When cancer patients start immunotherapy, many expect fewer side effects than with chemotherapy. But a hidden risk is quietly growing: immune-related adverse events, or irAEs. These aren’t just typical side effects. They’re the immune system turning against the body-attacking healthy organs like the colon, lungs, skin, or even the heart. And they can show up weeks, months, or even after treatment ends.
What Exactly Are irAEs?
irAEs happen because immune checkpoint inhibitors (ICIs)-drugs like pembrolizumab, nivolumab, and ipilimumab-remove the brakes on the immune system so it can better fight cancer. But sometimes, those brakes don’t just come off for cancer cells. They come off for everything. The result? Autoimmune-like reactions that look like lupus, colitis, thyroiditis, or even rare conditions like myocarditis or encephalitis.
These events aren’t rare. About 83% of patients on CTLA-4 inhibitors, 72% on PD-1 blockers, and 60% on PD-L1 inhibitors will experience at least one irAE. Some are mild-like a rash or loose stools. Others can be life-threatening. The key is catching them early.
When Do irAEs Show Up?
Most irAEs appear within the first 3 months of starting treatment. But here’s what catches doctors off guard: they can also show up 6, 8, or even 12 months after stopping therapy. A patient who thought they were in the clear can suddenly develop hepatitis or adrenal insufficiency. That’s why ongoing monitoring doesn’t end when treatment does.
Some organs are more commonly affected. Gastrointestinal issues like diarrhea and colitis are the most frequent. Skin rashes come next. Then endocrine problems-thyroid dysfunction, adrenal insufficiency, or pituitary inflammation (hypophysitis). Pneumonitis, hepatitis, and kidney inflammation are less common but more dangerous. Neurological and cardiac irAEs are rare, but they carry the highest risk of death.
How Doctors Grade irAEs
Not all irAEs are treated the same. Doctors use the Common Terminology Criteria for Adverse Events (CTCAE) to classify severity:
- Grade 1: Mild symptoms. No treatment needed beyond monitoring. A slight rash or mild fatigue.
- Grade 2: Moderate symptoms. Interferes with daily life. Requires stopping immunotherapy and starting corticosteroids.
- Grade 3: Severe symptoms. Hospitalization often needed. High-dose steroids and specialist input required.
- Grade 4: Life-threatening. ICU-level care. Immediate IV steroids and aggressive immunosuppression.
Grade 2 and above means immunotherapy is paused. The goal isn’t just to treat the symptom-it’s to prevent permanent damage. A delayed response can mean lifelong hormone replacement or irreversible lung scarring.
The Gold Standard: Steroids and How to Use Them
Corticosteroids are the first-line treatment for most irAEs. But timing and dosing matter.
For Grade 2 irAEs, doctors start with oral prednisolone at 1 mg per kg of body weight daily. For Grade 3 or 4, patients get IV methylprednisolone-up to 1 gram per day-for at least 3 days, then switch to high-dose oral steroids.
But here’s the catch: stopping steroids too fast can cause symptoms to bounce back. That’s why tapering is critical. The standard is to reduce the dose slowly over 4 to 6 weeks. A patient on 60 mg of prednisolone might drop by 5 mg every week, then slow to 2.5 mg reductions near the end. Rushing this process leads to flare-ups-and more hospital visits.
Patients often hate steroids. Weight gain, insomnia, mood swings, high blood sugar, and bone thinning are common. One survey found 72% of patients struggled with sleep, 65% gained weight, and 58% felt anxious or depressed. But these side effects are temporary. The alternative-untreated colitis or pneumonitis-can be fatal.
What If Steroids Don’t Work?
About 15-20% of patients don’t respond to steroids. These are called steroid-refractory irAEs. That’s when doctors turn to second-line drugs.
Infliximab, a TNF-alpha blocker, is the go-to for colitis and some forms of hepatitis. Mycophenolate mofetil is used for liver or lung issues. IVIG helps with neurological or blood-related irAEs. Cyclophosphamide is reserved for the toughest cases.
Newer options are emerging. Vedolizumab, originally used for Crohn’s disease, is now showing strong results in steroid-refractory colitis-with a 68% response rate compared to 52% for infliximab. Clinical trials are comparing these drugs head-to-head to find the best match for each organ.
Importantly, using these stronger drugs doesn’t make cancer treatment less effective. Early fears that suppressing the immune system would let tumors grow have been disproven. Multiple studies confirm: treating irAEs doesn’t hurt survival.
Organ-Specific Management Matters
Not all irAEs are handled the same way. Endocrine problems like thyroid failure or adrenal insufficiency don’t need steroids-they need hormone replacement. A patient with low cortisol gets hydrocortisone for life. Someone with hypothyroidism takes levothyroxine daily. These aren’t temporary fixes. They’re lifelong treatments.
Neurological irAEs-like meningitis, neuropathy, or myasthenia gravis-require neurologists on the team. One expert from Johns Hopkins says, “Specialist neurology input is vital.” Delayed diagnosis can lead to permanent disability.
Cardiac irAEs, though rare, are deadly. Myocarditis has a 2.7% fatality rate in reported cases. Symptoms like chest pain, shortness of breath, or irregular heartbeat must be treated as emergencies. An ECG, troponin test, and cardiac MRI are often needed within hours.
Why Early Reporting Saves Lives
Patients often downplay symptoms. “It’s just a little diarrhea,” they say. Or, “I’m tired-that’s normal.” But that’s exactly when things can spiral.
