Immune-Related Adverse Events: How to Recognize and Manage irAEs in Cancer Patients

When someone starts treatment with immune checkpoint inhibitors (ICIs) for cancer, the goal is simple: wake up the immune system to attack tumors. But sometimes, that same immune system turns on the body. This is where immune-related adverse events-or irAEs-come in. These aren’t typical chemo side effects like nausea or hair loss. They’re autoimmune reactions: the body attacks its own organs. And they can show up anytime-even months after treatment ends.

What Exactly Are irAEs?

irAEs happen because immune checkpoint inhibitors remove the brakes on T-cells. That’s great for killing cancer cells. But those same T-cells can start attacking healthy tissue. The result? Inflammation in the skin, gut, lungs, liver, thyroid, or even the heart and brain. These aren’t rare oddities. About 83% of people on CTLA-4 inhibitors, 72% on PD-1 inhibitors, and 60% on PD-L1 inhibitors will experience at least one irAE. Some are mild. Others are life-threatening.

What makes irAEs tricky is how unpredictable they are. One person might get a rash after two weeks. Another might develop colitis six months after stopping treatment. There’s no pattern. And unlike regular autoimmune diseases, irAEs don’t always follow the same rules. That’s why early recognition is everything.

Which Organs Are Most Affected?

Not all irAEs are created equal. Some are common. Others are rare-but dangerous.

• Gut (colitis): Diarrhea, abdominal pain, blood in stool. This is one of the most frequent irAEs. Grade 3 or 4 colitis can lead to bowel perforation if missed.
• Thyroid (endocrine): Fatigue, weight changes, sensitivity to cold or heat. Thyroid dysfunction is common and often permanent. It’s treated with hormone replacement, not steroids.
• Skin (rash, itching): Mild rashes are common. But blistering, peeling skin, or mouth sores signal something serious.
• Lungs (pneumonitis): Dry cough, shortness of breath, low oxygen. This one kills. About 2.7% of cardiac and lung irAEs are fatal.
• Liver (hepatitis): Yellow skin, dark urine, nausea. Liver enzymes rise before symptoms show up.
• Heart (myocarditis): Chest pain, irregular heartbeat, fatigue. Rare, but deadly. Often diagnosed too late.
• Nervous system: Muscle weakness, numbness, confusion. Requires neurology input immediately.

Endocrine irAEs like hypophysitis or adrenal insufficiency don’t respond to steroids. They need lifelong hormone replacement. Missing this distinction can be fatal.

How Are irAEs Graded?

Doctors use the Common Terminology Criteria for Adverse Events (CTCAE) to rate severity:

• Grade 1: Mild symptoms. No treatment needed. Just monitor.
• Grade 2: Moderate. Symptoms interfere with daily life. Hold ICI. Start oral steroids.
• Grade 3: Severe. Hospitalization needed. Stop ICI. Start IV steroids.
• Grade 4: Life-threatening. ICU-level care. Permanent discontinuation of ICI likely.

Grade 2 is the red flag. If you wait until Grade 3, you’re already behind. The rule? Don’t wait for symptoms to get worse. Treat early.

First-Line Treatment: Steroids

Corticosteroids are the go-to. But dosing matters.

• For Grade 2: Oral prednisolone at 1 mg per kg per day. Wait until symptoms drop to Grade 1 before restarting ICI.
• For Grade 3 or 4: Start with IV methylprednisolone-1 to 2 mg per kg per day-for at least 3 days. Then switch to high-dose oral prednisolone.

The taper is just as important as the start. Rushing it causes rebound inflammation. A slow taper over 4 to 6 weeks is standard. Many patients hate this part. Steroids cause insomnia, weight gain, mood swings, and high blood sugar. One survey found 72% of patients struggled with sleep, 65% gained weight, and 58% felt anxious or depressed.

But here’s the good news: treating irAEs doesn’t hurt cancer outcomes. Multiple studies confirm patients still respond to immunotherapy even after steroid treatment. That’s a relief for oncologists and patients alike.

What If Steroids Don’t Work?

About 10-20% of cases don’t improve after 48 hours of steroids. These are steroid-refractory irAEs. And they need stronger tools.

• Infliximab: A TNF-alpha blocker. Used for colitis, pneumonitis, and hepatitis. Given as an IV infusion.
• Mycophenolate mofetil: Used for liver or kidney involvement.
• IVIG: For neurological or hematologic irAEs.
• Vedolizumab: Newer option for colitis. Targets gut-specific immune cells. Less risk of systemic side effects.
• Cyclophosphamide: Last resort for severe, multi-organ cases.

A 2024 update from the Society for Immunotherapy of Cancer shows vedolizumab works better than infliximab for steroid-refractory colitis-68% response rate versus 52%. That’s changing practice.

Why Timing Matters

The biggest mistake? Delay.

Real-world data from Flatiron Health tracked over 12,500 patients. Those who got treatment within 48 hours of symptom onset had hospitalization rates cut in half-from 34% to 19%. Every hour counts. A rash that’s ignored today could be pneumonitis tomorrow.

Patients often don’t realize what’s happening. They think diarrhea is from food. Fatigue is from cancer. A dry cough? Just allergies. That’s why education is critical. A 2023 survey found 41% of patients couldn’t name key irAE symptoms. Oncology nurses report 79% of patients delay reporting symptoms because they’re afraid of stopping treatment.

The Team Approach

No oncologist can manage irAEs alone. It takes a team.

• Endocrinology: For thyroid, adrenal, or pituitary issues.
• Gastroenterology: For colitis or hepatitis.
• Pulmonology: For lung inflammation.
• Neurology: For nerve or muscle problems. Dr. Jacob Brahmer at Johns Hopkins says, “Specialist neurology input is vital.”
• Dermatology: For severe skin reactions.

Leading cancer centers like MD Anderson have dedicated immune toxicity teams. They cut complications by 37% in community practices that adopted similar models. Without this structure, patients fall through the cracks.

What’s New in 2026?

The field is moving fast.

• Predictive biomarkers: A 2023 study found patients with baseline IL-17 levels above 5.2 pg/mL had a 4.7 times higher risk of severe irAEs. Blood tests might soon predict who’s at risk before treatment even starts.
• Electronic alerts: Epic Systems now auto-triggers specialist referrals in its oncology module when patients report symptoms matching Grade 2+ irAEs.
• Global education: ESMO is rolling out patient guides in 15 languages. No more confusion because symptoms weren’t explained.
• Combination therapies: With over 287 ICI combinations in trials, irAEs are only going to get more complex. Specialized clinics are projected to grow 22% annually through 2028.

What Patients Should Know

If you’re on immunotherapy:

• Know the warning signs: diarrhea, rash, cough, fatigue, pain, vision changes.
• Report anything new-even if it seems small.
• Don’t stop steroids on your own. Tapering must be slow and supervised.
• Ask for a written irAE action plan. What to do, who to call, when to go to the ER.

Most irAEs are reversible. Eighty-five to ninety percent respond to treatment. But that only happens if you catch them early. The goal isn’t just survival. It’s living well while you’re fighting cancer.