Table 2

Critical IMARs requiring intervention and management12–14 18

IMAR*Possible presenting signs/symptomsRecommended workupGrade Management
Always inform the patient’s oncology team so that the ICI can be withheld or discontinued. Inform the on-call oncology coverage for the patient if a decision is made to initiate systemic immunosuppression
Colitis
prevalence 6–9:
Anti-PD-(L)1: 1.5%
Anti-CTLA-4: 8%
Anti-PD-1+anti-CTLA-4: 7%–10%
Rare but serious IMAR to consider: enterocolitis
  • Diarrhoea

  • Abdominal pain

  • Nausea

  • Cramping

  • Blood or mucus in stool

  • Changes in bowel habits

  • Fever

  • Abdominal distension

  • Obstipation

  • Constipation

  • CBC, UEC, LFTs, CRP, TFTs

  • Clostridium difficile/cryptosporidium screening

  • Consider:

    • Stool microscopy for leucocytes/parasites

    • Culture including drug-resistant organisms

    • Viral PCR

    • X-ray or CT abdomen/pelvis for colitis, particularly if abdominal pain

    • TB screen

    • CT abdomen/pelvis if moderate-to-severe abdominal pain and/or fever and/or vomiting are present

    • Gastroenterology input

    • Surgical review for bleeding, pain, distension

Grade 4: life-threatening consequences; urgent intervention indicated
  • Admission/isolation until infection ruled out

  • 1–2 mg/kg/day methylprednisolone or equivalent

  • Consider infliximab if already on steroids for >4 days

Grade 3: >6 liquid stools per day OR within 1 hour of eating; limiting self-care ADL
  • Admission if dehydration or electrolyte imbalance

  • 1–2 mg/kg/day methylprednisolone

Grade 2: 4–6 liquid stools per day over baseline, or ≥1 of:
  • Abdominal pain

  • Mucus or blood in stool

  • Nausea

  • Nocturnal episodes

  • Symptomatic management including fluids

  • Outpatient management possible with next-day follow-up

  • Consider 1 mg/kg/day methylprednisolone and/or prednisone at 1/mg/kg/day

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Dermatologic (rash, Stevens-Johnson syndrome or toxic epidermal necrolysis)
prevalence (all dermatologic toxicities)
6 7 10 12 28 29:
Anti-PD-(L)1: 9%–11%
Anti-CTLA-4: 29%–50%
Anti-PD-1+anti-CTLA-4: 23%
Rare but serious IMAR to consider: Stevens-Johnson syndrome
  • Rash

  • Blistering

  • Erythema

  • Skin sloughing

  • Purpura

  • Epidermal detachment

  • Mucous membrane detachment

  • Physical examination

  • Exclude other causes

Grade 4: skin sloughing >30% BSA with associated symptoms (eg, erythema, purpura, epidermal detachment)
  • Intravenous (methyl)prednisolone 1–2 mg/kg

  • Urgent dermatology review

  • Inpatient admission; ICU may be required

Grade 3: rash >30% BSA with moderate or severe symptoms
  • Topical treatment (potent)

  • Initiate steroids

    • If mild to moderate, 0.5–1 mg/kg prednisolone once daily for 3 days

    • If severe, intravenous (methyl)prednisolone 0.5–1 mg/kg and convert to oral steroids

  • Consider inpatient admission

Grade 2: rash covering 10%–30% BSA, potentially symptoms of pruritus or tenderness
  • Topical emollients

  • Topical steroids (moderate to potent) once or twice daily±oral/topical antihistamines for itch

Adrenal insufficiency
prevalence: see hypophysitis, which causes central/secondary adrenal insufficiency and other endocrinopathies
Primary adrenal insufficiency is rare but can be serious
  • Headache

  • Vision changes

  • Fatigue

  • Weakness

  • Dizziness

  • Nausea

  • Vomiting

  • Diarrhoea

  • Pituitary axis labs: 09:00 hour cortisol (or random if unwell and treatment cannot be delayed), ACTH, ACTH stimulation test for indeterminate results, metabolic panel (Na, K, CO2, glucose)

  • If primary adrenal insufficiency found:

    • Assess for cause (eg, infection)

