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

When someone starts treatment with immune checkpoint inhibitors (ICIs) for cancer, the goal is clear: wake up the immune system to attack tumors. But sometimes, that same immune system turns on the body. These unintended attacks are called immune-related adverse events, or irAEs. They’re not rare. In fact, up to 83% of people on CTLA-4 inhibitors and 72% on PD-1 inhibitors will experience some form of irAE. These aren’t just minor rashes or fatigue-they can be serious, even life-threatening if missed or mishandled.

What Causes irAEs?

Immune checkpoint inhibitors like pembrolizumab, nivolumab, and ipilimumab work by removing the brakes on T-cells. That’s great for killing cancer cells-but it also removes the brakes on healthy tissue. The immune system starts seeing normal organs as threats. This can trigger inflammation or autoimmune-like damage anywhere in the body. Unlike chemotherapy side effects, which usually show up early and fade after treatment stops, irAEs can appear weeks or even months after the last dose. Some patients develop colitis six months after finishing treatment. That’s why you can’t stop watching for symptoms just because the infusion schedule is done.

Common irAEs by Organ System

Not all irAEs are the same. Some show up more often than others. The most common are in the gut, skin, and endocrine system.

• Gastrointestinal: Diarrhea, abdominal pain, blood in stool. This is the most frequent irAE, especially with CTLA-4 inhibitors. Grade 3 or 4 colitis can lead to hospitalization.
• Dermatologic: Rash, itching, blistering skin. Often starts as a mild red patch but can spread quickly. It’s easy to mistake for an allergic reaction, but it’s not.
• Endocrine: Thyroid dysfunction (too much or too little hormone), adrenal insufficiency, hypophysitis. These don’t respond to steroids the way other irAEs do-they need hormone replacement, not immunosuppression.
• Lung: Pneumonitis. Cough, shortness of breath, low oxygen. This one can be deadly if not caught early.
• Liver: Hepatitis. Elevated liver enzymes, jaundice. Often found on routine blood tests before symptoms appear.
• Nervous system: Neuropathy, meningitis, myasthenia gravis. Rare, but among the most dangerous. Neurological irAEs require immediate specialist input.
• Heart: Myocarditis. Chest pain, irregular heartbeat, fatigue. Mortality rate is high-around 2.7% in reported cases.

Even though these are the most common, irAEs have been reported in almost every organ. Kidneys, eyes, joints, pancreas-you name it. That’s why doctors now treat every new symptom in an ICI patient as a possible irAE until proven otherwise.

How irAEs Are Graded and Diagnosed

Doctors don’t guess whether an irAE is serious. They use the Common Terminology Criteria for Adverse Events (CTCAE), a standardized system with four grades:

• Grade 1: Mild symptoms. No treatment needed beyond monitoring.
• Grade 2: Moderate symptoms. Interrupt ICI treatment. Start oral steroids.
• Grade 3: Severe symptoms. Stop ICI. Start high-dose IV steroids immediately.
• Grade 4: Life-threatening. Stop ICI permanently. ICU-level care often needed.

Before jumping to steroids, doctors must rule out infections, cancer progression, or other causes. A fever and diarrhea? Could be a virus. Could be colitis. Blood tests, imaging, and sometimes biopsies are needed to confirm it’s an irAE. For example, a colonoscopy with biopsy is the gold standard for diagnosing immune colitis. For pneumonitis, a chest CT scan is required. You can’t treat what you don’t diagnose correctly.

First-Line Treatment: Steroids

Corticosteroids are the go-to treatment for most irAEs. But how you give them matters.

• For Grade 2: Oral prednisolone at 1 mg per kg of body weight per day. Example: a 70 kg person gets 70 mg daily.
• For Grade 3 or 4: Start with IV methylprednisolone at 1-2 mg/kg/day (up to 1 gram daily) for at least three days, then switch to high-dose oral prednisolone.

