What is Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors ?
Immune system modulators, also known as immunomodulators, are substances that can change or influence how your immune system works. These substances can either stimulate or slow down the activity of your immune system by affecting its cells and the communication between them. A specific type of immunomodulator is an Immune Checkpoint Inhibitor (ICI).
ICIs have revolutionized the treatment of certain aggressive cancers that were previously considered untreatable. In fact, these ICIs have become the primary treatment for many types of advanced cancers. However, because these immunomodulators can interact with parts of the immune system that are found in many different parts of the body, they don’t exclusively target cancer cells. Due to this lack of selectivity, they can sometimes cause unwanted side effects due to the immune system overreacting, known as immune-related adverse events (IrAEs).
The endocrine system, which is responsible for producing hormones in the body, seems particularly prone to these side effects. This can often result in the onset of new hormone disorders related to the work of the endocrine system when using ICIs.
What Causes Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors ?
Immune checkpoint inhibitors (ICIs) are a type of treatment often used to fight cancer. They usually work by using monoclonal antibodies, which are lab-made versions of immune system proteins, to block specific proteins and receptors that T cells (a type of immune cell) use to stick to cells that show them what to attack or destroy. Usually, these proteins and receptors act like a brake system for the immune system. But when they’re blocked by ICIs, it’s like the brakes are released, allowing the immune system to kick into high gear and instruct the T cells to attack cancer cells.
One example of a receptor on a T cell that an ICI can block is called cytotoxic T lymphocyte-associated antigen-4 (or CTLA-4 for short). Normally, CTLA-4 puts the brakes on our immune system to prevent it from becoming overactive. But some cancer cells can ‘hide’ from the immune system by taking advantage of these braking pathways. ICIs like Ipilimumab and Tremelimumab work by stopping CTLA-4 from braking the immune system, which can help T cells see and attack these hiding cancer cells.
Another way that ICIs work involves blocking a pathway that involves the programmed cell death-1 receptor (PD-1) and its partner, programmed death-ligand-1 (PDL-1). PD-1 acts as a brake to prevent T cells from being overactive during infections. But blocking PD-1 with ICIs can strengthen the immune system’s response against certain types of cancer. The treatments nivolumab and pembrolizumab are examples of ICIs that can block PD-1.
Risk Factors and Frequency for Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
Endocrine disorders, or endocrinopathies, are one of the main side effects seen in patients using immune-checkpoint inhibitors (ICIs). About 10% of individuals undergoing ICI treatment develop new endocrinopathies. Endocrine organs that are most affected depend on the type of ICI therapy used.
- Various types of endocrine disorders may occur due to ICI use. These include disorders like hypophysitis (inflammation of a region in the brain called the hypophysis), thyroiditis, adrenal insufficiency, autoimmune diabetes, and calcium abnormalities.
- The most common endocrine disorders due to ICIs are hypothyroidism and hyperthyroidism. Combined, these occur in about 15% of individuals using ICIs. These thyroid disorders are primarily seen when using ICIs against PD-1 or PD-L1 proteins and are more prevalent in females.
- Hypophysitis and adrenal insufficiency are more common in older male patients and are often linked to the use of ICIs against CTLA-4 proteins. However, adrenal insufficiency is less common than hypophysitis. It is also more commonly associated with the use of ICIs against the PD-1 protein.
- On average, endocrine disorders appear after around 9 weeks of ICI treatment. Most side effects occur within the first 9 months of starting therapy with ICIs. However, sometimes endocrinopathies may appear years after starting ICI therapy, which can complicate things as these symptoms might be confused with side effects of other medications or as symptoms related to cancer.
Signs and Symptoms of Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
Immune checkpoint inhibitor (ICI) therapy can sometimes lead to problems with our endocrine system (the glands in our body that produce hormones). These problems depend on which gland is affected, how severely it’s affected, and the dose and length of our treatment. It’s tricky because patients might show signs that could easily be confused with usual cancer symptoms or side effects of chemotherapy.
Take the thyroid, for example. About 2.6% to 6% of people who have ICI treatment might end up with thyroid problems. These endocrine problems are common with various types of ICI therapy and might cause mild to moderate symptoms of a slow or overactive thyroid. This can include symptoms resembling Hashimoto’s or Graves’ diseases. However, symptoms of a slow thyroid are the most common. In rare cases, patients might experience symptoms suggesting their thyroid is being destroyed, which could lead to a normal, slow, or completely halted thyroid function that might or might not recover in the future.