    • Perform adrenal CT for metastasis/haemorrhage

  • Endocrinology referral

Grade 3/4: severe symptoms:
  • Severe hypoadrenalism, adrenal crisis (ie, hypotension, severe electrolyte disturbance)

  • Normal saline 2 L

  • Intravenous stress-dose corticosteroids

    • Hydrocortisone 100 mg OR

    • Dexamethasone 4 mg if stimulation test needed to confirm diagnosis

  • Consider admission

Grade 2: moderate symptoms:
  • Headache but no visual disturbance OR

  • Fatigue/mood alteration BUT haemodynamically stable, no electrolyte disturbance

  • ‘Stress-dose’ at 2×/3× maintenance (prednisone, 7.5 mg daily; hydrocortisone, 20 mg morning, 10 mg afternoon)

Hypophysitis
prevalence 8 10–13 19 29–31:
Anti-PD-(L)1: <1%
Anti-CTLA-4: ≤10%–17%
Anti-PD-1+anti-CTLA-4: 9%
  • Fatigue

  • Headache

  • Nausea

  • Vision changes

  • Confusion

  • Polyuria

  • Anorexia

  • Visual field assessment

  • Pituitary axis labs: 09:00 hour cortisol (or random if unwell and treatment cannot be delayed), ACTH, TSH/free T4

  • CNS imaging

    • CT head

    • MRI brain (pituitary protocol if available)

  • Endocrinology referral

  • Consider neurology consult if needed for pain relief beyond NSAIDs/paracetamol

Grade 3/4: severe mass effect symptoms:
  • Severe headache, any visual disturbance OR

  • Severe hypoadrenalism (ie, hypotension, severe electrolyte disturbance)

  • Intravenous (methyl)prednisolone 1–2 mg/kg

  • Start after sending pituitary assessment labs

  • Analgesia as needed for headache

Grade 2: moderate symptoms:
  • Headache but no visual disturbance OR

  • Fatigue/mood alteration BUT haemodynamically stable, no electrolyte disturbance

  • Consider:

    • Cortisol and/or thyroid replacement

    • Oral prednisolone 0.5–1 mg/kg once daily (start after sending labs for pituitary axis assessment) with oncology input

Hypothyroidism
prevalence 6–8 10 11 29 31:
Anti-PD-(L)1: 5%–9%
Anti-CTLA-4: <1%
Anti-PD-1+anti-CTLA-4: 22%
  • Fatigue

  • Constipation

  • Weight gain

  • Hair loss

  • Cold intolerance

  • Depression

  • Thyroid function (free T4, TSH)

  • Assess for adrenal insufficiency, which may be concurrent

Grade 4: life-threatening consequences; urgent intervention required
  • Start standard thyroid replacement therapy: initial dose can be the full dose (1.6 μg/kg) in young, healthy patients, but a reduced dose of 25–50 μg should be initiated in elderly patients with known cardiovascular disease

Grade 3: severe symptoms; limiting self-care ADL; hospitalisation indicated
Grade 2: symptomatic; thyroid replacement indicated; limiting instrumental ADL
Hyperthyroidism
prevalence 6–8 10 28 29 31:
Anti-PD-(L)1: 1%–5%
Anti-CTLA-4: <1%
Anti-PD-1+anti-CTLA-4: 8%
  • Weight loss

  • Palpitations

  • Heat intolerance

  • Tremors

  • Anxiety

  • Diarrhoea

  • Thyroid function (free T4, TSH)

Grade 4: life-threatening consequences; urgent intervention required
  • Follow standard therapy for hyperthyroidism

  • Thyroiditis is self-limiting and has two phases:

    • In the hyperthyroid phase, patients may benefit from beta-blockers if symptomatic (eg, atenolol 25‒50 mg daily, titrate for HR<90 if BP allows)

Grade 3: severe symptoms; limiting self-care ADL; hospitalisation indicated
Grade 2: symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL
Pneumonitis
prevalence (most common lung toxicity) 6–8 10 17 28–31:
Anti-PD-(L)1:<1%–4%
 Severe: 1%–2%
Anti-CTLA-4: <1%
Anti-PD-1+anti-CTLA-4: 6%
  • Dyspnoea

  • Fatigue

  • Chills

  • Weakness

  • Cough

  • Headache

  • History including travel, allergy, infections

  • Blood tests (CBC/UEC/LFTs/TFTs/Ca/ESR/CRP)