The key isn’t just the dose-it’s the taper. Too fast, and symptoms bounce back. Too slow, and you pile on steroid side effects. The standard is to reduce the dose slowly over 4 to 6 weeks. For example, drop by 5-10 mg every 1-2 weeks once symptoms improve to Grade 1. Some patients need to taper even slower, especially if they’ve had multiple irAEs.

Patients often don’t realize how harsh steroids can be. Insomnia, weight gain, mood swings, high blood sugar, bone thinning-these aren’t just side effects. They’re life-altering. One survey found 72% of patients struggled with sleep, 65% gained weight, and 58% had anxiety or depression during treatment. That’s why managing irAEs isn’t just about stopping inflammation-it’s about managing quality of life too.

What If Steroids Don’t Work?

Not everyone responds to steroids. About 10-20% of patients have steroid-refractory irAEs. That means symptoms don’t improve after 48 hours of high-dose steroids. When that happens, you need backup options.

• Infliximab: A TNF-alpha blocker. Used for colitis, hepatitis, and some cases of pneumonitis. Given as an IV infusion. Response rate around 60-70%.
• Vedolizumab: Targets gut-specific immune cells. Newer option for steroid-refractory colitis. A 2024 study showed 68% response rate-better than infliximab in some cases.
• Mycophenolate mofetil: Used for liver or lung irAEs. Slower to work but helps avoid long-term steroids.
• IVIG: For neurological or hematologic irAEs. Expensive, but effective when other drugs fail.
• Cyclophosphamide: Reserved for the most severe, rare cases like myocarditis or severe vasculitis.

Here’s the good news: treating irAEs doesn’t mean you lose the cancer-fighting power of the immunotherapy. Multiple studies now confirm that patients who get steroids or infliximab for irAEs still have similar tumor control rates as those who didn’t develop side effects. The fear that immunosuppression weakens the anti-cancer response? That’s been disproven.

The Role of Specialists

You can’t manage irAEs alone. A cancer doctor can’t be expected to know every nuance of thyroid disease, neurology, or gastroenterology. That’s why multidisciplinary teams are now standard.

For endocrine irAEs, you need an endocrinologist. For colitis, a gastroenterologist. For pneumonitis, a pulmonologist. For neurological symptoms, a neurologist. Leading cancer centers now have dedicated immune toxicity teams that respond within 24 hours for Grade 3+ events. Community hospitals without these teams see higher complication rates-37% fewer severe outcomes when protocols are in place.

Dr. Jacob Brahmer from Johns Hopkins says it plainly: “Specialist neurology input is vital” for any neurological irAE. Delaying that consultation can be fatal.

What Patients Need to Know

Patients are the first line of defense. Many irAEs start as mild symptoms-loose stools, a little rash, tiredness. If they don’t report it, it gets missed.

A 2023 survey found 79% of oncology nurses said patients didn’t understand how urgent early reporting was. One woman developed diarrhea for three days, thought it was “just stress,” and waited until she was hospitalized with severe colitis. Another ignored a dry cough for weeks, then ended up in the ER with pneumonia and low oxygen.

Education matters. The European Society for Medical Oncology is now creating patient guides in 15 languages because 41% of patients report they didn’t know what symptoms to watch for. Simple tools-like a printed list of warning signs to hang on the fridge-can save lives.

The Future of irAE Management

Scientists are working on better ways to predict who’s at risk. A 2023 study in Nature Medicine 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 pre-treatment blood tests to tailor therapy.

Real-world data from Flatiron Health shows that patients treated within 48 hours of symptom onset had hospitalization rates drop from 34% to 19%. Speed saves lives.

As more combination immunotherapies launch-over 287 are in trials right now-the number of irAEs will grow. By 2028, specialized irAE clinics are projected to increase by 22% annually. Hospitals are already integrating automated alerts into their electronic records. If a patient reports fatigue and diarrhea in an online portal, the system can flag it and notify the care team before the next appointment.

irAEs are no longer a surprise. They’re a predictable, manageable part of modern cancer care. The key is awareness, speed, and teamwork. Catch them early. Treat them right. And never assume a symptom is “just something else.”