When someone starts treatment with immune checkpoint inhibitors (ICIs) 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 can show up as diarrhea, rash, fatigue, or even heart or lung problems. And while they’re not common in every patient, when they happen, they can be serious-sometimes life-threatening-if not caught early.
What Causes irAEs?
Immune checkpoint inhibitors like pembrolizumab, nivolumab, and ipilimumab work by blocking signals that normally keep the immune system in check. This lets T-cells attack cancer cells more aggressively. But that same boost can also make the immune system mistake healthy organs for threats. The result? Autoimmune-like inflammation in the skin, gut, liver, lungs, thyroid, or even the brain.
These side effects weren’t fully understood until after ipilimumab was approved in 2011 for melanoma. Since then, studies have shown that up to 83% of patients on CTLA-4 inhibitors, 72% on PD-1 inhibitors, and 60% on PD-L1 inhibitors will experience at least one irAE. And unlike chemo side effects-which usually show up right after treatment-irAEs can appear weeks or even months after stopping therapy. That’s why vigilance doesn’t end when treatment does.
Which Organs Are Most Affected?
Not all irAEs are the same. Some are common. Others are rare but dangerous.
Gastrointestinal issues like colitis are among the most frequent. Patients might have watery diarrhea, abdominal pain, or blood in stool. If left untreated, it can lead to bowel perforation.
Endocrine problems like thyroid dysfunction or hypophysitis (pituitary inflammation) are also common. These don’t always need steroids. Instead, they often require lifelong hormone replacement-like levothyroxine for low thyroid or hydrocortisone for adrenal insufficiency.
Skin reactions range from mild rashes to severe blistering conditions like Stevens-Johnson syndrome. A simple itchy rash might be Grade 1, but if it covers more than 30% of the body, it’s Grade 3 and needs urgent care.
Then there are the rare but deadly ones: myocarditis (heart inflammation) and neurotoxicity (nerve or brain damage). A 2021 study in JAMA Oncology found that 2.7% of patients with cardiac irAEs died from it. Neurological irAEs-like meningitis or neuropathy-often need neurologists involved from day one. As Dr. Jacob Brahmer from Johns Hopkins puts it, “Specialist neurology input is vital.”
How Are irAEs Graded and Treated?
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. Interrupt ICI therapy. Start oral prednisolone at 1 mg/kg per day.
- Grade 3: Severe symptoms. Stop ICI. Give IV methylprednisolone (1-2 mg/kg/day) for 3 days, then switch to high-dose oral steroids.
- Grade 4: Life-threatening. Hospitalize immediately. Use high-dose IV steroids and consider additional immunosuppressants.
For most Grade 2-3 cases, steroids are the first line. But here’s the catch: you can’t just stop them suddenly. The taper has to be slow-over 4 to 6 weeks. Rushing it can cause symptoms to bounce back. Many patients report this taper as one of the hardest parts. Insomnia, weight gain, mood swings, and fatigue from steroids can be as disruptive as the original irAE.
If steroids don’t work after 48 hours, it’s called steroid-refractory. That’s when doctors turn to other drugs:
- Infliximab (anti-TNF): Used for colitis, hepatitis, or pneumonitis.
- Mycophenolate mofetil: Often for kidney or lung involvement.
- IVIG: For neurological or hematologic irAEs.
- Vedolizumab: A newer option for colitis, especially if infliximab fails. SITC’s 2024 guidelines show it works in 68% of cases.
Importantly, using these drugs doesn’t make the cancer come back. Early fears that immunosuppression would weaken the anti-tumor effect have been disproven. Multiple studies now confirm that patients who get treated for irAEs still respond well to their cancer therapy.
Why Timing Matters
Early detection saves lives. A 2023 Flatiron Health analysis of over 12,500 patients showed that if treatment for an irAE starts within 48 hours of symptom onset, hospitalization rates drop from 34% to just 19%. That’s a huge difference.
But patients often delay reporting symptoms. Oncology nurses say 79% of patients don’t realize how urgent early signs are. A little diarrhea? They think it’s just stress. A new rash? They blame the laundry detergent. By the time they call their oncologist, it’s Grade 3.
That’s why education is critical. The European Society for Medical Oncology is launching patient guides in 15 languages to fix this gap. In the meantime, patients need to know: If something feels off, say something-even if it seems small.
Who Needs to Be Involved?
Managing irAEs isn’t just the oncologist’s job. It takes a team.
