Immune Checkpoint Inhibitor Toxicity (irAEs)

Approved ICI drugs (high-yield)

• Anti-PD-1: pembrolizumab, nivolumab, cemiplimab, dostarlimab, tislelizumab, retifanlimab, toripalimab, penpulimab.
• Anti-PD-L1: atezolizumab, durvalumab, avelumab, cosibelimab.
• Anti-CTLA-4: ipilimumab, tremelimumab.
• Anti-LAG-3: relatlimab (only in combination with nivolumab, Opdualag, melanoma).

Mechanism and epidemiology

• Mechanism: blockade of inhibitory checkpoints (PD-1, CTLA-4) "unleashes" T-cell responses against tumor, and incidentally against self-antigens, producing autoimmune-like inflammation. CTLA-4 blockade acts at lymph-node priming (peripheral tolerance); PD-1/PD-L1 acts at the tumor/tissue level (effector phase), which explains the higher overall toxicity with CTLA-4 inhibitors.
• Frequency (any-grade irAE): anti-PD-1/PD-L1 monotherapy ~70%; anti-CTLA-4 monotherapy ~70 to 90%; combination ipilimumab + nivolumab ~95%.
• Frequency (grade ≥3): anti-PD-1/PD-L1 monotherapy ~10 to 15%; anti-CTLA-4 monotherapy ~20 to 30%; combination ipilimumab/nivolumab ~40 to 55%.
• Timing: median onset 2 to 16 weeks but can occur at ANY time, including after stopping therapy. Skin and GI typically early; endocrine, pneumonitis, hepatitis, neuro later; myocarditis often EARLY (median ~34 d, frequently within first 1 to 3 cycles). Late-onset (>6 mo) also described.
• Class differences:
  • Anti-CTLA-4: more colitis, hypophysitis, rash.
  • Anti-PD-1/PD-L1: more pneumonitis, hypothyroidism, hepatitis, arthritis.
  • Combination: additive or supra-additive in nearly every organ.

Baseline workup before starting ICI

• History: autoimmune disease, prior organ transplant, baseline rashes, GI/endocrine/neurologic symptoms.
• Labs: CBC, CMP (liver, renal), TSH plus free T4, fasting glucose, cortisol (AM if endocrine risk), lipase, troponin (especially before combo therapy), HIV/HBV/HCV serologies.
• Baseline imaging: chest CT typically already done for staging; ECG and echo before combo or cardiotoxic agents.
• Vaccinations: inactivated vaccines (influenza, pneumococcal, COVID) prior to start; live vaccines contraindicated during therapy.

General management principles

• Grading: CTCAE v5.0 per organ system.
• Grade 1: continue ICI with close monitoring (with exceptions: hold for neuro, cardiac, hematologic). Grade 1 ocular (mild uveitis/episcleritis): continue ICI with ophthalmology evaluation and topical therapy.
• Grade 2: hold ICI; consider prednisone 0.5 to 1 mg/kg/day PO (or equivalent); resume ICI once back to ≤grade 1 and prednisone ≤10 mg/day.
• Grade 3: hold ICI; prednisone 1 to 2 mg/kg/day (PO or IV); if no improvement in 48 to 72 h, add second-line immunosuppression (organ-specific, see below).
• Grade 4: permanently discontinue ICI (with rare exceptions like endocrine, where replacement allows continuation); methylprednisolone 1 to 2 mg/kg/day IV, escalate immunosuppression; ICU as needed.
• Steroid taper: over at least 4 to 6 weeks once symptoms resolve (longer for hepatitis, pneumonitis, cardiac). Rapid taper causes relapse.
• PJP prophylaxis if steroids ≥20 mg prednisone for ≥4 weeks; fungal prophylaxis if prolonged high-dose; PPI for steroid-induced gastritis; bone protection for chronic courses.
• Re-challenge after irAE: generally safe for grade 1 to 2 events that have resolved; grade 3 case-by-case (cardiac, neuro, pneumonitis usually permanent discontinuation); grade 4 generally permanent discontinuation. Re-challenge with a single agent (dropping the CTLA-4 component) is a common strategy after combo-induced severe irAE.

