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: get the immune system to attack the tumor. But sometimes, the immune system doesn’t stop at cancer. It turns on healthy tissue. That’s when immune-related adverse events - or irAEs - show up. These aren’t just mild rashes or upset stomachs. They can be serious, even life-threatening. And they don’t always appear right away. Some show up weeks after treatment ends. If you’re on an ICI or caring for someone who is, knowing what to watch for - and what to do - can make all the difference.

What Exactly Are irAEs?

irAEs are side effects caused by immune checkpoint inhibitors like pembrolizumab, nivolumab, ipilimumab, and atezolizumab. These drugs block proteins that normally keep the immune system in check. By removing those brakes, they help T-cells find and kill cancer cells. But they also remove the brakes on autoimmunity. The result? Inflammation in organs that have nothing to do with cancer.

It’s not rare. About 83% of people on CTLA-4 inhibitors, 72% on PD-1 inhibitors, and 60% on PD-L1 inhibitors develop at least one irAE. They can hit any organ: skin, gut, lungs, liver, thyroid, even the heart or brain. The most common? Diarrhea and colitis, rash, thyroid problems, and hepatitis. But the rare ones - like myocarditis or neurological damage - are the most dangerous.

When Do irAEs Show Up?

Most irAEs appear within the first three months of starting treatment. But that’s not the whole story. About 1 in 5 patients develop symptoms after stopping therapy - sometimes months later. That’s why you can’t just stop monitoring after the last infusion. A patient who feels fine six months after treatment might still get a sudden, severe case of pneumonitis or adrenal failure.

Timing matters because early action saves lives. If diarrhea starts on day 10, it’s more likely to be an irAE than if it shows up on day 200. But symptoms alone aren’t enough. Doctors have to rule out infections, other drugs, or cancer progression first. A stool test for C. difficile, a chest CT for pneumonia, liver enzymes for hepatitis - all need checking before calling it an irAE.

How Are irAEs Graded?

Not all irAEs are the same. They’re graded from 1 to 4 using the Common Terminology Criteria for Adverse Events (CTCAE):

• Grade 1: Mild symptoms. No treatment needed. Just watch.
• Grade 2: Moderate. Disrupts daily life. Requires treatment interruption and steroids.
• Grade 3: Severe. Hospitalization needed. High-dose steroids.
• Grade 4: Life-threatening. Emergency care required.

Grading isn’t just paperwork. It tells you what to do next. A Grade 1 rash? Keep going. A Grade 3 diarrhea? Stop the drug, start IV steroids, call a gastroenterologist - now.

First-Line Treatment: Steroids

Corticosteroids are the backbone of irAE treatment. For Grade 2 or higher, you don’t wait. You start prednisone or methylprednisolone immediately - after ruling out infection.

For Grade 2: Oral prednisone at 1 mg per kg per day. For Grade 3 or 4: IV methylprednisolone at 1-2 mg/kg/day (up to 1 gram daily) for three days, then switch to oral prednisone at the same dose.

But here’s the catch: steroids aren’t a cure. They’re a fire extinguisher. The real challenge is tapering. If you pull the dose too fast, the inflammation comes back. If you go too slow, you get steroid side effects: weight gain, insomnia, mood swings, high blood sugar, bone loss.

Guidelines say taper over 4 to 6 weeks. But in real life, some patients need months. One patient told me she was on 40 mg of prednisone for 10 weeks. Her mood was gone. She couldn’t sleep. She gained 25 pounds. She felt like a different person. And she still had to keep seeing her oncologist every week.

What If Steroids Don’t Work?

Not everyone responds. About 10-15% of cases are steroid-refractory. That means after 48 hours of high-dose steroids, symptoms don’t improve. That’s when you switch to second-line drugs.

Infliximab (a TNF-alpha blocker) is the go-to for colitis, hepatitis, and some cases of pneumonitis. Mycophenolate mofetil is used for kidney or lung involvement. IVIG helps with neurological irAEs. Cyclophosphamide is reserved for the toughest cases.

And new options are coming. Vedolizumab, a drug originally for Crohn’s disease, is now showing promise for steroid-refractory colitis. In a 2024 trial, it worked in 68% of cases - better than infliximab. Clinical trials are now comparing these drugs head-to-head.

