Immune checkpoint inhibitors cause organ-specific inflammatory/autoimmune toxicity (irAEs). Rule out infection first; moderate-to-severe cases require holding immunotherapy and high-dose systemic corticosteroids. For agents, mechanisms, and biomarkers, see

immune checkpoint inhibitors.

general principles

irAEs can affect any organ system at any time during or after treatment — toxicities can emerge months after discontinuation
any new symptom in a patient on or recently exposed to ICI is an irAE until proven otherwise
typical onset weeks 6–12; skin and GI typically earlier, hepatic/pulmonary/endocrine later
rule out infection before attributing symptoms to irAEs: collect infectious workup before high-dose steroids if feasible, but don’t delay steroids in an unstable patient
severity graded 1–4 (CTCAE); grade ≥3 → hold immunotherapy, initiate high-dose corticosteroids, involve relevant subspecialty
anti-CTLA-4 → higher rates of colitis, hypophysitis; anti-PD-1/PD-L1 → higher rates of pneumonitis, thyroiditis, hepatitis
combination CTLA-4 + PD-1 → grade ≥3 irAEs in ~55%; earlier onset, greater severity, more multi-organ involvement

workup

Baseline before starting ICI: TSH/fT4, AM cortisol, LFTs, Cr, glucose/HbA1c, hepatitis B serology.

First-line workup for suspected irAE: CBC, lytes, Cr, LFTs, TSH/fT4, AM cortisol, glucose, CRP, cultures — plus organ-specific tests below.

organ-specific irAEs

Organ	Presentation	Key workup	Management pearls
skin	maculopapular rash, pruritus, vitiligo	clinical assessment	grade 1–2: emollients, topical steroids, antihistamines; systemic steroids if severe
skin — SJS/TEN	diffuse painful rash + mucosal involvement (oral/ocular/genital) ± fever	urgent derm, skin biopsy	emergency — hold ICI, admit, urgent derm + ophtho; high-dose steroids
colitis	diarrhoea, abdominal pain, haematochezia; grade 3 = ≥7 stools/day over baseline	stool C. difficile, fecal calprotectin, CT abdomen, colonoscopy if grade ≥2 persistent or bleeding	hold ICI; IV methylprednisolone; steroid-refractory → infliximab (vedolizumab if high infection risk); exclude CMV colitis if refractory
hepatitis	often asymptomatic transaminase elevation; grade 2 ≈ ALT 3–5× ULN, grade 3 ≈ 5–20× ULN	hepatitis serologies, review other hepatotoxic drugs, RUQ US/MRCP to exclude mets/obstruction	hold ICI; high-dose steroids; steroid-refractory → mycophenolate (never infliximab — hepatotoxic)
pneumonitis	dyspnoea, cough, hypoxia; high risk in lung cancer/prior thoracic RT; new dyspnoea on ICI is pneumonitis until proven otherwise	CT chest preferred over CXR (ground-glass, organising pneumonia); bronchoscopy/BAL for grade ≥2–3 to exclude infection/lymphangitic spread	hold ICI; grade 2 = prednisone 1 mg/kg/day; grade 3–4 = IV methylprednisolone; reassess 24–72 h
thyroiditis	initial thyrotoxicosis → hypothyroidism	TSH, free T4	thyrotoxic phase: supportive (beta-blockers); hypothyroid phase: levothyroxine replacement
hypophysitis	fatigue, headache, visual changes, adrenal insufficiency	MRI pituitary, AM cortisol, TSH, gonadotropins	high-dose steroids acutely; long-term hormone replacement often needed
adrenalitis	adrenal insufficiency without pituitary involvement (ACTH elevated)	AM cortisol, ACTH	hydrocortisone replacement
nephritis	AKI, sterile pyuria, proteinuria — often misattributed to contrast/NSAIDs/PPI	urinalysis, Cr, UPCR, renal biopsy if unclear	hold ICI; steroids
myocarditis	chest pain, dyspnoea, arrhythmia, new conduction abnormalities (BBB, AV block)	troponin, BNP, ECG, echo, cardiac MRI; CK for myositis overlap	hold ICI; admit ICU; urgent cardiology; pulse IV methylprednisolone (see below)
neurological	myasthenia-like syndrome, Guillain-Barré, encephalitis	CK, EMG/NCS, MRI, LP	hold ICI; high-dose steroids; IVIG or plasmapheresis
rheumatologic	inflammatory arthritis, PMR-like syndrome, sicca	clinical ± RF/CCP, inflammatory markers	NSAIDs, low-dose prednisone; often chronic and persists after ICI — rheumatology input; rarely requires stopping ICI
haematologic	autoimmune haemolytic anaemia, aplastic anaemia, HLH	CBC, reticulocytes, DAT, haptoglobin, ferritin, fibrinogen, triglycerides	hold ICI; steroids; haematology input

Others: uveitis (red painful eye → ophtho), asymptomatic lipase elevation (common, does not require treatment unless clinical pancreatitis).

