. 2018 Jun 12;11(2):132–137. doi: 10.1007/s12254-018-0416-y

Table 1.

Management of ir-AEs in patients treated with ICIs/overview of the most relevant (S)AEs (severe adverse events) focused on severe adverse events (CTCAE 5.0 ≥ 3). (Adapted from [10]; based on expert consensus based recommendations with benefits outweighing harms—strength of recommendations is moderate)

	Grading	Management
1. Skin toxicities	According to CTCAE is a challenge for skin. Severity is based on BSA, tolerability, morbidity and duration
1.1. Rash/inflammatory dermatitis Erythema multiforme minor, lichenoid, eczematous	G3: as G2 but with failure to respond to indicated interventions for G2 dermatitis	Holding ICI & weekly monitoring and treat with topical emollients, antihistamines & high-potency topical corticosteroids + initiate 1–2 mg/kg corticosteroid^a + tapering over at least 4 weeks
	G4: all severe rashes unmanageable with prior interventions	Systemic corticosteroids IV ^a 1–2 mg/kg with slow tapering when toxicity resolves. Consult with dermatology. Consider alternative antineoplastic therapy, if ICIs are the patient’s only option, consider restarting once these adverse effects have resolved to a G1 level
1.2. Bullous dermatoses including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction	G3: skin sloughing covering >30% BSA with associated pain and limiting self-care ADL	Hold ICI & consult with dermatology; administer IV corticosteroids^a 1–2 mg/kg, tapering over at least 4 weeks, if bullous pemphigoid is diagnosed, it may be possible to avoid long term use of systemic corticosteroids and start with rituximab as an alternative approach to treat ir-AEs. Seek infectious disease consultation if patient have secondary cellulitis or other infection risk factors like neutropenia etc.
	G4: blisters covering >30% BSA with associated fluid or electrolyte abnormalities	Permanently discontinue ICIs, place patient under supervision of a dermatologist, administer IV corticosteroids^a 1–2 mg/kg & treat with rituximab as an alternative approach + seek infectious disease consultation if patient have secondary cellulitis or other infection risk factors like neutropenia etc.
1.3. SCARs (including SJS, TEN, acute generalized exanthematous pustulosis, DRESS/DIHS) severe changes in either structure or function of skin, the appendages or the mucous membranes due to a drug	G3: skin sloughing covering <10% BSA with mucosal involvement associated signs (e.g., erythema, purpura, epidermal detachment, mucous membrane detachment)	Hold ICI & consult with dermatology; treat skin with topical emollients & other petrolatum emollients; administer IV corticosteroids^a 0.5-1 mg/kg & convert to oral on response, wean over at least 4 weeks; add additional immunosuppressive agent (cyclosporine) in corticosteroid unresponsive cases
	G4:skin erythema & blistering/ sloughing covering ≥10 to >30% BSA with associated signs (e.g., erythema, purpura, epidermal detachment, mucous membrane detachment) and/or systemic symptoms and concerning associated blood work abnormalities (e.g., liver function test elevations in the setting of DRESS/DIHS)	Permanently discontinue ICIs; admit patient immediately to a burn unit or ICU with consulted dermatology & wound care services. Initiate IV corticosteroids^a 1–2 mg/kg and tapering when toxicity resolves to normal; IVIG or cyclosporine may also be considered in corticosteroid unresponsive cases
Additional considerations: the usual prohibition of corticosteroids for SJS is not relevant here, as the underlying mechanism is a T-cell immunodirected toxicity. Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of DRESS/DIHS
2. Enterocolitis		Work up of blood; testing of lactoferrin (to determine who needs more urgent endoscopy) & calprotectin (to follow-up on disease activity); screening laboratories (HIV , hepatitis A & B, blood quantiferon for tuberculosis) to prepare patients for infliximab treatment & should be routinely determined in patients at high risk; imaging (e.g., CT scan of abdomen & pelvis & GI endoscopy with biopsy) for early detection of ulceration in the colon that can predict a corticosteroid-refractory course that may require early infliximab treatment
	G3: increase of 7 or more stools per day over baseline, incontinence, hospitalization indicated, severe increase in ostomy output compared with baseline, limited self-care ADL	Consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to G1 or less., administer corticosteroids^a 1–2 mg/kg; if symptoms persist ≥3–5 days or recur after improvement, consider administering IV corticosteroids^a or infliximab; consider colonoscopy in cases where patients have been on immunosuppression & may be at risk for opportunistic infections (i.e., CMV colitis) & for those who are anti-TNF or corticosteroid refractory
	G4: life-threatening situation; urgent intervention indicated	Permanently discontinue treatment; administer 1–2 mg/kg corticosteroids^a until symptoms improve to G1 & then start taper over 4–6 weeks; if symptoms are refractory to corticosteroids administer infliximab 5–10 mg/kg within 2–3 days. If there is concern of new infection or symptoms remain refractory to treatment consider lower GI endoscopy and consider vedolizumab in patients refractory to infliximab and/or contraindicated to TNF-alpha blockade.^b
3. Hepatitis	G3: symptomatic liver dysfunction, fibrosis by biopsy, compensated cirrhosis, reactivation of chronic hepatitis (AST or ALT 5–20 × ULN and/or total bilirubin 3–10 × ULN)	Permanently discontinue ICIs, immediately start corticosteroid^a 1–2 mg/kg; if no improvement assessed after 3 days or if corticosteroid refractory, consider mycophenolate mofetil or azathioprine, daily laboratories & close monitoring for patients with AST/ALT > 8 × ULN and or elevated TB 3 × ULN (infliximab should not be used—potential risk of liver failure); corticosteroid taper can be attempted around 4–6 weeks; re-escalate if needed, optimal duration is unclear
3. Hepatitis	G4: decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma; AST or ALT > 20 × ULN and/or total bilirubin >10 ULN)	Permanently discontinue ICIs, immediately start corticosteroid^a 2 mg/kg, if no improvement assessed after 3 days or if corticosteroid refractory the same management as in the case of G3