The pituitary gland, another endocrine organ, can also be affected, particularly by specific types of ICI therapy. Problems usually start 4 to 10 weeks after the beginning of treatment, but can appear as late as 22 weeks after starting or even after stopping treatment. Patients might face pituitary inflammation, hormone deficiencies, and enlargement of certain parts of the gland. Sometimes they might have a deficiency in ACTH, which is a hormone that helps regulate our response to stress. Generally, men are more affected than women.
- Pituitary inflammation
- Hormone deficiencies
- Enlargement of certain parts of the gland
These complications might not resolve after stopping ICIs, resulting in lasting effects that require ongoing hormone treatment. Other common problems include secondary adrenal insufficiency, central hypothyroidism, and secondary hypogonadism. Patients frequently report headaches. Diabetes insipidus, a rare condition that results in intense thirst and heavy urination, has also been noted in some cases.
It’s rare for the adrenal gland, yet another endocrine gland, to be affected. It can result in hormone deficiencies that cause fatigue, general discomfort, and muscle weakness, which are common in patients going through cancer treatment. Although the presence of low sodium, high potassium, low blood sugar, or increased pigmentation can hint towards primary adrenal insufficiency, not having these symptoms doesn’t mean that there’s no problem. Sometimes patients might not show any symptoms at all until a stressful event reveals the disorder. Ignoring and not treating an adrenal crisis can be life-threatening.
Autoimmune diabetes is also a pretty rare complication of ICI therapy, occurring in less than 1% of patients. But for those affected, the onset is typically severe and sudden. Signs of high blood sugar, such as frequent urination and excessive thirst, can develop rapidly and become life-threatening. Severe high blood sugar along with life-threatening conditions like diabetic ketoacidosis and hyperosmolar hyperglycemic state are common initial symptoms of ICI-induced diabetes.
Certain calcium imbalances have also been described in some cases. For example, acute low calcium levels resulting from ICI-induced deficiency of parathyroid hormone have been reported. But more research is needed to understand the exact mechanism behind it.
Testing for Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
If you have symptoms that suggest a problem with your endocrine system (the system of glands in the body that make hormones), the first step will usually be lab tests. The kinds of tests your doctor orders may depend on what specific part of the endocrine system they think could be causing your symptoms.
If your doctor thinks you might have a problem with your thyroid (a butterfly-shaped gland in your neck), they will usually start by checking the levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in your blood. These are hormones that help to control your metabolism. If these hormone levels are too high or too low, it could be a sign of thyroid problems. A high TSH and a low FT4 usually indicate hypothyroidism (an underactive thyroid), while a low TSH and a high FT4 usually indicate hyperthyroidism (an overactive thyroid). In some cases, an ultrasound of the thyroid may also be needed.
If your doctor suspects a problem with your pituitary gland (a small gland at the base of your brain), they will first make sure you aren’t dealing with adrenal insufficiency (which is when your body does not produce enough cortisol, a critical hormone). If you have symptoms of adrenal insufficiency, your doctor won’t want to wait for test results to start treatment. They might measure your cortisol levels, especially in the morning, because lower than normal levels might mean you have adrenal insufficiency. A more detailed test called a cosyntropin-stimulation test might also be needed in some cases. If hypothyroidism might be a possibility, the pituitary gland’s function will be evaluated through several blood tests. Your doctor might also order an MRI of the brain to get a better look at your pituitary gland.
If you have high blood sugar levels and might have developed insulin-dependent diabetes, your doctor will measure your blood glucose and hemoglobin A1c, which gives an average of your blood sugar levels over the past few months. Some other blood tests that look for certain antibodies can also help to confirm the diagnosis.
Treatment Options for Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
When it comes to immune system-related treatments, sometimes our body might react adversely, leading to what we call endocrine-related side effects. These are ranked from Grade 1 to Grade 5 based on how severe they are. Grade 1 indicates mild symptoms and Grade 5 means the person has passed away due to complications. If someone experiences such side effects, doctors might stop the immune system treatment for a bit until they are able to start a hormonal treatment, especially if their symptoms are severe.
It’s important to deal with adrenal insufficiency, a condition where the adrenal glands don’t produce enough hormones, before starting any other hormone treatments. If the root of this is in the brain (central adrenal insufficiency), steroids that resemble hormones are used. If the problem lies in the adrenal glands themselves (primary adrenal insufficiency), adding a type of hormone known as mineralocorticoids is required.
Those suffering from hypothyroidism, where the thyroid gland doesn’t produce enough thyroid hormone, are often given a medication called levothyroxine. Beta-blockers are used to help with symptoms of thyrotoxicosis, a condition caused by too much thyroid hormone. The American Society of Clinical Oncology (ASCO) advises to have your thyroid function tested every 2 to 3 weeks as thyrotoxicosis can come and go. If the hyperthyroidism, or overactivity of the thyroid gland, lasts for more than 6 weeks, doctors usually suggest medication to suppress thyroid activity.
