Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy

JAMA Dermatol. 2018 Sep 1;154(9):1057-1061. doi: 10.1001/jamadermatol.2018.1912.

Abstract

Importance: An increasing number of cutaneous adverse reactions resulting from use of programmed cell death protein 1 (PD-1) inhibitors have been described, but with relatively little focus to date on the timing of these reactions.

Objective: To determine the timing of cutaneous drug reactions after initiation of PD-1 inhibitor therapy.

Design, setting, and participants: This retrospective observational study included patients referred to an academic dermatology clinic by an oncologist from January 1, 2014, through February 28, 2018, with at least 1 skin biopsy specimen of a skin reaction associated with PD-1 inhibitor use. Participants were included if they had a biopsy-proven cutaneous reaction in response to a PD-1 inhibitor used alone or in combination with ipilimumab.

Exposures: All patients included in this study received pembrolizumab, nivolumab, or nivolumab with ipilimumab as immunotherapy for cancer.

Main outcomes and measures: The main outcome measure was time to onset of biopsy-proven cutaneous reactions that occurred during or after use of pembrolizumab or nivolumab.

Results: A total of 17 patients (12 men, 5 women; mean [SD] age, 68.6 [11.1] years) were identified who presented with cutaneous adverse reactions associated with PD-1 inhibitor therapy; these reactions included lichenoid dermatitis, bullous pemphigoid, erythema multiforme, eczema, lupus, and sarcoidosis. Twelve patients presented with reactions at least 3 months after beginning pembrolizumab or nivolumab therapy. The skin reactions presented a median (range) of 4.2 months (0.5-38.0 months) after drug initiation. In 5 cases, the cutaneous adverse reactions attributed to the PD-1 inhibitor therapy developed after the drug therapy was terminated.

Conclusions and relevance: Diverse cutaneous adverse reactions secondary to PD-1 inhibitor use may present with delayed onsets and even after discontinuation of therapy. Dermatologists should be aware of the potential for delayed presentations of cutaneous adverse reactions.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antineoplastic Agents, Immunological / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Biopsy
  • Drug Eruptions / etiology*
  • Drug Eruptions / pathology
  • Eczema / chemically induced
  • Erythema Multiforme / chemically induced
  • Female
  • Humans
  • Ipilimumab / administration & dosage
  • Lichenoid Eruptions / chemically induced
  • Male
  • Middle Aged
  • Nivolumab / administration & dosage
  • Nivolumab / adverse effects*
  • Pemphigoid, Bullous / chemically induced
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Retrospective Studies
  • Sarcoidosis / chemically induced
  • Time Factors

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • Ipilimumab
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • pembrolizumab