Immune checkpoint inhibitors (ICIs) have been changing the paradigm of cancer treatment. However, immune-related adverse effects (irAEs) have also increased with the exponential increase in the use of ICIs. ICIs can break up the immunologic homeostasis and reduce T-cell tolerance. Therefore, inhibition of immune checkpoint can lead to the activation of autoreactive T-cells, resulting in various irAEs similar to autoimmune diseases. Gastrointestinal toxicity, endocrine toxicity, and dermatologic toxicity are common side effects. Neurotoxicity, cardiotoxicity, and pulmonary toxicity are relatively rare but can be fatal. ICI-related gastrointestinal toxicity, dermatologic toxicity, and hypophysitis are more common with anti- CTLA-4 agents. ICI-related pulmonary toxicity, thyroid dysfunction, and myasthenia gravis are more common with PD-1/PD-L1 inhibitors. Treatment with systemic steroids is the principal strategy against irAEs. The use of immune-modulatory agents should be considered in case of no response to the steroid therapy. Treatment under the supervision of multidisciplinary specialists is also essential, because the symptoms and treatments of irAEs could involve many organs. Thus, this review focuses on the mechanism, clinical presentation, incidence, and treatment of various irAEs.
Enterocolitis related to immune checkpoint inhibitors. (A) Before steroid treatment, axial contrast computed tomography scan shows wall thickening and abnormal enhancement in intestine. (B) After steroid treatment, intestinal wall thickening and abnormal enhancement are reduced.
Inflammatory arthritis related to immune checkpoint inhibitors on both knees; axial contrast computed tomography scan show moderate joint effusion of both knees (right > left) with associated synovial thickening.
Exacerbation of psoriasis under immune checkpoint inhibitors; plaque psoriasis with silvery scales on trunk.
Grading system (Common Terminology Criteria for Adverse Events version 5.0, European Society for Medical Oncology guideline, American Society of Clinical Oncology guideline)
The organ(s) | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
---|---|---|---|---|
Acute kidney injury | 1.0–1.5 × ULN | 1.5–3.0 × ULN | 3.0–6.0 × ULN | >6.0 × ULN |
(Cr increased) | <1.5 × baseline | 1.5–3.0 × baseline | >3.0 × baseline | Dialysis indicated |
Inflammatory arthritis | – Mild pain with inflammation, erythema, or joint swelling | – Moderate pain with inflammation, erythema, or joint swelling |
– Severe pain with inflammation, erythema, or joint swelling |
|
Colitis | – Asymptomatic |
– Abdominal pain |
– Severe abdominal pain peritoneal signs |
– Life-threatening consequences |
Hepatitis (AST, ALT increased) | <3.0 × ULN |
3.0–5.0 × ULN |
5.0–20.0 × ULN |
>20.0 × ULN |
Hypophysitis | – Asymptomatic or mild symptoms | – Moderate symptoms limiting age-appropriate instrumental ADL | – Severe or medically significant limiting self-care ADL | – Life-threatening consequences (visual field impairment) |
Skin rash | – Target lesions covering <10% BSA and not associated with skin tenderness | – Target lesions covering 10%–30% BSA and associated with skin tenderness | – Target lesions covering >30% BSA |
bullous rash |
Fatal adverse effects Myasthenia gravis | – Asymptomatic or mild symptoms | – Moderate symptoms |
– Severe or medically significant |
– Life-threatening consequences (respiratory muscle involved) |
Myocarditis | – Asymptomatic |
– Symptoms with moderate activity or exertion | – Severe with symptoms at rest or with minimal activity or exertion | – Life-threatening consequences (hemodynamic impairment) |
Pneumonitis | – Asymptomatic |
– Symptomatic (dyspnea, cough or chest pain) |
– Severe symptoms (new or worsening hypoxia) |
– Life-threatening respiratory compromise (need intubation and ventilator care) |
– Need oxygen therapy |
Cr, creatinine; ULN, upper limit normal; ADL, activity of daily living; BSA, body surface area; EKG, electrocardiogram.
Management of irAEs (European Society for Medical Oncology guideline, American Society of Clinical Oncology guideline)
The organ(s) | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
---|---|---|---|---|
Acute kidney injury | – Consider ‘Hold immunotherapy'- Hydration |
– Hold immunotherapy |
– Permanently discontinue immunotherapy |
– IV methylprednisone 1–2 mg/kg/day |
Inflammatory arthritis | – Continue immunotherapy |
– Consider ‘Hold immunotherapy' |
– Hold immunotherapy |
|
Colitis | – Continue immunotherapy |
– Consider ‘Hold immunotherapy' |
– Hold immunotherapy |
– Permanently discontinue immunotherapy |
Hepatitis | – Continue immunotherapy |
– Hold immunotherapy |
– Permanently discontinue immunotherapy |
|
Hypophysitis | – Consider ‘Hold immunotherapy' |
– Consider ‘Hold immunotherapy' |
– Hold immunotherapy |
|
Skin rash | – Continue immunotherapy |
– Consider ‘Hold immunotherapy' |
– Hold immunotherapy |
– IV prednisone 1–2 mg/kg/day |
Fatal adverse effects | ||||
Myasthenia gravis | – Continue immunotherapy |
– Hold immunotherapy |
– Permanently discontinue immunotherapy |
|
Myocarditis | – Hold or permanently discontinue immunotherapy at any sign of cardiotoxicity |
|||
Pneumonitis | – Hold immunotherapy | – Hold immunotherapy |
– Permanently discontinue immunotherapy |
DMARD, disease-modifying anti-rheumatic drug; IVIG, intravenous immunoglobulin; BAL, bronchoalveolar lavage.