For patients who have developed autoimmune diabetes, a condition where the immune system destroys insulin-producing cells in the pancreas, insulin is the first choice of treatment. This is especially the case if they’ve developed diabetic ketoacidosis (a serious complication of diabetes) or hyperosmolar state (a complication of very high blood sugar).
ASCO suggests that all patients under hormone treatment should be closely watched. It can be beneficial to get an endocrinologist involved, especially for those patients who have issues with adrenal or pituitary glands, to help with dosing and additional management.
What else can Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors be?
The symptoms of endocrine system disorders can be difficult to identify as they can often be vague and misleading. Many people who are having cancer treatment may experience symptoms like tiredness, feeling unwell, generalized weakness, or muscle disorders due to the effects of chemotherapy. These symptoms are not specific and are similar to those of disorders like adrenal insufficiency or an underactive thyroid (hypothyroidism).
People diagnosed with cancer often have higher levels of depression and anxiety due to their treatment. Tiredness, weight loss, and feelings of a rapid, fluttering or pounding heart (palpitations) can mimic symptoms of IrAEs, a group of side effects that are caused by medicines known as immune checkpoint inhibitors (ICIs). Diagnosing endocrine system disorders can be particularly tough if healthcare professionals are not familiar with how ICIs can potentially affect the body.
Furthermore, the high doses of drugs called corticosteroids, which are often used in chemotherapy treatments, can potentially suppress the hypothalamus and pituitary gland’s effect on adrenal gland function. This can cause a condition known as secondary adrenal insufficiency, which makes it difficult to diagnose adrenal insufficiency caused by ICIs. In such cases, the baseline cortisol level (a hormone your body makes when stressed) of these patients will not be reliable.
What to expect with Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
When a gland in your body is disrupted, the effects and recovery time can vary depending on which gland is involved and how much it has been affected. Unfortunately, many problems related to these glands can lead to chronic deficiencies, meaning you might need to take supplements of the affected hormones for your entire life.
However, not all hormones from the anterior pituitary gland, which is an important hormone-producing gland in your brain, are affected equally or recover at the same rate. For instance, there have been documented cases of recovery in terms of thyroid function, which has to do with your metabolism and energy levels. However, other hormone systems in your body might be less likely to recover. Hormone-related conditions such as hypogonadism (a condition characterized by low sex hormone production) and ACTH-hyposecretion (a condition resulting in lower production of a hormone called ACTH that regulates stress response) often seem to persist in most cases. Insulin deficiency in autoimmune diabetes, which relates to how your body regulates blood sugar, also appears to be a permanent condition in most patients.
Although these conditions can negatively impact a patient’s quality of life, most people can still lead a reasonably normal life when they supplement their bodies with the missing hormones.
Possible Complications When Diagnosed with Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
If a person is wrongly diagnosed or not treated correctly, it can have disastrous outcomes, especially when it involves the hormone-producing glands in the body, known as the endocrine system. This is bad news because conditions linked to the endocrine system, like adrenal insufficiency (a condition where your body doesn’t produce enough of certain hormones) or insulin-dependent diabetes (a condition where your body can’t regulate its blood sugar levels), can get worse very quickly. If not identified and treated in time, these conditions can become life-threatening.
Common Consequences:
- Adrenal insufficiency – a condition where your body doesn’t produce enough of certain hormones
- Insulin-dependent diabetes – a condition where your body can’t regulate its blood sugar levels
Preventing Endocrine-Related Adverse Events From Immune Checkpoint Inhibitors
Immune checkpoint inhibitors, also known as ICIs, are a type of medicine often used to treat different types of cancer. They work by helping the body’s immune system fight off cancer cells. However, sometimes, the immune system can mistakenly attack regular cells in your body, a phenomenon known as “cross-reactivity”.
This can sometimes affect your endocrine glands, which are responsible for producing hormones. If these glands are affected, they might produce too much or too little hormone, leading to various symptoms depending on which gland(s) are affected and to what extent.
As a patient, it’s important that you are aware of the possible side effects that can occur when using ICIs. This will make it easier for you to report any unexpected symptoms or changes to your healthcare team. Regular check-ins with your general practitioner and oncologist are crucial to spot and assess new symptoms or changes.
Some patients may need to see a specialist, like an endocrinologist (a doctor who specializes in hormone-related conditions), for further evaluation and to set up a treatment plan. The role of these specialists is to figure out exactly what’s going on, make a formal diagnosis, and manage treatments.
