title: Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy.
abstract: OBJECTIVE
  Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies.
  
  
  METHODS
  Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN).
  
  
  RESULTS
  Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions.
  
  
  CONCLUSIONS
  As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023-9. ©2016 AACR.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Stieger
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meier
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Micaletto
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Contassot
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. reinhard.dummer@usz.ch.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001706:Biopsy; D002986:Clinical Trials as Topic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D012871:Skin Diseases / Q000175:diagnosis / Q000209:etiology*
chemical_list: D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor