Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

Eur J Cancer. 2016 Jun:60:210-25. doi: 10.1016/j.ejca.2016.02.024. Epub 2016 Apr 13.


Background: Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.

Methods and findings: In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.

Conclusion: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Keywords: Adverse event; Anti-PD-1; Checkpoint inhibitors; Immune-related; Nivolumab; Pembrolizumab; Side-effect; Tolerability; Toxicity.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antineoplastic Agents / adverse effects*
  • Cell Cycle Checkpoints
  • Eye Diseases / chemically induced
  • Female
  • Heart Diseases / chemically induced
  • Humans
  • Ipilimumab
  • Male
  • Melanoma / drug therapy*
  • Middle Aged
  • Musculoskeletal Diseases / chemically induced
  • Nervous System Diseases / chemically induced
  • Nivolumab
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Respiratory Tract Diseases / chemically induced
  • Retrospective Studies
  • Skin Neoplasms / drug therapy*


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