-771Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Hence, we sought to characterize these reactions, their management and outcomes with the potential to improve patients’ quality of life and ICI therapy adherence. Acneiform rash attributed to epidermal growth factor receptor or extracellular signal-regulated kinase and the mitogen-activated protein kinase inhibitors typically appears during the first 2 to 4 weeks of therapy. However, follicular cirAEs caused by ICIs were diagnosed much later (median 21 weeks). Moreover, the response to dermatologic therapy was similar when compared to the published experience with acneiform rash in patients receiving epidermal growth factor receptor inhibitors.4Gerber P.A. Meller S. Eames T. et al.Management of EGFR-inhibitor associated rash: a retrospective study in 49 patients.Eur J Med Res. 2012; 17: 4Crossref PubMed Scopus (23) Google Scholar We may speculate that changes on the skin microbiome may also play a role, since epithelial abnormalities with bacterial proliferation, and further local inflammation is relevant in the pathogenesis of acne and rosacea.5Kim H.S. Microbiota in rosacea.Am J Clin Dermatol. 2020; 21: 25-35Crossref PubMed Scopus (19) Google Scholar All our patients with follicular cirAEs were treated effectively principally with topical dermatologic therapy including antibiotics alone or in combination with corticosteroids. There is a need to develop clinical guidelines and trials for the prevention and management of these follicular cirAEs and to determine their incidence. VN, KL, CC, PS, ZA, MS, DF, GF, SS, and JR, have nothing to disclose. AF-M, consultant of ISDIN, L'Oreal, Galderma, and Shook, Hardy, Bacon LLP who represent Sanofi Aventis US LLC, and VS, speaker, or advisory role for Incyte, Bristol Myers Squibb, Novartis, Pierre Fabre, Bayer, Astellas, Amgen, Synox, MSD.