Organ-specific irAEs

Skin (most common, ~30 to 50%)

• Patterns: maculopapular/morbilliform rash, pruritus, lichenoid, psoriasiform, eczematous, bullous pemphigoid, vitiligo (especially with melanoma, paradoxically associated with response).
• Severe cutaneous adverse reactions (SCARs): SJS/TEN, DRESS, RARE but high mortality. Permanent ICI discontinuation, derm consult, ICU/burn unit, supportive care, IVIG/cyclosporine/etanercept per derm.
• Grade 1 to 2: topical steroids, antihistamines, emollients; continue ICI (grade 2: consider holding ICI, high-potency topical steroids, and prednisone 0.5 to 1 mg/kg/day if not improving).
• Grade 3: hold ICI; prednisone 0.5 to 1 mg/kg/day.
• Grade 4 / SCAR: permanent discontinuation; methylprednisolone IV; derm-driven management.

GI, colitis / diarrhea (5 to 25%)

• Pattern: watery diarrhea ± blood/mucus, abdominal pain, ileal/right-sided colitis (more common with anti-CTLA-4) or pancolitis. Microscopic colitis common with anti-PD-1.
• Workup: stool studies (C. diff, culture, ova/parasites, CMV PCR if immunocompromised), CRP, fecal calprotectin/lactoferrin, CT abdomen if severe, flex sig/colonoscopy with biopsy (especially grade ≥2 or steroid-refractory).
• Grade 1: loperamide, hydration, dietary modification; continue ICI.
• Grade 2: hold ICI; prednisone 1 mg/kg/day; if no improvement in 3 to 5 d, escalate.
• Grade 3 to 4: hold/discontinue ICI; methylprednisolone 1 to 2 mg/kg/day IV; if no improvement in 48 to 72 h, infliximab 5 mg/kg IV (may repeat at 2 wk) OR vedolizumab 300 mg IV (preferred in TB/HBV concerns or refractory to infliximab); add ustekinumab in refractory cases.
• Avoid antimotility agents in severe colitis (risk of toxic megacolon).

Hepatitis (5 to 10% any grade, ~1 to 2% grade ≥3)

• Pattern: asymptomatic LFT elevation more often than jaundice; hepatocellular predominant (AST/ALT), can be mixed or cholestatic.
• Workup: rule out viral (HAV/B/C/E, EBV, CMV), drug-induced, alcohol, biliary obstruction (RUQ ultrasound); ANA, ASMA, AMA; liver biopsy in severe or refractory cases (usually lobular/centrilobular hepatitis without classic AIH features).
• Grade 1: continue ICI; monitor q1wk.
• Grade 2: hold ICI; prednisone 0.5 to 1 mg/kg/day.
• Grade 3: permanently discontinue; methylprednisolone 1 to 2 mg/kg/day IV.
• Grade 4: permanently discontinue; methylprednisolone 2 mg/kg/day IV; if no improvement in 3 d, add mycophenolate mofetil 500 to 1000 mg BID; avoid infliximab in severe hepatitis (hepatotoxicity); azathioprine or tacrolimus in refractory cases.
• Slow taper (≥4 to 6 wk): hepatitis frequently relapses with rapid taper.

