Immune-related adverse events

What it is

Immune-related adverse events are side effects from checkpoint immunotherapy that can affect almost any organ, including skin, gut, lungs, and glands. They are caused by immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 blockers, and they most often involve the skin, gastrointestinal tract, endocrine glands, and lungs. The most important practical fact is that irAEs can start during treatment or even after treatment has stopped, and some can become severe or rarely fatal if not recognised early.

Unlike chemotherapy side effects, irAEs happen because the treatment removes some of the immune system's normal brakes. That can help immune cells attack cancer, but it can also make them attack healthy tissues. Doctors may also call these immune-mediated adverse events or immune-related side effects.

Common examples include rash, itching, diarrhoea, colitis, hepatitis, thyroid problems, pneumonitis, arthritis, and inflammation of the pituitary gland, kidneys, nerves, or heart. Many cases are mild, but some need urgent treatment with corticosteroids or other immunosuppressive medicines. In Indian cancer centres, patients receiving immunotherapy are usually advised to report new diarrhoea, cough, breathlessness, jaundice, severe fatigue, headache, or vision changes promptly because delay can make management harder.

Common organ system affected	Examples of irAEs
Skin	Rash, itching, vitiligo
Gut and liver	Diarrhoea, colitis, hepatitis
Endocrine	Thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes
Lungs	Pneumonitis
Less common but serious	Myocarditis, nephritis, neurologic toxicity

How it works

Immune checkpoints are molecules that help prevent excessive immune activation. Drugs that block CTLA-4, PD-1, or PD-L1 release these brakes so T cells can attack cancer more effectively. The same mechanism can also trigger inflammation in normal organs.

IrAEs do not all happen in the same way. Some appear to involve activated T cells attacking normal tissue. Others may involve autoantibodies, inflammatory cytokines, or changes in immune tolerance. Different checkpoint drugs also have somewhat different toxicity patterns. CTLA-4 inhibitors are often linked with more gastrointestinal and pituitary toxicity, while PD-1 or PD-L1 inhibitors are commonly associated with thyroid problems and pneumonitis.

Combination immunotherapy generally causes more irAEs than single-agent treatment. Severity is often graded using the Common Terminology Criteria for Adverse Events, from grade 1 mild symptoms to grade 4 life-threatening toxicity.

Evidence and uses

IrAEs are a recognised class effect of immune checkpoint inhibitors used in cancers such as melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and some gastrointestinal cancers. Reviews consistently show that the skin, GI tract, endocrine organs, and lungs are the most frequently affected sites, while cardiac, neurologic, and some haematologic irAEs are less common but can be especially dangerous.

Timing varies. Skin reactions may occur relatively early, while endocrine problems can appear later and may persist long term. Some patients develop chronic irAEs that continue for months or longer after immunotherapy ends. Endocrine toxicities are particularly likely to become long-lasting, sometimes requiring lifelong hormone replacement.

Management depends on the organ involved and the severity:

1. Mild irAEs: treatment may continue with close monitoring and symptom control.
2. Moderate irAEs: immunotherapy is often held temporarily, and corticosteroids may be started.
3. Severe irAEs: immunotherapy is usually stopped, high-dose corticosteroids are commonly used, and some patients need other immunosuppressive drugs such as infliximab or mycophenolate for steroid-refractory cases.
4. Endocrine irAEs: these may need hormone replacement rather than escalating immunosuppression alone.

There is ongoing research on whether developing an irAE is linked with better cancer outcomes. Some studies suggest an association in certain cancers, but this is not consistent enough to use as a rule. A serious irAE is never considered a desirable sign, and treatment decisions should be based on the patient's overall clinical situation.

Diagnosis / how it's measured

There is no single test that proves an irAE. Diagnosis is based on the treatment history, the organ involved, symptom pattern, blood tests, scans, and ruling out other causes such as infection, cancer progression, blood clots, or side effects from other drugs.

Typical evaluation may include:

• Complete blood count and liver and kidney function tests
• Thyroid function tests and sometimes cortisol or other hormone tests
• Oxygen levels and chest imaging if cough or breathlessness occurs
• Stool tests and sometimes colonoscopy for significant diarrhoea
• Troponin, ECG, and echocardiography if myocarditis is suspected
• Brain imaging or neurologic assessment for severe headache, weakness, confusion, or nerve symptoms

Because symptoms can overlap with common problems in cancer care, diagnosis can be challenging. For example, diarrhoea may be due to infection, antibiotics, or colitis; breathlessness may be due to pneumonitis, infection, pulmonary embolism, or tumour progression. That is why clinicians often use a broad work-up before labeling a problem as an irAE.

When to see a clinician

Contact your oncology team urgently if you are on checkpoint immunotherapy and develop new or worsening symptoms, even if they seem minor. Early reporting matters because irAEs can worsen quickly.

Seek urgent medical care for:

• Shortness of breath, chest pain, or low oxygen levels
• Severe diarrhoea, blood in stool, or dehydration
• Yellowing of the eyes or skin
• Severe weakness, dizziness, fainting, or confusion
• New severe headache, vision change, or extreme fatigue
• Marked reduction in urine output
• Palpitations or unexplained muscle weakness

If you go to an emergency department, tell the team that you are receiving or recently received immunotherapy. This detail can change the differential diagnosis and treatment plan.

Limitations and open questions

IrAEs are well described, but several questions remain. Doctors still cannot reliably predict who will develop a serious irAE, which organ will be affected, or who will have chronic symptoms. Biomarkers for prediction are being studied, but none are accurate enough for routine use across all cancers.

Evidence is also still evolving on the safest way to restart immunotherapy after an irAE. In some patients, rechallenge is possible; in others, especially after grade 4 or certain cardiac or neurologic toxicities, it may not be recommended. Long-term follow-up data are improving, but chronic endocrine, rheumatologic, neurologic, and other persistent irAEs remain an active area of research.

For patients and families, the key point is practical: immunotherapy side effects are different from standard chemotherapy side effects, can involve almost any organ, and should be reported early rather than watched at home for too long.