4. Pneumonitis focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging)	G3: severe symptoms, hospitalization required, involves all lung lobes or >50% of lung parenchyma, limiting self-care ADL, oxygen indicated	Permanently discontinue ICI, empirical antibiotics; administer corticosteroid^a 1–2 mg/kg, no improvement after 48 h, add infliximab 5 mg/kg or mycophenolate mofetil IV 1 g twice a day or IVIG for 5 days or cyclophosphamide; taper corticosteroids over 4–6 weeks. Pulmonary & infectious disease consults if necessary, BAL ± transbronchial biopsy offered
	G4: life threatening respiratory compromise, urgent intervention indicated (intubation)
5. Endocrinopathies
5.1. Primary hypothyroidism	G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold ICI until symptoms resolve to baseline with appropriate supplementation; endocrine consultation, add IV therapy if signs of myxedema (bradycardia, hypothermia); thyroid supplementation and reassessment as in G2
5.2. Hyperthyroidism	G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold ICIs until symptoms resolve to baseline, endocrine consultation, beta blocker for symptomatic relief, for severe symptoms administer corticosteroids^a 1–2 mg/kg and taper over 1–2 weeks & consider also use of SSKI or thionamide (methimazole or PTU)
5.3. Primary adrenal insufficiency	G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold ICIs until patient is stable on replacement hormone, endocrine consultation, IV stress dose corticosteroids on presentation (hydrocortisone 100 mg or dexamethasone 4 mg—if diagnosis is not clear & stimulation testing will be needed). Taper stress dose corticosteroids down to maintenance doses over 7–14 days after discharge, continue maintenance therapy as in G1 and titrate down as symptoms dictate
5.4. Hypophysitis Low ACTH with low cortisol; low or normal TSH with a low FT4; hypernatremia and volume depletion with diabetes insipidus; low testosterone or estradiol with low LH & FSH		Consider MRI of the brain with or without contrast with pituitary/sellar cuts in patients with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes
	G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold ICIs until patient is stable on replacement hormone; hormonal replacement as in G1; consider initial pulse therapy with corticosteroid^a 1–2 mg/kg oral daily with subsequent tapering over at least 1–2 weeks
5.5. Diabetes T1DM (autoimmune) results from islet destruction and is often acute onset, with ketosis and an insulin requirement	G3–4: severe symptoms, medically significant or life-threatening consequences, unable to perform ADL G3: >250–500 mg/dl	Hold ICIs until glucose control is obtained on therapy with reduction of toxicity to G1 or less, urgent endocrine consultation for all patients, admit for inpatient management: possibility of developing DKA
	G4: >500 mg/dl
6. Nervous system toxicities
6.1. Myastenia gravis	G3–4: limiting self-care and aids warranted, weakness limiting walking, any dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms	Permanently discontinue ICIs; admit patient, may need ICU level monitoring, neurology consult, continue corticosteroids^a 1–2 mg/kg and initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) or plasmapheresis for 5 days, frequent pulmonary function assessment, daily neurologic review. Pyridostigmine starting at 30 mg orally three times a day and gradually increase based on symptoms
6.2. Guillain-Barré syndrome Corticosteroids are usually not recommended for idiopathic Guillain-Barré syndrome, however, in ICIs related forms a treatment is reasonable	G3–4: severe, limiting self-care and aids warranted, weakness limiting walking, any dysphagia, facial weakness, respiratory muscle weakness or rapidly progressive symptoms	Rapid transfer to ICU-level monitoring, start IVIG (0.4 g/kg/day for 5 days) or plasmapheresis; administer corticosteroids^a 2–4 mg/kg/day followed by slow taper, frequent pulmonary function assessment, daily neurologic review; nonopioid management of neuropathic pain
6.3. Peripheral neuropathy	G3–4: severe, limiting self-care and aids warranted, weakness limiting walking; severe may be Guillain-Barré syndrome	Proceed as per Guillain-Barré syndrome
6.4. Autonomic neuropathy	G3–4: severe limiting self-care and aids warranted	Permanently discontinue ICIs; admit patient; initiate corticosteroid^a 1 g daily for 3 days followed by taper, neurologic consultation
6.5. Aseptic meningitis	G3–4: severe, limiting self-care and aids warranted	Hold ICI and discuss resumption with patient only after taking into account the risks and benefits. Consider empirical antiviral (IV acyclovir) and antibacterial therapy until CSF results—once bacterial & viral infection are negative, may closely monitor off corticosteroids^a or consider oral corticosteroids^a 0.5 –1 mg/kg/day if moderate/severe symptoms
6.6. Encephalitis	G3–4: severe, limiting self-care and aids warranted	Proceed as per aseptic meningitis, consider administration of corticosteroid^a 1–2 mg/kg if severe: pulse corticosteroid^a 1 g IV for 3–5 days plus IVIG 2 g/kg over 5 days; if positive for autoimmune encephalopathy antibody and limited or no improvement, consider rituximab or plasmapheresis in consultation with neurology
6.7. Transverse myelitis	G3–4: severe, limiting self-care and aids warranted	Permanently discontinue ICIs; administer corticosteroid^a 2 mg/kg; strongly consider higher doses of 2 g/day for 3–5 days; strongly consider IVIG
7. Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis	G3: moderately abnormal testing or symptoms with mild activity	Hold ICIs and permanently discontinue after G1
	G4: moderate or severe decompensation; IV medication or intervention required, life-threatening conditions	High dose corticosteroids^a 1–2 mg/kg initiated rapidly (oral or IV depending on symptoms), admit patient, cardiology consultation; in patients without immediate response to high dose corticosteroids^a, increase to 1 g every day of corticosteroids and consider the addition of either mycophenolate, infliximab or antithymocyte globulin
Statement: Holding of checkpoint inhibitor therapies recommended for all grades of cardiovascular complications
8. Nephritis	G3: creatinine > 3 × baseline or > 4.0 mg/dl; hospitalization indicated	Permanently discontinue ICIs; administer corticosteroids^a 0.5–1 mg/kg, if worsening or no improvement increase to 1–2 mg/kg/day and taper over 4–6 weeks
8. Nephritis	G4: life threatening consequences; dialysis indicated	Consult nephrology, evaluate for other causes; administer corticosteroids^a 1–2 mg/kg/day