  • CXR

  • CT angiogram

  • Respiratory/pulmonology review

  • Consider:

    • Sputum sample and screening for infections

Grade 3/4: severe new symptoms; limiting self-care ADL; new/worsening hypoxia; life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation)
  • Admit to hospital

  • Cover with empirical antibiotics

  • Intravenous (methyl)prednisolone 1–2 mg/kg/day

  • Discuss need for escalation/ventilation

Grade 2: symptomatic mild/moderate (cough, dyspnoea, chest pain); no hypoxia; vitals normal
  • Start antibiotics if infection suspected based on fever, CRP, neutrophils

  • Intravenous (methyl)prednisolone 1–2 mg/kg/day and/or oral dosing

Hepatitis
prevalence 6–8 10 28 29 31:
Anti-PD-(L)1: <1%–2%
Anti-CTLA-4: 11%
Anti-PD-1+anti-CTLA-4: 13%
  • Jaundice of skin or sclera

  • Nausea

  • Vomiting

  • Abdominal pain

  • Fatigue

  • Dark urine

  • Anorexia

  • Metabolic panel or hepatic function panel

  • Hepatitis A/B/C serology if not done previously

  • Consider:

    • Ultrasound

    • CT abdomen/pelvis

Grade 3/4: AST, ALT>5×  ULN; total bilirubin>3×  ULN
  • Start prednisone 1–2 mg/kg/day

Grade 2: AST, ALT>3 to ≤5×  ULN; total bilirubin>1.5 to ≤3× ULN
  • Start prednisone 0.5–1 mg/kg/day (or equivalent dose of methylprednisolone)

Encephalitis
prevalence 6–8 10 28 31:
Anti-PD-(L)1: <1%
Anti-CTLA-4: <1%
Anti-PD-1+anti-CTLA-4: <1%
  • Confusion

  • Altered behaviour

  • Headache

  • Seizures

  • Short-term memory loss

  • Depressed level of consciousness

  • Focal weakness

  • Speech abnormality

  • Blood tests: metabolic panel, CBC, ESR, CRP, ANCA (if suspect vasculitis process), morning cortisol, ACTH, thyroid panel including TPO and thyroglobulin

  • MRI brain with and without contrast

  • Lumbar puncture (cell count, check for HSV/other viral PCRs, oligoclonal bands, check for autoimmune encephalopathy)

  • EEG (subclinical seizures)

Grade 3/4: severe, limiting self-care and aids warranted
  • Inform oncology team so that ICI can be withheld, intravenous acyclovir until PCR proven negative

  • Trial of methylprednisolone 1–2 mg/kg

  • Severe/progressing symptoms or oligoclonal bands:

    • Pulse corticosteroids (methylprednisolone 1 g intravenous daily 3–5 days) plus IVIG 2 g/kg over 5 days

Grade 2: moderate, some interference with ADL, symptoms concerning to patient (ie, pain but no weakness or gait limitation)
Nephritis
prevalence 6 7 10 28 29:
Anti-PD-(L)1:<1%–1%
Anti-CTLA-4: <1%
Anti-PD-1+anti-CTLA-4: 2%
  • Oliguria

  • Haematuria

  • Peripheral oedema

  • Anorexia

  • Ask patient about urination frequency

  • Review hydration status and medications

  • Urine test/culture if symptoms of urinary tract infection

  • Dipstick urine and send for protein assessment UPCR

  • Renal ultrasound±Doppler if obstruction suspected

  • Proteinuria: 24 hours collection or UPCR

  • Haematuria: phase contrast microscopy and glomerulonephritis screen

Grade 4: creatinine>6×  ULN
  • Admit patient for monitoring/fluid balance

  • Repeat creatinine every 24 hours

  • If worsening or severe renal failure, intravenous (methyl)prednisolone 1–2 mg/kg

Grade 3: creatinine>3×  baseline or >3–6× ULN
Grade 2: creatinine>1.5–3× baseline or >1.5–3× ULN
  • Hydration

  • Review creatinine

Pancreatitis
prevalence 6–8 28 31:
Anti-PD-(L)1: <1%
Anti-CTLA-4: 1.3%
Anti-PD-1+anti-CTLA-4: <1%
  • Abdominal pain