Organ-Specific irAEs Need Special Care

Not all irAEs are treated the same. Some need more than steroids.

• Thyroid problems: Usually hypothyroidism. No steroids needed. Just thyroid hormone replacement - lifelong.
• Hypophysitis: Pituitary inflammation. Needs high-dose steroids short-term, then hormone replacement (cortisol, thyroid, sex hormones).
• Colitis: Rule out infection first. Steroids first. Infliximab or vedolizumab if no response.
• Pneumonitis: CT scan needed. Steroids immediately. Avoid infliximab - it can make lung damage worse.
• Myocarditis: Rare, but deadly. Mortality rate hits 2.7%. Requires ICU-level care: high-dose steroids, IVIG, sometimes rituximab or abatacept.
• Neurological irAEs: Myasthenia gravis, encephalitis, neuropathy. These need neurology input fast. IVIG or plasmapheresis often needed.

Dr. Jacob Brahmer at Johns Hopkins says: “If a patient on immunotherapy develops new weakness or confusion, don’t assume it’s fatigue. Call neurology. Now.”

Why Multidisciplinary Care Matters

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

Endocrinology for thyroid and pituitary issues. Gastroenterology for colitis. Pulmonology for lung problems. Neurology for brain and nerve damage. Dermatology for rashes. Cardiology for heart inflammation.

Leading cancer centers like MD Anderson have dedicated immune toxicity teams. They’re on call 24/7. They review every Grade 2+ case. They write protocols. They train nurses. Their hospitalization rates for severe irAEs dropped from 28% to 17.6% in 18 months.

Community clinics? Not so much. Only 62% have formal irAE protocols. That’s why patients in smaller towns are more likely to get delayed care - or misdiagnosed.

Patients Don’t Know What to Watch For

Here’s the scary part: many patients don’t realize their symptoms could be serious.

A 2023 survey found that 79% of oncology nurses say patients delay reporting symptoms because they think it’s “just a cold” or “side effects of chemo.” But irAEs aren’t like nausea or fatigue. They’re new, different, and often worsening.

Patients need clear instructions: “If you get diarrhea more than 4 times a day, call your team immediately.” “If you feel short of breath when walking up stairs, don’t wait - get checked.” “If your vision blurs or you feel weak in your arms, go to the ER.”

The European Society for Medical Oncology is now creating patient education materials in 15 languages. Because if you don’t understand the warning signs, you won’t act fast enough.

Does Treating irAEs Hurt Cancer Outcomes?

For years, doctors worried: if we suppress the immune system to treat an irAE, will the cancer come back?

The answer, based on multiple studies since 2020, is no. Treating irAEs with steroids or infliximab doesn’t reduce the chance of tumor control. In fact, patients who get timely treatment often live longer - because they can stay on therapy longer.

One 2022 review in Cancer Therapy Advisor looked at over 2,000 patients. Those who had irAEs and were treated properly had similar or better survival rates than those who didn’t have side effects.

What’s Next?

The future of irAE management is moving fast.

Biomarkers are on the horizon. 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 mean testing before treatment starts - and adjusting therapy before the first dose.

Electronic health records are catching up. Epic Systems now has built-in alerts that pop up when a patient reports diarrhea, rash, or fatigue. It automatically flags the case for review and suggests specialist referrals.

And the numbers are growing. In 2019, about 40% of cancer patients were eligible for ICIs. By 2023, that jumped to 48%. More drugs. More combinations. More irAEs.

By 2028, specialized irAE clinics are expected to grow by 22% per year. Because we can’t afford to ignore this anymore.

Bottom Line

irAEs are the price we pay for powerful cancer treatments. But they’re not unavoidable. They’re manageable - if you know the signs, act fast, and have the right team behind you.

For patients: Don’t ignore new symptoms. Don’t wait. Call your oncology team the moment something feels off.

For providers: Don’t assume it’s something else. Rule out infection. Grade it. Treat it. Call the right specialist. Document it.

irAEs aren’t a failure of treatment. They’re a sign the immune system is working - just too well. And with the right response, we can keep that immune system fighting cancer - without destroying the body.