ACTH adrenocorticotropic hormone, ADL activities of daily living, ALT alanine aminotransferase, AST aspartate aminotransferase, BAL bronchoalveolar lavage, BSA body surface area, CSF cerebrospinal fluid, CTCAE 5.0 Common Terminology Criteria for Adverse Events, CTLA‑4 cytotoxic T‑lymphocyte-associated Protein 4, DIHS drug-induced hypersensitivity syndrome, DKA diabetic ketoacidosis, DRESS drug reaction with eosinophilia and systemic syndrome, FT4 free thyroxine, G grade, HIV humane immunodeficiency virus, ICIs immune-checkpoint inhibitors, ICU intensive care unit, IV intravenous, IVIG intravenous immunoglobulin, MRI magnetic resonance imaging, PD‑1 programmed cell death Protein 1, PD-L1 programmed death ligand 1, PTU propylthiouracil, SCARs severe cutaneous adverse reactions, SJS Stevens-Johnson syndrome, SSKI potassium iodide, TB total bilirubin, TEN toxic epidermal necrolysis, TNF alpha tumor necrosis factor alpha, T1DM type 1 diabetes mellitus, TSH thyroid-stimulating hormone, ULN upper limit of normal

^a(Methyl)prednisolone or equivalent

^bThis decision should be made on an individual basis and is based on case series showing promising results