Immune-Related Adverse Events: Symptoms, Causes & Treatment

An immune-related adverse event (irAE) is a side effect that can arise from certain medical treatments. These events happen when the body’s immune system is stimulated and then mistakenly targets and attacks healthy cells and tissues, leading to inflammation and damage in various organs. The occurrence of irAEs has become more recognized with therapies that work by influencing the immune system.

While this enhanced activity is beneficial for fighting diseases, the misdirected attacks on healthy tissues result in these adverse events. The symptoms and severity can vary widely depending on which part of the body is affected.

The Link to Immunotherapy

Immune-related adverse events are most frequently associated with a category of cancer treatment known as immunotherapy. Specifically, drugs called immune checkpoint inhibitors (ICIs) are a primary example. These therapies are designed to boost the immune system’s ability to find and destroy cancer cells by blocking proteins on immune cells that normally act as “brakes.”

When these brakes are released, the immune system’s T-cells are better able to recognize and attack cancer cells. However, this heightened state of alert can sometimes cause the T-cells to also identify normal, healthy tissues as foreign and attack them. This disruption of the body’s natural self-tolerance leads to irAEs, which can manifest in ways that resemble autoimmune diseases. The likelihood of developing an irAE can be higher when different types of immunotherapy drugs are used in combination.

Recognizing Immune-Related Adverse Events

The signs and symptoms of immune-related adverse events are diverse because they can affect nearly any organ system. Because the symptoms can be nonspecific, any new or worsening symptom experienced during immunotherapy could potentially be an irAE. Some of the most common reactions include:

• Skin reactions, which are often one of the first irAEs to appear and can include rashes, significant itching, or vitiligo.
• Gastrointestinal problems, with symptoms ranging from diarrhea and abdominal pain to more severe inflammation of the colon (colitis).
• Liver inflammation (hepatitis), which may not cause obvious symptoms initially but can be detected through blood tests.
• Lung inflammation (pneumonitis), a less common but serious irAE that can cause a dry cough and shortness of breath.
• Endocrine system issues, which can lead to conditions like thyroiditis (inflammation of the thyroid) or problems with the pituitary and adrenal glands.
• Musculoskeletal problems, presenting as arthritis with joint pain or myositis, which is inflammation of the muscles.

Diagnostic Process for irAEs

Identifying an immune-related adverse event begins with a detailed clinical evaluation by a healthcare provider. This involves discussing the patient’s symptoms and their timing, since irAEs can mimic many other conditions. A key part of the diagnostic process is ruling out other potential causes for the symptoms.

Laboratory tests are a standard part of the investigation. Blood work can be used to check the function of organs like the liver and kidneys, measure hormone levels to assess the endocrine system, and look for markers of inflammation.

In some situations, imaging studies are necessary to get a clearer picture of what is happening inside the body. A chest X-ray or a CT scan might be ordered to look for signs of inflammation. For certain conditions, such as suspected colitis or hepatitis, a biopsy may be performed to examine a small tissue sample from the affected organ to confirm the diagnosis.

Approaches to Managing irAEs

The management of immune-related adverse events is tailored to the specific type and severity of the reaction. For mild symptoms, treatment might involve close monitoring and medications to manage the symptoms, such as topical corticosteroids for a skin rash or antihistamines for itching. The underlying immunotherapy may often continue with careful observation.

For moderate to severe irAEs, the primary treatment is the use of corticosteroids, such as prednisone. These medications work by suppressing the overactive immune response that is causing the damage. Depending on the severity, the immunotherapy treatment may need to be temporarily paused or, in cases of severe reactions, stopped permanently.

If the irAEs do not respond to corticosteroids, other types of immunosuppressive drugs may be used. Because symptoms can escalate quickly, it is important for patients to report any new or worsening symptoms to their oncology team as soon as possible for early intervention.

Understanding irAE Timelines and Outcomes

The timing of when an immune-related adverse event appears can vary significantly. Some irAEs, particularly skin reactions, can develop within the first few weeks of starting immunotherapy. Others may not appear for several months, and in some cases, they can even occur after the immunotherapy treatment has been completed. Most irAEs tend to occur within the first six months of commencing treatment.

With prompt diagnosis and appropriate management, many immune-related adverse events are reversible. The duration of the irAE depends on its severity and the effectiveness of the treatment. Mild events may clear up quickly, while more severe cases requiring corticosteroids may need a longer period of management, often involving a slow tapering of the medication.

While most irAEs can be managed effectively, some can be serious or lead to long-term issues. For example, endocrine problems affecting glands like the thyroid may require lifelong hormone replacement therapy.