Endocrine

• Thyroid dysfunction (most common endocrine irAE, ~15 to 20%)
  • Biphasic: transient hyperthyroidism (often asymptomatic, low TSH high T4, lasts weeks) then hypothyroidism (often permanent).
  • Workup: TSH, free T4, T3; TPO/TRAb optional. Distinguish destructive thyroiditis (low/normal RAIU, transient) from Graves (rare).
  • Hyperthyroid phase: beta-blocker for symptoms; no antithyroid drugs (it is destructive, not Graves).
  • Hypothyroid: levothyroxine replacement, lifelong. Continue ICI.
• Hypophysitis (more common with anti-CTLA-4 ~10%; rare with PD-1/L1 <1%)
  • Headache, fatigue, visual changes (uncommon), nausea, hyponatremia. MRI may show pituitary enlargement.
  • Multiple axis deficiencies: ACTH/cortisol, TSH/T4, gonadotropins, GH; posterior pituitary (ADH) rarely affected.
  • Replace hormones (hydrocortisone first if adrenal insufficiency, THEN levothyroxine, never the reverse, because of adrenal-crisis risk). Sex hormones in select patients.
  • High-dose steroids only for mass effect/visual compromise; physiologic replacement otherwise.
  • Most patients continue ICI on replacement.
• Primary adrenal insufficiency: rare; bilateral adrenalitis. Hydrocortisone plus fludrocortisone replacement.
• Type 1 diabetes (insulin-dependent, autoimmune): rare (~1%) but can present as DKA. Anti-GAD/IA-2/insulin antibodies often negative. Permanent insulin replacement. Hold ICI during DKA or uncontrolled hyperglycemia (urgent insulin/fluids/electrolytes); resume once DKA resolves and glycemic control established.

Pneumonitis (anti-PD-1/L1 ~3 to 6%; combo ~10%)

• Pattern: dyspnea, cough, hypoxia, fevers. Patterns include organizing pneumonia (most common), NSIP, hypersensitivity, AIP/ARDS-like.
• Workup: high-resolution chest CT, pulse oximetry/ABG, rule out infection (sputum, BAL with viral PCR, PJP studies, fungal markers), pulmonary consult.
• Grade 1 (radiographic only): hold ICI; close monitoring (clinical reassessment in 1 to 2 wk); rescan in 3 to 4 wk.
• Grade 2 (symptomatic; limiting instrumental ADLs): hold ICI; prednisone 1 to 2 mg/kg/day; bronchoscopy if not improving in 48 to 72 h.
• Grade 3 to 4: permanently discontinue; methylprednisolone 1 to 2 mg/kg/day IV; if no improvement in 48 h, infliximab 5 mg/kg, mycophenolate, IVIG, or cyclophosphamide; empiric antibiotics for superinfection.
• Slow taper over ≥6 wk; recurrence with rapid taper is common.

Cardiac, myocarditis (rare ~1% but mortality ~25 to 50%)

• Highest mortality of any irAE. Often early (median about 4 weeks, 27 to 34 days in the main series, frequently within the first 1 to 3 cycles), often co-occurs with myositis and a myasthenia-gravis-like syndrome (the "3M syndrome": myocarditis, myositis, myasthenia).
• Presentation: fatigue, dyspnea, chest pain, palpitations, syncope, ptosis, diplopia, proximal weakness, elevated CK; can be fulminant.
• Workup: troponin (very sensitive), NT-proBNP, ECG, echo, cardiac MRI, CK, aldolase, myositis panel, AChR Ab; coronary angiography to rule out ACS; endomyocardial biopsy is the gold standard.
• Hold ICI permanently for any confirmed grade ≥1 myocarditis.
• Treatment: methylprednisolone 1 g IV daily ×3 d, then prednisone 1 mg/kg/day, slow taper. If steroid-refractory or fulminant: mycophenolate, infliximab (caution, case reports of worsening heart failure), abatacept (CTLA-4-Ig fusion protein, T-cell costimulation blocker, emerging therapy), ATG, plasmapheresis, IVIG, alemtuzumab. ICU monitoring, pacing/ECMO support as needed.
• Baseline troponin before each of the first 4 doses of combination therapy or with cardiotoxic combos is recommended by many centers.

