Residency · Residency · Internal Medicine

Immune Checkpoint Inhibitor Toxicity

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Alright, intern, pull up a chair. You’re wiped, I know. But this one’s important. Imagine your patient, Mr. Henderson, a really nice guy with melanoma, started on one of these fancy new immune checkpoint inhibitors last month. He’s been doing great, tumor shrinking, feeling stronger. Then, suddenly, he’s spiking fevers, his gut is cramping, and he’s having diarrhea every hour. Your mind immediately goes to C. diff, right? But with Mr. Henderson, you’ve got to think broader. These ICIs, while brilliant at unleashing the immune system to fight cancer, sometimes get a little too enthusiastic and start attacking healthy tissue. We call these immune-related adverse events, or irAEs. They can hit any organ, any time, even months after the drug is stopped. Your job is to recognize them early, because acting fast with immunosuppression, usually steroids, can literally save a life.

So, Mr. Henderson's diarrhea isn't just any diarrhea. Given his history, it's immune-mediated colitis until proven otherwise. You get stool studies, sure, but while you wait, you’re already thinking about holding his ICI dose and starting him on steroids. If it’s just a little bit of loose stool, maybe we watch closely. But if he’s going more than six times a day, with pain and some blood? That’s a moderate to severe situation, and we’re jumping straight to prednisone, often 1-2 mg/kg. The key here is not to hesitate. These toxicities can escalate quickly. If those steroids don't kick in within a couple of days, we're already thinking about adding a second agent like infliximab.

Now, imagine Mrs. Davies, also on an ICI, presents with new shortness of breath and a persistent cough. Your first thought might be pneumonia or even cancer progression. But in the ICI world, you also have to consider immune pneumonitis. Same drill: rule out infection, but if the CT scan shows those tell-tale ground-glass opacities, you're again thinking steroids, and you're holding that ICI. Or what if Mr. Henderson suddenly develops severe muscle weakness, trouble swallowing, and a droopy eyelid? That could be immune-mediated myasthenia gravis. These are rare, but potentially devastating. The mantra is: new symptom + ICI = rule out irAE. Early, aggressive steroid use, and a slow taper once things improve, is your best friend here. Always remember, the immune system is a powerful tool, but sometimes it needs to be gently reined in.

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized oncology by unleashing anti-tumor immune responses. However, this immune activation can lead to immune-related adverse events (irAEs) affecting virtually any organ system. Internists and hospitalists increasingly manage these toxicities as ICI use expands across cancer types. Early recognition and prompt immunosuppressive therapy are critical to preventing morbidity and mortality.

Checkpoint Inhibitor Classes

• Anti-CTLA-4: ipilimumab; blocks the inhibitory CTLA-4 receptor on T-cells
• Anti-PD-1: nivolumab, pembrolizumab, cemiplimab; block PD-1 receptor on T-cells
• Anti-PD-L1: atezolizumab, durvalumab, avelumab; block PD-L1 ligand on tumor cells
• Combination therapy (anti-CTLA-4 + anti-PD-1) has the highest efficacy but also the highest toxicity rate (55-60% grade 3-4 irAEs)
• irAEs can occur at any time during therapy and even months after discontinuation

General Principles of irAE Management

• Grading: CTCAE (Common Terminology Criteria for Adverse Events) grades 1-4
• Grade 1: continue ICI with close monitoring
• Grade 2: hold ICI; consider moderate-dose corticosteroids (0.5-1 mg/kg prednisone)
• Grade 3: hold ICI; high-dose corticosteroids (1-2 mg/kg prednisone or methylprednisolone)
• Grade 4: permanently discontinue ICI; high-dose IV corticosteroids; consider additional immunosuppression
• Taper steroids slowly over 4-6 weeks minimum to prevent relapse
• If no response to steroids within 48-72 hours, escalate to infliximab, mycophenolate, or other immunosuppressants

Organ-Specific Toxicities

Dermatologic (Most Common, 30-50%)

• Maculopapular rash: most common irAE; usually mild; topical steroids for grade 1-2
• Pruritus: antihistamines and topical steroids
• Severe reactions: SJS/TEN, bullous pemphigoid; permanently discontinue ICI; dermatology consultation

Gastrointestinal (20-35%)

• Colitis: diarrhea, abdominal pain, hematochezia; more common with anti-CTLA-4
• Evaluate with stool studies (C. difficile, cultures), CT abdomen, and colonoscopy if grade 2+
• Management: high-dose steroids; infliximab (5 mg/kg) if steroid-refractory; vedolizumab as alternative
• Avoid opioids and anti-motility agents until infection is excluded

Hepatic (5-15%)

• Immune hepatitis: elevated AST/ALT, often asymptomatic
• Rule out viral hepatitis, drug-induced liver injury, and metastatic disease
• Management: hold ICI for grade 2+; steroids for grade 3+; mycophenolate for steroid-refractory cases
• Avoid infliximab for hepatotoxicity (hepatotoxic itself)

Endocrine (10-20%)

• Thyroiditis: may present as initial thyrotoxicosis followed by hypothyroidism; check TSH, free T4
• Hypophysitis: headache, fatigue, hypopituitarism; more common with anti-CTLA-4; MRI shows pituitary enlargement
• Primary adrenal insufficiency: rare but life-threatening; morning cortisol, ACTH stimulation test
• Type 1 diabetes (fulminant): can present as DKA; check C-peptide, GAD antibodies
• Hormone replacement is typically lifelong; steroids do not reverse endocrine destruction