  • Nausea

  • Vomiting

  • Metabolic panel

  • Pancreatic enzymes (amylase, lipase)

  • Consider CT abdomen/pelvis

Grade 4: life-threatening consequences; urgent intervention indicated
  • Intravenous (methyl)prednisolone 1–2 mg/kg for grade 3 or greater toxicity

Grade 3: severe pain; vomiting; medical intervention indicated
Grade 2: elevated enzymes or radiographic findings only
Peripheral motor and sensory neuropathy
prevalence 28:
Anti-PD-(L)1:<1%
Anti-PD-1+anti-CTLA-4: <1%
  • Numbness

  • Paraesthesias with or without pain

  • Sensory ataxia

  • Hyporeflexia or areflexia

  • Neurology referral

Grade 4: life-threatening consequences; urgent intervention indicated
  • Start 1–2 mg/kg/day methylprednisolone equivalents intravenous

Grade 3: severe symptoms; limiting self-care ADL
Grade 2: moderate symptoms; limiting instrumental ADL
  • Treatment to be guided by neurology

Myocarditis, pericarditis, arrhythmias
prevalence (all cardiac toxicities) 10–12 14 29 30:
Anti-PD-(L)1: <1%–5%
Anti-PD-1+anti-CTLA-4: <1%
  • Dyspnoea

  • Chest pain

  • Arrhythmia

  • Pleural effusion

  • Fatigue

  • Palpitations

  • Weakness

  • Dizziness

  • Nausea

  • Vomiting

  • ECG, telemetry monitoring

  • CBC

  • Troponin, CK, CRP

  • B-type natriuretic peptide

  • CXR

  • Echocardiogram

  • Cardiology referral

Grade 4: moderate-to-severe decompensation, intravenous medication or intervention required, life-threatening conditions
  • 1–2 mg/kg of prednisone initiated rapidly (oral or intravenous depending on symptoms)

  • Admit to hospital

  • Manage symptoms with cardiology consultation

  • Transfer to coronary care if elevated troponin/conduction abnormalities

Grade 3: moderately abnormal testing or symptoms with mild activity
Grade 2: abnormal screening tests with mild symptoms
Uveitis
prevalence 12:
Any ICI: <1%
  • Blurred vision

  • Change in colour vision

  • Photophobia

  • Distortion

  • Scotomas

  • Visual field changes

  • Double vision

  • Tenderness

  • Pain with eye movement

  • Eyelid swelling

  • Proptosis

  • Ophthalmology referral (urgent for anterior uveitis with 1+ or greater cells)

  • Vision testing by/under guidance of ophthalmology:

    • Visual acuity (each eye)

    • Colour vision

    • Pupil size/shape/reactivity

    • Red reflex

    • Fundoscopic examination

Grade 4: best-corrected visual acuity of 20/200 or worse in the affected eye
  • Treatment to be guided by ophthalmology

  • To include ophthalmic/systemic prednisone/methylprednisolone

Grade 3: anterior uveitis with 3+ or greater cells; intermediate posterior or pan-uveitis
Grade 2: anterior uveitis with 1+ or 2+ cells
  • G1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated.

  • G2: moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL.

  • G3: severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care ADL.

  • G4: life-threatening consequences; urgent intervention indicated.

  • *Prevalence of IMARs is for any-grade IMARs.

  • CTCAE grade definitions18:

  • ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ALT, alanine aminotransferase; ANCA, antineutrophil cytoplasmic antibodies; AST, aspartate aminotransferase; BSA, body surface area; CBC, complete blood count; CK, creatine kinase; CNS, central nervous system; CRP, C reactive protein; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxic T-lymphocyte antigen-4; CXR, chest X-ray (roentgenogram); ECG, electrocardiogram; EEG, electroencephalography; ESR, erythrocyte sedimentation rate; HSV, herpes simplex virus; ICI, immune checkpoint inhibitor; ICU, intensive care unit; IMAR, immune-mediated adverse reaction; IVIG, intravenous immunoglobulin; LFT, liver function test; NSAID, non-steroidal anti-inflammatory drug; PCR, polymerase chain reaction; PD-1, programmed death-1; PD-L1, programmed death ligand 1; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TPO, thyroid peroxidase antibody; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine; ULN, upper limit of normal; UPCR, urine protein/creatinine ratio.