Renal, tubulointerstitial nephritis (~2 to 5%)

• Acute kidney injury with sterile pyuria, mild proteinuria. Mechanism: tubulointerstitial inflammation (rarely glomerular). PPIs are a common co-trigger.
• Workup: Cr trend, UA plus sediment, urine eosinophils, renal ultrasound, hold nephrotoxic meds (especially PPIs and NSAIDs), renal biopsy if Cr doubling or no recovery in 1 wk.
• Grade 2: hold ICI; prednisone 0.5 to 1 mg/kg/day.
• Grade 3 to 4: hold/discontinue; methylprednisolone 1 to 2 mg/kg/day IV; consider biopsy; second-line, mycophenolate, infliximab, cyclophosphamide.

Neurologic (rare ~1 to 4% any grade, but heterogeneous)

• Spectrum: peripheral neuropathy (axonal/demyelinating), Guillain-Barre-like, myasthenia gravis (often AChR Ab+, can overlap with myocarditis/myositis), aseptic meningitis, encephalitis, transverse myelitis, cerebellitis.
• Discontinue ICI per syndrome: permanent discontinuation for MG, GBS, encephalitis, transverse myelitis; grade 2 peripheral neuropathy or aseptic meningitis, hold and may resume after improvement to grade ≤1.
• Treatment: methylprednisolone 1 to 2 mg/kg/day IV; IVIG (2 g/kg over 5 d) or plasmapheresis for severe GBS-like or MG; pyridostigmine for MG symptoms; neuro consult.

Rheumatologic / musculoskeletal (~5 to 15%)

• Inflammatory arthritis (small or large joints, sometimes seronegative RA-like), polymyalgia-rheumatica-like, sicca syndrome, vasculitis.
• NSAIDs for mild disease; oral prednisone 10 to 20 mg/day for moderate; intra-articular steroids; methotrexate, sulfasalazine, anti-TNF, anti-IL-6 (tocilizumab) for refractory.
• Continue ICI in most grade 1 to 2 cases.

Hematologic (rare)

• Immune thrombocytopenia (ITP): steroids ± IVIG, romiplostim/eltrombopag, rituximab.
• Autoimmune hemolytic anemia (AIHA): typically warm; steroids ± rituximab.
• Aplastic anemia / pure red cell aplasia: rare, severe; ATG, cyclosporine, eltrombopag.
• HLH: rare; high-dose steroids, anakinra, etoposide.

Ocular (rare)

• Uveitis, dry eye, episcleritis, optic neuritis. Topical steroids for mild; systemic for posterior uveitis or refractory; ophthalmology consult mandatory.
• VKH-like syndrome reported (melanoma patients).

Pancreatic

• Asymptomatic lipase elevation common; does not require treatment if no clinical pancreatitis.
• True pancreatitis (2 of 3: characteristic pain, lipase/amylase >3x ULN, or imaging; imaging not mandatory): hold ICI, supportive care; consider steroids if not improving after 3 to 5 days.

Organ-by-organ NCCN grading and management tables

Skin

Diarrhea / colitis

• Infliximab: ↓ TNF-alpha, ↓ pro-inflammatory cytokines, ↓ leukocyte migration, ↓ neutrophil/eosinophil activation. Dose 5 mg/kg IV; may repeat in 2 weeks. AEs: abdominal pain, transaminitis, antibody development, infection, infusion reactions. Contraindications: perforation, sepsis, tuberculosis, hepatitis, NYHA class III or IV heart failure. Case series: 29 patients, 21 (72%) responded, 3 needed a 2nd dose.
• Vedolizumab: selective adhesion-molecule inhibitor blocking memory T-cell migration to gut. Dose 300 mg IV, repeated at weeks 2 and 6. AEs: antibody development, arthralgia, nasopharyngitis, fatigue, transaminitis, fever. Case series of 7 steroid-refractory patients: 6/7 remission at a median of 56 days.
• Mycophenolate is used in steroid-refractory pneumonitis and hepatitis, but NOT typically for colitis; infliximab is the most commonly used biologic for steroid-refractory colitis without contraindications.