A 2023 survey found that 79% of oncology nurses say patients don’t understand how urgent early symptoms are. A single day’s delay in treating Grade 2 colitis can turn into Grade 4 with sepsis. Real-world data shows that patients who get treated within 48 hours of symptom onset cut their hospitalization risk by almost half.
That’s why every patient on immunotherapy gets a clear action plan: “If you have more than 4 loose stools a day, call your oncology team immediately. If you’re short of breath, don’t wait-go to the ER. If your skin turns bright red and peels, get checked today.”
The Hidden Infrastructure Behind irAE Care
Managing irAEs isn’t just about drugs. It’s about systems. Leading cancer centers have dedicated immune toxicity teams-oncologists, endocrinologists, gastroenterologists, and nurses who meet weekly to review complex cases.
Community hospitals without these teams struggle. One study showed that practices with formal irAE protocols reduced severe complications by 37% in just 18 months. That’s because they train staff, create checklists, and build fast-track pathways to specialists.
Technology is helping too. Epic Systems, the biggest electronic health record provider, now has built-in alerts. If a patient reports diarrhea or rash in their portal, the system flags it and auto-sends a referral to the right specialist-before the patient even calls.
What’s Next for irAE Management?
The future is personalization. Researchers are looking for biomarkers that predict who’s at risk. A 2023 study found that patients with baseline IL-17 levels above 5.2 pg/mL had nearly 5 times the risk of severe irAEs. That could mean blood tests before treatment start to tailor monitoring.
There’s also a push for better patient education. The European Society for Medical Oncology is creating multilingual guides because 41% of patients say they don’t know what symptoms to watch for. Simple pamphlets, video tutorials, and text reminders are now part of standard care.
As more patients get combination immunotherapies-two or more checkpoint inhibitors at once-the rate of irAEs is expected to climb. By 2028, specialized irAE clinics could grow by 22% per year. The goal isn’t to stop immunotherapy. It’s to make it safer.
Final Takeaway
irAEs are the price of progress. Immunotherapy has changed cancer survival rates. But it’s not magic. It’s a powerful tool that needs careful handling. The best outcomes come when patients speak up early, doctors act fast, and teams work together. Steroids aren’t perfect. Tapering is hard. But untreated, irAEs can end lives. Treated right, they’re a manageable part of beating cancer.
Can irAEs happen after stopping immunotherapy?
Yes. While most immune-related adverse events appear within the first 3 months of treatment, they can develop months-even over a year-after stopping immune checkpoint inhibitors. This delayed onset is why ongoing monitoring is critical, even after treatment ends. Symptoms like fatigue, diarrhea, or skin rashes that appear later should never be dismissed as unrelated.
Are steroids the only treatment for irAEs?
No. Steroids are the first-line treatment for most irAEs, especially Grades 2-4. But if symptoms don’t improve after 48 hours of steroid use (called steroid-refractory), doctors turn to other drugs. These include infliximab for colitis or hepatitis, mycophenolate for lung or liver issues, IVIG for neurological cases, and newer options like vedolizumab for colitis. Each case is matched to the best drug based on the affected organ and patient history.
Do irAEs reduce the effectiveness of cancer treatment?
No. Early concerns that suppressing the immune system to treat irAEs might let cancer grow have been proven wrong. Multiple studies, including large retrospective analyses and clinical trials, show that treating irAEs with steroids or other immunosuppressants does not reduce the cancer-fighting benefit of immune checkpoint inhibitors. In fact, managing side effects well often allows patients to stay on treatment longer and have better long-term outcomes.
Which organs are most commonly affected by irAEs?
The most common organs affected are the gastrointestinal tract (diarrhea, colitis), skin (rash, itching), and endocrine glands (thyroid, adrenal, pituitary). Less common but more dangerous are the lungs (pneumonitis), liver (hepatitis), and heart (myocarditis). Neurological and kidney involvement are rare but require urgent specialist care. The pattern varies by drug-CTLA-4 inhibitors tend to cause more gut issues, while PD-1 inhibitors are more linked to lung and thyroid problems.
How long does it take to recover from an irAE?
Most irAEs resolve within 4 to 8 weeks with proper treatment. However, recovery depends on severity and organ involved. Mild rashes or thyroid issues may clear in days. Severe colitis or pneumonitis can take weeks to months. About 10-15% of patients develop chronic irAEs requiring lifelong treatment-like hormone replacement for adrenal or thyroid failure. The key is early intervention to avoid permanent damage.
Can I keep taking immunotherapy after having an irAE?
It depends. For Grade 1 irAEs, treatment often continues with close monitoring. For Grade 2, immunotherapy is paused until symptoms improve to Grade 1, then may be restarted cautiously. For Grade 3 or higher, most guidelines recommend permanently stopping the drug. Some patients with mild, non-life-threatening irAEs can be rechallenged under strict supervision, but this carries a high risk of recurrence. Decisions are made case by case with input from oncology and specialist teams.
What should I do if I notice new symptoms during immunotherapy?
Don’t wait. Contact your oncology team immediately. Keep a symptom diary: note when it started, how bad it is, and what makes it better or worse. For diarrhea (more than 4 stools/day), shortness of breath, chest pain, severe rash, confusion, or unusual fatigue-seek help within 24 hours. Early action can prevent hospitalization and irreversible damage. Many centers provide 24/7 access lines for patients on immunotherapy.