For endocrine issues: endocrinologist.
For colitis or hepatitis: gastroenterologist or hepatologist.
For lung inflammation (pneumonitis): pulmonologist.
For neurological symptoms: neurologist.
At top cancer centers like MD Anderson, dedicated immune toxicity teams handle all these cases. They have protocols ready, specialists on call, and 24/7 access to IV steroids. In community clinics without this structure, complications are 37% higher. That’s why hospitals are now building automated alerts into their electronic records. Epic Systems’ 2023 update flags patient-reported symptoms like diarrhea or fatigue and triggers automatic referrals to specialists.
What’s Next?
The future of irAE management is moving toward prediction and precision.
A 2023 study in Nature Medicine found that patients with baseline IL-17 levels above 5.2 pg/mL had nearly a fivefold higher risk of severe irAEs. That’s a potential biomarker-something doctors could test before starting ICI therapy to identify high-risk patients.
Meanwhile, combination therapies are exploding. Right now, over 287 ICI combinations are being tested in clinical trials. More drugs = more chances for side effects. Experts predict a 22% annual growth in specialized irAE clinics by 2028.
For now, the best defense is awareness. Know the signs. Report them fast. Follow the taper. Trust your team. And remember: managing irAEs isn’t a detour from cancer treatment-it’s part of it.
Can irAEs happen after stopping immunotherapy?
Yes. While most irAEs appear within the first 3 months of treatment, some can develop weeks or even months after therapy ends. This is especially true for endocrine issues like thyroid dysfunction or hypophysitis. Patients should continue monitoring for symptoms and report any new issues to their care team, even if they’ve finished treatment.
Do steroids reduce the effectiveness of cancer treatment?
No. Early concerns that corticosteroids might weaken the immune system’s ability to fight cancer have been disproven. Multiple studies, including those published in the Journal of Clinical Oncology and Cancer Therapy Advisor, show that patients treated for irAEs with steroids or other immunosuppressants still respond well to immune checkpoint inhibitors. The priority is controlling the side effect without sacrificing cancer control.
What should I do if I get a rash while on immunotherapy?
Don’t ignore it. Even a mild rash can be an early sign of an irAE. Contact your oncology team right away. They’ll assess the extent and severity. A small, itchy rash may just need moisturizer and monitoring. But if it spreads, blisters, or covers more than 30% of your skin, it’s Grade 3 or higher and requires immediate steroid treatment. Never try to treat it with over-the-counter creams without medical advice.
Are there alternatives to steroids for treating irAEs?
Yes, if steroids don’t work or can’t be tolerated. For steroid-refractory cases, doctors may use infliximab (for colitis or pneumonitis), mycophenolate mofetil (for lung or kidney involvement), IVIG (for neurological or blood-related issues), or vedolizumab (a newer option for colitis). These are targeted immunosuppressants that help calm the immune response without relying on high-dose steroids.
How long does irAE treatment usually last?
Most irAEs resolve within 4 to 8 weeks with proper treatment. However, steroid tapering can take 4 to 6 weeks to avoid rebound symptoms. In about 10-15% of cases, especially with endocrine damage like thyroid or adrenal failure, the effects are permanent and require lifelong hormone replacement. Chronic irAEs are manageable but need ongoing monitoring.
Can I continue immunotherapy after having an irAE?
It depends. For Grade 1 irAEs, treatment often continues with close monitoring. For Grade 2, ICI therapy is paused until symptoms improve to Grade 1, then may be restarted. Grade 3 or higher usually means permanent discontinuation. However, if the irAE was mild and fully resolved, some patients can be rechallenged under strict supervision. Decisions are individualized and based on cancer type, treatment response, and severity of the side effect.
What Patients Should Remember
Living with cancer is hard enough. Dealing with unexpected side effects on top of that can feel overwhelming. But irAEs are predictable, manageable, and treatable-if you act fast.
Keep a symptom journal. Note changes in bowel habits, skin, energy, or mood. Write down when they started and how bad they are. Bring it to every appointment. Ask questions. Don’t assume your oncologist knows what you’re feeling. If you’re tired, say so. If your stool is loose, tell them. If your chest feels tight, don’t wait.
The goal isn’t just to beat cancer. It’s to live well while doing it. And that means listening to your body-and trusting your care team to help you through the bumps along the way.
Written by Mallory Blackburn
View all posts by: Mallory Blackburn