Hepatitis (transaminitis without bilirubin elevation)

Transaminitis with elevated bilirubin

• Workup: viral (hepatitis A/B/C, CMV, EBV, HSV, VZV, HIV, anti-HAV IgM, HBsAg, anti-HBc, HCV RNA); ceruloplasmin, alpha-1-antitrypsin, ferritin, ANA titer, mitochondrial Ab M2, smooth-muscle Ab, liver/kidney microsome type 1 Ab, IgG, IgM, tissue transglutaminase IgA and IgG, TSH, iron, transferrin, HbA1c, lipid panel. Consider biopsy for grade 3.

• Mycophenolate mofetil (MMF); enteric-coated mycophenolate sodium is not mg-for-mg equivalent (720 mg BID approximates MMF 1,000 mg BID): ↓ B- and T-cell proliferation, T-cell apoptosis, suppressed dendritic cells. PO dose 0.5 to 1 g every 12 hours or 1 g TID. AEs: dizziness, rash, endocrine and electrolyte disturbances, anemia/leukopenia/thrombocytopenia, infection, renal toxicity.

Hypophysitis

Hypothyroidism

Thyrotoxicosis

Pneumonitis

• IVIG: replacement therapy for primary and secondary immunodeficiencies; modulates B- and T-lymphocyte activity and antigen presentation. Dose 0.4 g/kg/day ×5 days. AEs: hypotension, bradycardia, fatigue, chills, infusion reactions, arthralgias.

Acute pancreatitis

Elevated serum creatinine (nephritis)

• Azathioprine: forms 6-thioguanine nucleotide metabolites mediating immunosuppression. 1 mg/kg/day PO (dose-reduce if TPMT deficient). AEs: nausea, vomiting, diarrhea, leukopenia, myalgia, fever.
• Cyclosporine: inhibits IL-2 production/release and IL-2-induced T-lymphocyte activation. 2 to 4 mg/kg/day PO. AEs: hypertension, edema, headache, nausea, diarrhea.

Vision change (uveitis and episcleritis)

Myasthenia gravis

Guillain-Barre syndrome (GBS)

Encephalitis

Transverse myelitis

Myocarditis / pericarditis

• Registry (35 cases, 11/2013 to 7/2017): prevalence 1.14%; median onset 34 days after starting immunotherapy; 54% had no other irAE; more common with combination immunotherapy and in patients with diabetes; major adverse cardiac events (MACE) in 46%; 4-fold increase in MACE when troponin ≥1.5 ng/mL.

Second-line agent by toxicity (summary matrix)

Note: hypothyroidism and thyrotoxicosis are managed with hormone modulation (levothyroxine; beta-blocker) rather than the immunosuppressants above.

Special populations

• Pre-existing autoimmune disease: NOT an absolute contraindication; risk of flare ~30 to 50% but most are manageable. Discuss risk/benefit; consider rheum co-management.
• Prior organ transplant: high risk of rejection (~40% for renal); typically discuss with the transplant team, generally avoided unless no alternative.
• HIV: safe at well-controlled CD4 counts; checkpoint inhibition does not worsen viral control.
• HBV: antiviral prophylaxis (entecavir/tenofovir) if HBsAg+; isolated HBcAb+ (HBsAg negative): monitor ALT and HBV DNA.
• Pregnancy: avoid (can cause fetal harm; effective contraception during and for several months after therapy); IgG crosses the placenta, and in animal models PD-1/PD-L1 or CTLA-4 blockade causes immune-mediated fetal loss and premature delivery (not classic teratogenicity).

Drug interactions to know

• Corticosteroids at physiologic replacement dose (e.g., hydrocortisone 20 mg/day for adrenal insufficiency) do NOT impair ICI efficacy.
• Pharmacologic steroids ≥10 mg prednisone at baseline have been associated with worse ICI outcomes in some studies (NSCLC, melanoma); limit when possible, but never withhold treatment for an active irAE.
• Antibiotics in the 30 days before ICI start are associated with worse outcomes in some series (gut-microbiome hypothesis); avoid unnecessary courses.
• PPIs: a possible adverse signal on ICI efficacy in some retrospective data; weigh against AKI/colitis risk.

