Immune toxicity
Description
- Autoimmune-like inflammation from removing physiological brakes on T cells
- Any organ, any time - including months after the last dose
- The differential for any new symptom in a patient on a checkpoint inhibitor is an irAE until proven otherwise
Agents
| Target | Drugs |
|---|---|
| CTLA-4 | Ipilimumab, tremelimumab |
| PD-1 | Nivolumab, pembrolizumab, cemiplimab, dostarlimab |
| PD-L1 | Atezolizumab, durvalumab, avelumab |
| LAG-3 | Relatlimab |
Toxicity burden
- Combination ipi/nivo > ipilimumab alone > anti-PD-1 alone
- Combination -> more hepatic and pulmonary toxicity, and more concurrent multi-organ toxicity
Class-specific pattern - high yield
| Anti-CTLA-4 | Anti-PD-1/PD-L1 | |
|---|---|---|
| Signature | Colitis, hypophysitis | Thyroiditis, pneumonitis |
| Dose-related | Yes | No |
| Onset | Earlier, weeks 6-12 | Variable |
Distinguish from other immune toxicity
- CAR-T / bispecifics -> cytokine release syndrome + ICANS, not irAEs - different mechanism, tocilizumab first
- Chemo/TKI toxicity is dose-dependent and predictable; irAEs are not
Epidemiology
- Any-grade irAE in ~70-90% on anti-PD-1; grade 3-4 in ~10-15%
- Combination ipi/nivo: grade 3-4 in ~55%; ~1/3 discontinue for toxicity
- Endocrine (thyroid ~12%) is the commonest organ system affected; skin is the earliest
- Fatal irAEs ~0.3-1.3% - myocarditis, pneumonitis, colitis/perforation, hepatitis, neurological
- irAE occurrence correlates with tumour response - but never accept toxicity as "a good sign" and undertreat it
Aetiopathogenesis
- Checkpoints normally maintain peripheral tolerance
- CTLA-4 - competes with CD28 for B7 in the lymph node -> limits T-cell priming
- Also constitutively expressed on Tregs -> blockade depletes/impairs Tregs
- PD-1/PD-L1 - acts in peripheral tissue -> limits effector T-cell activity in the tumour microenvironment
- CTLA-4 - competes with CD28 for B7 in the lymph node -> limits T-cell priming
- Blockade -> loss of self-tolerance
- -> autoreactive T-cell expansion, epitope spreading
- -> autoantibody unmasking, cytokine release, complement activation
- The site of action explains the toxicity profile
- CTLA-4 acts centrally/systemically -> colitis, hypophysitis
- PD-1 acts in tissue -> organ-specific thyroiditis, pneumonitis
- Risk higher with pre-existing autoimmune disease, prior irAE, certain HLA types, gut microbiome composition
Diagnosis
Timing - a rough guide, but any organ at any time
| Weeks | Typical |
|---|---|
| 2-4 | Skin (earliest) |
| 5-8 | Colitis, hepatitis |
| 6-12 | Endocrine (hypophysitis, thyroiditis) |
| 8-16 | Pneumonitis, nephritis |
| Any / late | Neurological, myocarditis, rheumatological |
- Peak in the first 3 months, but can occur after discontinuation - patients keep an alert card
Always exclude the mimic first
- Diarrhoea -> stool culture, C. difficile, CMV (esp. if steroid-refractory)
- Dyspnoea -> infection, PE, lymphangitis, disease progression
- Transaminitis -> viral hepatitis, drugs, alcohol, biliary obstruction, liver metastases
- Fatigue -> anaemia, hypothyroidism, adrenal insufficiency, hypercalcaemia
- New endocrine picture -> do not attribute low sodium to SIADH before excluding adrenal insufficiency
Baseline and on-treatment monitoring
- Every cycle: FBE, UEC, LFT, TSH, clinical review
- Baseline plus periodic: cortisol (morning), glucose/HbA1c, troponin and ECG (myocarditis screening in high-risk regimens), CK
- Symptom triggers: visual change, headache, lethargy, weight loss, hypotension, electrolyte disturbance
- CT chest/HRCT for any new respiratory symptom
Grading drives management
- CTCAE grade 1 (mild) / 2 (moderate, limiting instrumental ADLs) / 3 (severe, limiting self-care, hospitalisation) / 4 (life-threatening)
Management
General principles
| Grade | Action |
|---|---|
| 1 | Continue, monitor closely (exception: neurological, cardiac, haematological - act early) |
| 2 | Withhold drug; prednisolone 0.5-1 mg/kg if not resolving; resume once grade <=1 and steroids <10 mg |
| 3-4 | Permanently discontinue (except endocrine); admit; IV methylprednisolone 1-2 mg/kg/day; specialist referral |
- Steroid taper over at least 4 weeks (6-8 weeks for pneumonitis, hepatitis, myocarditis) - too fast -> rebound
- No response in 48-72 h (severe) or 5-7 days -> escalate to second-line immunosuppression and cease the drug permanently
- PJP prophylaxis if prednisolone >=20 mg for >4 weeks; PPI, calcium/vitD, glucose monitoring
- Corticosteroids do not appear to compromise antitumour efficacy
Organ-specific
Skin (commonest overall, earliest)
- Maculopapular rash, pruritus, lichenoid, vitiligo (good prognostic sign in melanoma)
- G1-2: topical steroid, antihistamine, emollient
- G3 (>30% BSA): withhold, urgent dermatology, prednisolone 1 mg/kg
- G4 - SJS/TEN, bullous, full-thickness ulceration: permanent discontinuation, IV methylprednisolone 1-2 mg/kg/day
