Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors

Juwhan Choi; Sung Yong Lee

doi:10.4110/in.2020.20.e9

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Choi and Lee: Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors

Review Article

Immune Netw 2020;20(1):e9.

Published online: 4 February 2020

DOI: https://doi.org/10.4110/in.2020.20.e9

Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors

Juwhan Choi, Sung Yong Lee^*

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea

^*Correspondence to Sung Yong Lee Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea. E-mail: syl0801@korea.ac.kr

Conflict of Interest The authors declare no potential conflicts of interest.

Received 23 November 2019 Revised 5 February 2020 Accepted 6 February 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.

Keywords: Immune checkpoint inhibitor, Adverse events, Programmed cell death 1

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Figure 1.

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.

Figure 2.

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.

Figure 3.

Exacerbation of psoriasis under immune checkpoint inhibitors; plaque psoriasis with silvery scales on trunk.

Table 1.

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 - Limiting instrumental ADL	– Severe pain with inflammation, erythema, or joint swelling - Irreversible joint damage - Limiting self-care ADL
Colitis	– Asymptomatic - Increase of fewer than 4 stools per day	– Abdominal pain - Mucus or blood in stool - Increase of four to 6 stools per day	– Severe abdominal pain peritoneal signs - Change in bowel habit - Increase of seven or more stools per day	– Life-threatening consequences
Hepatitis (AST, ALT increased)	<3.0 × ULN - Asymptomatic	3.0–5.0 × ULN - Asymptomatic	5.0–20.0 × ULN - Symptomatic liver dysfunction - Compensated cirrhosis - Reactivation of chronic hepatitis	>20.0 × ULN - Decompensated liver function (ascites, coagulopathy, encephalopathy, coma)
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 - Severe/life-threatening symptoms - Generalized exfoliative/ulcerated/b	bullous rash
Fatal adverse effects Myasthenia gravis	– Asymptomatic or mild symptoms	– Moderate symptoms - Limiting age-appropriate instrumental ADL	– Severe or medically significant - Limiting self-care ADL	– Life-threatening consequences (respiratory muscle involved)
Myocarditis	– Asymptomatic - Cardiac enzyme elevation or abnormal EKG	– Symptoms with moderate activity or exertion	– Severe with symptoms at rest or with minimal activity or exertion	– Life-threatening consequences (hemodynamic impairment)
Pneumonitis	– Asymptomatic - Confined to one lobe of the lung or <25% of lung parenchyma	– Symptomatic (dyspnea, cough or chest pain) - More than one lobe of the lung or 25%–50% of lung parenchyma	– Severe symptoms (new or worsening hypoxia) - All lung lobes or >50% of lung parenchyma	– 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.

Table 2.

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 - Check and stop nephrotoxic drug (PPI or NSAIDs)	– Hold immunotherapy - Oral prednisone 0.5–1 mg/kg/day - A nephrology consultation	– Permanently discontinue immunotherapy - Oral prednisone 1–2 mg/kg/day	– IV methylprednisone 1–2 mg/kg/day - Start dialysis
Inflammatory arthritis	– Continue immunotherapy - NSAIDs (eg, ibuprofen) or acetaminophen	– Consider ‘Hold immunotherapy' - Oral prednisone 10–20 mg/day - Intra-articular steroid injection - A rheumatology consultation	– Hold immunotherapy - Oral prednisone 0.5–1 mg/kg/day - Consider immunomodulatory therapy (DMARDs) in steroid non-responders
Colitis	– Continue immunotherapy - Oral fluids - Antidiarrheal agents (eg, loperamide) - Avoid high fibre/lactose diet	– Consider ‘Hold immunotherapy' - Oral prednisone 0.5–1 mg/kg/day - Consider sigmoidoscopy/ colonoscopy - A gastroenterology consultation	– Hold immunotherapy - Oral prednisone 1–2 mg/kg/day	– Permanently discontinue immunotherapy - IV methylprednisone 1–2 mg/kg/day - Consider immunomodulatory therapy (infliximab 5–10mg/ kg, mycophenolate mofetil or tacrolimus) in steroid non-responders
Hepatitis	– Continue immunotherapy - Check hepatotoxic drug	– Hold immunotherapy - Oral prednisone 0.5–1 mg/kg/day	– Permanently discontinue immunotherapy - IV methylprednisone 1–2 mg/kg/day - Consider immunomodulatory therapy (mycophenolate mofetil, azathioprine or tacrolimus) in steroid non-responders - Do not offer infliximab - A hepatology consultation
Hypophysitis	– Consider ‘Hold immunotherapy' - Start glucocorticoid replacement with stress day rules (e.g., hydrocortisone 10–20 mg orally in the morning, 5–10 mg orally in early afternoon, levothyroxine by weight)	– Consider ‘Hold immunotherapy' - Oral prednisone 0.5–1 mg/kg/day - An endocrinology consultation	– Hold immunotherapy - Oral prednisone 1–2 mg/kg/day
Skin rash	– Continue immunotherapy - Topical emollients - Topical corticosteroids - Oral antihistamines for pruritus	– Consider ‘Hold immunotherapy' - Oral prednisone 1 mg/kg/day	– Hold immunotherapy - A dermatology consultation - Oral prednisone 1–2 mg/kg/day	– IV prednisone 1–2 mg/kg/day - Consider immunomodulatory therapy in steroid non-responders
Fatal adverse effects
Myasthenia gravis	– Continue immunotherapy - Monitor symptoms for progression	– Hold immunotherapy - Oral prednisone 1–1.5 mg/kg/day - Pyridostigmine starting at 30 mg orally three times a day	– Permanently discontinue immunotherapy - IV methylprednisone 1–2 mg/kg/day - Consider IVIG or plasmapheresis in steroid non-responders - Consider immunomodulatory therapy (azathioprine, cyclosporine, mycophenolate) in steroid non-responders - A neurology consultation
Myocarditis	– Hold or permanently discontinue immunotherapy at any sign of cardiotoxicity - Systemic steroid (oral prednisone 1–2 mg/kg/day – methylprednisolone 1 g every day) - Consider additional immunomodulatory therapy (mycophenolate, infliximab, tacrolimus, or antithymocyte globulin) - Consider IVIG or plasmapheresis for unstable patients
Pneumonitis	– Hold immunotherapy	– Hold immunotherapy - Oral prednisone 1–2 mg/kg/day - Consider empirical antibiotics - Consider bronchoscopy and/or BAL	– Permanently discontinue immunotherapy - IV methylprednisone 1–2 mg/kg/day - Empirical antibiotics - Consider additional immunomodulatory therapy (infliximab 5 mg/kg, mycophenolate mofetil IV 1 g twice a day or cyclophosphamide) - Consider IVIG if there is no improvement - A pulmonology consultation

DMARD, disease-modifying anti-rheumatic drug; IVIG, intravenous immunoglobulin; BAL, bronchoalveolar lavage.

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