life-threatening irAEs

immune-mediated myocarditis — mortality up to 50%; elevated troponin + new conduction abnormality (BBB, AV block) is the hallmark; conduction disease is the leading cause of death
the fatal triad (the “3 M’s”) — myocarditis + myositis + myasthenia gravis can overlap; troponin elevation in any ICI patient with weakness is myocarditis until proven otherwise; screen for all three at presentation
immune-mediated DKA — sudden autoimmune beta-cell destruction → new DKA without prior diabetes; lifelong insulin
severe colitis — bloody diarrhoea, fever, or peritoneal signs; → risk of perforation; steroid-refractory → infliximab
SJS/TEN — mucosal involvement + painful rash → hold ICI, admit, urgent derm
myasthenic crisis / Guillain-Barré — respiratory failure risk → serial FVC/NIF, ICU monitoring

ICI myocarditis — why telemetry alone is unsafe

ICI myocarditis is fulminant and unpredictable; it can progress within hours from a stable-looking conduction abnormality to complete heart block, sustained VT, cardiogenic shock, and death.

Management:

permanently discontinue ICI
admit to ICU/monitored bed — continuous telemetry, pacing pads on, readiness for temporary transvenous pacing and mechanical circulatory support
pulse IV methylprednisolone 1 g/day × 3–5 days → oral prednisone 1 mg/kg/day with slow taper over 6–12 weeks
screen for the 3 M’s overlap — CK (myositis), bedside swallow/forced vital capacity (myasthenia); overlap worsens prognosis
steroid-refractory (no improvement 24–48 h) → abatacept, ATG, mycophenolate, IVIG, or plasmapheresis; avoid infliximab if reduced LVEF
urgent cardiology/cardio-oncology — serial troponin, ECG, echo; cardiac MRI when stable

ICI-induced type 1 diabetes and DKA

Abrupt autoimmune beta-cell destruction → insulin-deficient diabetes, often presenting as DKA. Unlike most irAEs, this is not steroid-responsive and the destruction is irreversible.

Management:

hold ICI until DKA resolved and glucose stabilised (may restart once on stable insulin)
treat DKA per standard protocol — IV fluids, insulin infusion, potassium repletion, glucose and gap monitoring
urgent endocrinology — anticipate lifelong insulin; C-peptide and anti-GAD/IA-2 antibodies confirmatory
corticosteroids have no role — they do not reverse beta-cell destruction and actively worsen hyperglycaemia

concurrent myocarditis + DKA

When both coexist, pulse methylprednisolone is mandatory for the cardiac toxicity but will dramatically worsen glycaemic control. Manage with aggressive insulin titration (often high-dose insulin infusion) alongside the steroids. Coordinate cardiology, endocrinology, and oncology simultaneously.

endocrine safety — the levothyroxine trap

Never start levothyroxine until adrenal insufficiency has been excluded or treated. Thyroid hormone increases cortisol clearance and can precipitate a fatal adrenal crisis. Always check AM cortisol/ACTH before initiating levothyroxine in ICI patients.

management framework

Grade	Action
1 (mild/asymptomatic)	continue ICI with close monitoring
2 (moderate, limits daily activities)	hold ICI; oral prednisone 0.5–1 mg/kg/day; subspecialty input
3 (severe, hospitalisation usually indicated)	hold ICI; IV methylprednisolone 1–2 mg/kg/day; subspecialty consult
4 (life-threatening)	permanently discontinue ICI; IV methylprednisolone ± additional immunosuppression

Exceptions to the framework: endocrine irAEs (replacement, not steroids — see above); rheumatologic irAEs (often managed through continued ICI).

steroid safety checklist

monitor glucose, BP, mental status
PJP prophylaxis (TMP-SMX) if ≥4 weeks of high-dose steroids anticipated
gastric mucosal protection (PPI)
bone protection (calcium, vitamin D ± bisphosphonate)

steroid-refractory irAEs

defined as no meaningful improvement after 48–72 hours of adequate corticosteroids (24–48 h for myocarditis)
escalation is organ-specific: colitis → infliximab (vedolizumab if high infection risk); hepatitis → mycophenolate (never infliximab); pneumonitis → infliximab, mycophenolate, or IVIG; neurological → IVIG/plasmapheresis; myocarditis → abatacept, ATG (avoid infliximab if low LVEF); haematologic → IVIG, rituximab per haematology
before infliximab: check hepatitis B serology (reactivation risk), exclude CMV in refractory colitis, consider TB risk

tapering and rechallenge

wait for improvement to grade ≤1 before initiating taper
taper over ≥4–6 weeks — rapid taper dramatically increases flare risk
monitor the organ during taper: hepatitis → ALT/AST/bili/INR; pneumonitis → SpO₂, O₂ requirement; colitis → stool frequency, CRP, fecal calprotectin
rechallenge depends on peak grade and cancer benefit: grade 4 generally precludes it; grade 2 and most resolved grade 3 non-cardiac/non-neuro irAEs are often rechallenged with close monitoring
endocrine exception: ICI can typically resume once stable on hormone replacement
permanent discontinuation regardless of grade: myocarditis, severe neurological toxicity, severe hepatitis, SJS/TEN

immune checkpoint inhibitor toxicity