2024-2026 irAE management updates

• Myocarditis: abatacept + ruxolitinib, Salem et al (Cancer Discov 2023 series of 40 patients, myotoxicity fatality 3.4% vs 60%; abatacept vs placebo being tested in the phase 3 ATRIUM RCT, NCT05335928, recruiting) suggests the CTLA-4 fusion protein abatacept plus the JAK inhibitor ruxolitinib as steroid-refractory myocarditis rescue; reduces mortality vs historical controls. High-dose steroids remain first-line but early escalation is critical.
• Colitis: vedolizumab as an alternative to infliximab, vedolizumab (gut-selective) is increasingly used for steroid-refractory colitis with a favorable safety profile (Abu-Sbeih JITC 2018); ASCO, NCCN and ESMO (2022) list infliximab or vedolizumab as options, with vedolizumab favored when TNF blockade is undesirable (e.g., TB/HBV, heart failure, concurrent hepatitis). FMT shows early promise for refractory ICI colitis in small case series (investigational). (CP101 targets recurrent C. difficile; SER-155 phase 1b targets allo-HSCT infection, not ICI colitis.)
• Arthritis: IL-6 blockade, tocilizumab (subcutaneous or IV) increasingly used for refractory inflammatory arthritis when MTX/sulfasalazine fail; supported by observational series (Fa'ak JITC 2023; Petit Ann Oncol 2025).
• Extended-interval IO dosing: pembrolizumab 400 mg Q6W (already approved), nivolumab 480 mg Q4W standard; longer intervals being tested prospectively (e.g., phase 3 REFINE-Lung, NCT05085028: reduced-frequency pembrolizumab, 9 to 18 weekly vs standard 6-weekly, after 6 months); may reduce clinic burden, efficacy not yet proven.
• irAE-predictive HLA typing: HLA-DRB1 shared-epitope alleles for inflammatory arthritis (Cappelli Rheumatology 2019), HLA-DR4 for ICI-induced diabetes, HLA-B*35 and DRB1*11 for pneumonitis (Correale Cells 2020); not routine screening but explanatory.
• Steroid impact on efficacy: retrospective NSCLC cohort (Ricciuti JCO 2019), baseline steroids for cancer-unrelated indications did NOT compromise IO efficacy (steroids for irAEs likewise generally do not, Horvat JCO 2015); steroids for cancer symptoms (brain mets, dyspnea) at baseline DO correlate with worse outcomes. Distinguish the indication.
• irAE and IO efficacy correlation: development of an irAE, especially cutaneous (vitiligo in melanoma, rash), is associated with improved response and OS; but do NOT withhold treatment of severe irAEs.
• irAE guideline topics (ASCO guideline current version is the 2021 update, Schneider JCO 2021; no 2024 update identified): guidance on rechallenge algorithms, extended dosing schedules, pregnancy considerations (IgG placental transfer), transplant-recipient risk.

References (open-access or freely citable)

• Schneider BJ et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:4073-4126. PMID 34724392.
• Brahmer JR et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021;9:e002435.
• Haanen J et al. ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up of toxicities from immunotherapy. Ann Oncol 2022;33:1217-1238.
• NCCN Guidelines. Management of Immunotherapy-Related Toxicities (version 1.2019 and later updates), the source of the organ-by-organ grading tables above.
• Postow MA et al. Immune-related adverse events associated with immune checkpoint blockade. NEJM 2018;378:158-168. PMID 29320654.
• Wang DY et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4:1721-1728. PMID 30242316.
• FDA package inserts: pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab, avelumab, cemiplimab, dostarlimab, tremelimumab, relatlimab.