Pneumonitis (3-10%)

• Cough, dyspnea, hypoxia; more common with anti-PD-1/PD-L1
• CT chest shows ground-glass opacities, organizing pneumonia, or interstitial patterns
• Rule out infection (sputum cultures, BAL if needed) and disease progression
• Management: hold ICI; high-dose steroids; infliximab or mycophenolate if refractory

Cardiac (1-2%, but High Mortality)

• Myocarditis: most feared cardiac irAE; mortality 25-50%
• Presents with chest pain, dyspnea, arrhythmias, heart failure, cardiogenic shock
• Elevated troponin, BNP; ECG changes; cardiac MRI showing edema; endomyocardial biopsy is definitive
• Management: high-dose IV methylprednisolone (1 g/day x 3-5 days); early cardiology consultation
• Often co-occurs with myositis and myasthenia gravis

Neurologic (1-5%)

• Myasthenia gravis: fatigable weakness, ptosis, dysphagia, respiratory failure
• Guillain-Barre syndrome: ascending weakness, areflexia
• Encephalitis: confusion, seizures, personality changes
• Peripheral neuropathy: sensory or motor; may be asymmetric
• Neurology consultation mandatory; treatment includes steroids, IVIG, or plasmapheresis

Renal (2-5%)

• Acute interstitial nephritis: most common; rising creatinine, sterile pyuria, eosinophiluria
• Rule out other causes: obstruction, dehydration, nephrotoxins
• Renal biopsy may be needed for diagnosis
• Management: hold ICI; steroids for grade 2+

Monitoring and Surveillance

• Baseline labs before each cycle: CBC, CMP, TSH, LFTs, urinalysis
• Educate patients to report new symptoms promptly; irAEs can present insidiously
• Monitor for irAEs for at least 12 months after discontinuation
• Multidisciplinary collaboration between oncology, affected subspecialties, and primary care is essential

Key Clinical Pearls

• irAEs can affect any organ system and can present weeks to months after ICI discontinuation.
• Corticosteroids are the cornerstone of irAE management; taper slowly over at least 4-6 weeks.
• Myocarditis is rare but carries the highest mortality of all irAEs; maintain a high index of suspicion.
• Endocrine irAEs (thyroiditis, hypophysitis) require lifelong hormone replacement; steroids do not reverse them.
• When in doubt, hold the checkpoint inhibitor and start steroids; early treatment improves outcomes.

References

1. Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) Clinical Practice Guideline on Immune Checkpoint Inhibitor-Related Adverse Events. Journal for ImmunoTherapy of Cancer. 2021;9(6):e002435.
2. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. New England Journal of Medicine. 2018;378(2):158-168.
3. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of Clinical Oncology. 2021;39(36):4073-4126.
4. Moslehi JJ, Salem JE, Sosman JA, et al. Increased Reporting of Fatal Immune Checkpoint Inhibitor-Associated Myocarditis. The Lancet. 2018;391(10124):933.

For the intern

When consulted overnight for possible immune checkpoint inhibitor (ICI) toxicity, prioritize life-threatening presentations: suspected myocarditis (chest pain, troponin elevation, arrhythmias), pneumonitis with respiratory distress, severe colitis with hemodynamic instability, or acute adrenal crisis. These require immediate high-dose intravenous methylprednisolone (1-2 mg/kg), cardiac monitoring, and subspecialty consultation. For milder presentations like asymptomatic transaminitis, rash, or stable diarrhea, obtain basic labs and imaging as appropriate, but definitive management can wait until morning when oncology can guide therapy. Always hold the ICI for grade 2 or higher toxicity. Remember that immune-related adverse events (irAEs) can occur months after treatment discontinuation, so maintain suspicion even in patients no longer actively receiving therapy.

Common pitfalls

• Treating like sepsis: irAEs often present with systemic symptoms mimicking infection. Broad-spectrum antibiotics are appropriate until infection is excluded, but don't delay corticosteroids if clinical suspicion for irAE is high, particularly in pneumonitis or colitis.

• Undertreating cardiac toxicity: ICI-associated myocarditis has 25-50% mortality. A mildly elevated troponin in this population warrants aggressive immunosuppression and cardiology involvement, not just observation.

• Rapid steroid tapers: irAEs frequently flare with premature taper. Plan for minimum 4-6 weeks; coordinate with oncology before adjusting.

• Missing endocrine crises: Hypophysitis and adrenal insufficiency present subtly with fatigue and hypotension. Check morning cortisol and give stress-dose steroids empirically in shock states.

Make it stick

You're the night float intern, and Mrs. Davis, receiving pembrolizumab for metastatic melanoma, develops new-onset diarrhea. She's had three loose stools tonight, but denies fever or abdominal pain. Her vitals are stable. You recall the lecture on immune checkpoint inhibitor (ICI) toxicity. Is this immune-related colitis? You order stool studies (C. difficile, cultures) and basic labs. While awaiting results, you hold her next scheduled pembrolizumab dose and discuss with the senior resident. They agree to start oral prednisone 0.5 mg/kg while awaiting stool studies, emphasizing that early intervention prevents progression to severe colitis. This proactive approach, balancing infection rule-out with prompt immunosuppression, exemplifies managing immune-related adverse events.

If you remember one thing

Immune checkpoint inhibitor toxicities can affect any organ system and require prompt recognition and often corticosteroids. Always consider immune-related adverse events in patients on or recently off these therapies, even for vague symptoms.

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