- DRESS and SJS/TEN are the ones that kill
Colitis (CTLA-4 signature)
- G2 = 4-6 stools/day above baseline, or blood/mucus/abdominal pain
- Withhold; exclude infection; prednisolone 1 mg/kg; consider permanently ceasing CTLA-4
- G3-4 = >=7 stools/day, severe pain, peritonism, perforation
- Permanently stop CTLA-4 (PD-1 may be re-challenged later); gastroenterology + flexible sigmoidoscopy; CT to exclude perforation
- IV methylprednisolone 1-2 mg/kg/day
- Infliximab if no improvement by 72 h (contraindicated if perforation suspected or sepsis); vedolizumab as alternative
Hepatitis
- G2: AST/ALT 3-5x ULN or bili 1.5-3x - withhold, LFTs every 3 days, prednisolone, taper over 1 month
- G3-4: AST/ALT >5x ULN or bili >3x - permanent discontinuation, LFTs 1-2 daily, hepatology, IV methylprednisolone 1-2 mg/kg
- *Infliximab is contraindicated in irAE hepatitis - use mycophenolate* (or tacrolimus/ATG in refractory disease)
Pneumonitis (PD-1/PD-L1 signature; a leading cause of irAE death)
- G2: withhold, HRCT, consider bronchoscopy/BAL to exclude infection, prednisolone 1-2 mg/kg; discontinue permanently if recurrent
- G3-4: permanent discontinuation, admit, IV methylprednisolone 1-2 mg/kg, respiratory referral; add infliximab/MMF/IVIG if refractory at 48 h
- Radiological patterns: organising pneumonia, NSIP, hypersensitivity, diffuse alveolar damage
Endocrine - the exception to every rule
- *Continue the checkpoint inhibitor and replace the hormone* - steroids do not restore gland function
- Hypothyroidism -> thyroxine (often preceded by a transient painless thyrotoxic phase)
- Thyrotoxicosis -> usually transient thyroiditis; beta-blocker symptomatically; not carbimazole
- Hypophysitis (CTLA-4) -> headache, fatigue, visual field defect, hyponatraemia; MRI pituitary; hydrocortisone replacement; high-dose steroid only for mass effect
- Primary adrenal insufficiency -> hydrocortisone + fludrocortisone; *give steroid before thyroxine or you precipitate a crisis*
- Autoimmune (fulminant) type 1 diabetes -> may present as DKA with a near-normal HbA1c; insulin, permanently
Myocarditis - rare (~1%) but fatality up to 50%
- Any chest pain, dyspnoea, arrhythmia, raised troponin -> stop drug, admit to a monitored bed
- High-dose methylprednisolone 1 g daily; cardiology, echo, cardiac MRI
- Often overlaps with myositis and myasthenia gravis - the "triple M" syndrome; check CK and acetylcholine receptor antibodies
- Second-line: abatacept, ATG, plasma exchange
Neurological - myasthenia gravis, GBS, aseptic meningitis, encephalitis, transverse myelitis, peripheral neuropathy
- Low threshold to stop the drug, admit, steroids +/- IVIG/plasma exchange
- Myasthenia from checkpoint inhibitors is more often bulbar/respiratory and rapidly progressive than idiopathic MG
Other - nephritis (interstitial), inflammatory arthritis, sicca, uveitis, haemolytic anaemia, ITP, HLH, pancreatitis (often asymptomatic lipase rise - do not treat the number)
Re-challenge
- Reasonable after grade 2 resolution and steroid taper
- Recurrence rate ~30-50%; often the same organ
- Do not re-challenge after grade 3-4 neurological, myocarditis, SJS/TEN, or haemophagocytic syndrome
Pre-existing autoimmune disease
- Not an absolute contraindication - ~50% flare, most manageable
- Avoid in active severe disease or where flare would be catastrophic (e.g. myasthenia, active IBD)
Associations
- Melanoma, NSCLC, RCC, urothelial, head and neck SCC, Hodgkin lymphoma, MSI-H tumours - the settings where irAEs are encountered
- Pre-existing autoimmune disease, prior irAE, family history of autoimmunity
- Gut microbiome composition (higher Faecalibacterium diversity - better response, more colitis)
- HLA associations - HLA-DR4 and autoimmune diabetes; HLA-DQA1*05 and anti-TNF immunogenicity
- Solid organ transplant recipients - risk of allograft rejection
- Concurrent radiotherapy - radiation recall, inc pneumonitis risk
- Chronic hepatitis B/C, HIV - generally safe, but require monitoring
Natural history & complications
- Most irAEs are reversible with drug cessation and immunosuppression
- *Endocrinopathies are the exception - the gland is destroyed; replacement is lifelong*
- Hypothyroidism, adrenal insufficiency, hypophysitis (esp. ACTH deficiency), type 1 diabetes
- Thyrotoxic phase may recover; the hypothyroid endpoint rarely does
- Vitiligo is permanent
- Pneumonitis may leave fibrosis; colitis may leave chronic diarrhoea or need long-term biologic therapy
- Delayed irAEs occur months to years after the last dose - the patient's oncology history stays relevant to every future presentation
- irAE occurrence is associated with better tumour response and survival
- Chronic low-grade irAEs (arthritis, sicca, neuropathy, endocrine) affect ~40% of long-term survivors
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