When someone starts treatment with immune checkpoint inhibitors for cancer, the goal is simple: wake up the immune system to fight tumors. But sometimes, the immune system doesn’t stop at cancer. It turns on healthy tissues instead. These unintended attacks are called immune-related adverse events, or irAEs. They’re not rare. In fact, up to 83% of patients on certain immunotherapies experience them. And while many are mild, some can be life-threatening if missed or mishandled.

What Are irAEs and Why Do They Happen?

irAEs are side effects caused by immune checkpoint inhibitors (ICIs) - drugs like pembrolizumab, nivolumab, and ipilimumab. These drugs block signals that normally keep the immune system in check. Without those brakes, T-cells attack cancer cells more aggressively. But they can also attack the thyroid, colon, lungs, skin, liver, and even the heart. It’s like removing the safety lock on a gun - the target gets hit, but so does everything nearby.

Unlike chemotherapy side effects, which usually show up quickly and fade after treatment ends, irAEs can appear anytime. Most happen within the first three months, but some don’t show up until months after the last dose. That’s why patients need to stay alert long after finishing treatment.

Which Organs Are Most Affected?

Not all irAEs are the same. Some are common. Others are rare but deadly. The most frequent involve the gut, skin, and endocrine system.

• Gastrointestinal: Diarrhea and colitis are the most common. Patients may have more than six watery stools a day, abdominal cramps, or blood in stool. Grade 3 or higher colitis requires immediate action.
• Endocrine: The thyroid often gets hit - causing fatigue, weight changes, or heart palpitations. Hypophysitis (pituitary inflammation) can mess up cortisol and thyroid hormone production. These don’t respond to steroids the way other irAEs do. Instead, they need lifelong hormone replacement.
• Dermatologic: Rashes, itching, and blistering skin are common. Most are mild, but Stevens-Johnson syndrome - a severe skin reaction - can be fatal.
• Lungs: Pneumonitis causes cough, shortness of breath, and low oxygen. It’s one of the leading causes of death from irAEs.
• Heart: Myocarditis is rare (under 1% of cases) but carries a 2.7% fatality rate. Chest pain, irregular heartbeat, or sudden fatigue must be treated as an emergency.
• Nervous system: Nerve damage, muscle weakness, or confusion can signal neurotoxicity. These require neurologist involvement right away.

How Are irAEs Graded and Managed?

Doctors use the Common Terminology Criteria for Adverse Events (CTCAE) to rate severity. It’s simple:

• Grade 1: Mild symptoms. No treatment needed. Just monitor.
• Grade 2: Moderate. Symptoms interfere with daily life. Hold ICI treatment. Start oral steroids like prednisone (1 mg/kg per day).
• Grade 3: Severe. Hospitalization often needed. Switch to IV steroids (methylprednisolone, 1-2 mg/kg/day). Stop ICI permanently in many cases.
• Grade 4: Life-threatening. ICU-level care. High-dose steroids, plus second-line drugs like infliximab or IVIG.

For most Grade 2-3 irAEs, steroids are the first line. But here’s the catch: you can’t just stop them suddenly. Tapering over 4-6 weeks is critical. If you rush it, symptoms come back - sometimes worse. Patients often report feeling trapped by steroid side effects: weight gain, insomnia, mood swings. One study found 68% of patients said these side effects hurt their quality of life more than the original cancer symptoms.

What If Steroids Don’t Work?

About 20-30% of patients don’t respond to steroids. These are called steroid-refractory irAEs. When that happens, doctors turn to stronger immunosuppressants:

• Infliximab: Targets TNF-alpha. Used for colitis, pneumonitis, and some liver cases. Given as an IV infusion.
• Mycophenolate mofetil: Used for liver or kidney involvement.
• IVIG: Packed antibodies. Good for neurological or hematologic irAEs.
• Vedolizumab: Newer option. Blocks gut-specific immune cells. Shown to work better than infliximab in some colitis cases, with fewer side effects.
• Cyclophosphamide: Reserved for the toughest cases, like severe myocarditis.

Importantly, using these drugs doesn’t mean the cancer treatment is ruined. Multiple studies confirm that managing irAEs doesn’t reduce the chances of tumor control. The immune system can still fight cancer - even while being calmed down.

Why Timing Matters

Early detection saves lives. A 2023 analysis of over 12,500 patients showed that if treatment starts within 48 hours of symptom onset, hospitalization rates drop from 34% to 19%. That’s a huge difference.

But here’s the problem: patients often ignore early signs. A sore throat? Just a cold. Diarrhea? Maybe it’s the food. Fatigue? Of course they’re tired - they have cancer. Nurses report that 79% of patients don’t realize how urgent it is to call their oncologist about new symptoms. That delay can turn a mild rash into a life-threatening condition.

That’s why education is part of the treatment. Leading cancer centers now give patients printed guides, video tutorials, and 24/7 hotlines. The European Society for Medical Oncology is rolling out patient materials in 15 languages because language barriers are a real problem.

Who’s Involved in Care?

Managing irAEs isn’t just an oncologist’s job. It takes a team:

• Endocrinologists: For thyroid, adrenal, or pituitary issues.
• Gastroenterologists: For colitis or hepatitis.
• Pulmonologists: For lung inflammation.
• Neurologists: For nerve or muscle damage - absolutely essential.
• Dermatologists: For severe rashes or blistering.
• Oncology nurses: Often the first to notice changes. They’re the frontline.

Hospitals with dedicated immune toxicity teams - like MD Anderson - see 92% protocol adherence. Community clinics without those teams? Only 68%. That gap is why some patients die from delays.

What’s New in irAE Management?

The field is moving fast. In February 2024, the Society for Immunotherapy of Cancer updated its guidelines to include vedolizumab as a top choice for steroid-resistant colitis. Clinical trials are now comparing it directly to infliximab.

Scientists are also looking for biomarkers. A 2023 study found that patients with baseline IL-17 levels above 5.2 pg/mL had nearly five times the risk of severe irAEs. That could one day mean a simple blood test tells doctors who needs extra monitoring before starting treatment.

Electronic health records are catching up too. Epic Systems now has built-in alerts in its oncology module. If a patient reports new diarrhea or rash, the system flags it and auto-sends a referral to the right specialist - cutting hours off response time.

What Happens Long-Term?

Most irAEs resolve with treatment. About 85-90% of patients fully recover. But 10-15% end up with chronic issues. A damaged thyroid? Lifelong hormone pills. A destroyed adrenal gland? Daily steroid replacement. Some patients need ongoing immunosuppression for years.

And as more people get access to immunotherapy - now used in nearly half of all cancer patients in the U.S. - the number of people living with long-term irAEs is rising fast. Experts predict a 22% annual increase in specialized irAE clinics by 2028. These aren’t just side effects anymore. They’re a new kind of chronic disease.

Bottom Line: Know the Signs, Act Fast

irAEs are the price of a powerful therapy. But they don’t have to be a death sentence. The key is awareness - from patients, nurses, and doctors. If you’re on an immune checkpoint inhibitor, learn the warning signs. Don’t wait for them to get worse. Call your team the moment something feels off. Speed saves organs. Speed saves lives.