Diagnosing and Managing Endocrine Immune-Related Adverse Events (irAEs)

“Endocrine irAEs, including ICI-induced diabetes mellitus, thyroiditis and hypophysitis, present a clinical challenge,” says Melissa Lechner, MD, PhD, director of the Onco-Endocrinology Program at the UCLA David Geffen School of Medicine. “The diagnosis and management of endocrine irAEs are distinct from their spontaneous endocrine disease counterparts. In addition, cancer and irAE treatments may not always align, requiring providers to balance a patient’s treatment goals with their prognosis.”

Dr. Lechner presented updates in endocrine irAE treatment and emerging areas of research during a recent Fred Hutchinson Cancer Center panel series. Fred Hutch physicians Shailender Bhatia, MD, and Petros Grivas, MD, PhD co-hosted the March 2023 event.

“Patients who experience irAEs may need to temporarily hold or permanently discontinue ICI therapy,” says Dr. Grivas. “Having the most up-to-date information about what to look for and how to best manage irAEs can help patients achieve better outcomes and continue immunotherapy, when possible.”

Endocrine irAEs are Associated with Improved Survival

Multiple studies show that irAEs correlate with ICI anti-tumor response. In general, patients who experience endocrine irAEs have longer progression-free survival, says Dr. Lechner.

Thyroid irAEs, in particular, are linked to better outcomes. One meta-analysis found the development of thyroid irAEs was associated with a significant improvement in overall survival (HR=0.52) and progression-free survival (HR=0.58).

While irAEs may be associated with an immunotherapy benefit, effective irAE management strategies are essential to reduce morbidity and mortality. 

ICI-Induced Diabetes Mellitus (DM)

ICI-induced Type 1 DM is relatively rare, affecting about 1% of people receiving combination or single agent ICI therapy. Hyperglycemia occurs quickly over the course of a few weeks. Due to its rapid onset, most patients (50-67%) present with diabetic ketoacidosis.

The timing of the onset of ICI-induced DM varies widely. The median onset is 16–20 weeks after the start of ICI therapy with a range of 1–52 weeks.

C-Peptide is Key to Diagnosing ICI-Induced DM

Low or absent C-peptide occurs in more than 80% of patients and is strongly suggestive of Type 1 DM. The presence of antibodies against insulin-producing cells can also be an important biomarker in immune-related type 1 DM. It occurs in about 40¬–70% of patients with ICI-induced DM, so the absence of antibodies should not preclude diagnosis in the right clinical setting.

Long-Term Insulin is the Main Treatment for ICI-Induced DM

Because ICI-induced DM occurs due to an immune-mediated destruction of insulin-producing beta cells, the main treatment is long-term insulin, as in patients with type 1 DM. Dr. Lechner recommends coding this condition as “type 1 DM” so patients can access the medications and supplies they need.

“Unlike most patients with spontaneous autoimmune diabetes, patients with ICI-induced diabetes don’t have a ‘honeymoon’ phase of residual insulin production and must balance blood glucose control with other cancer treatments,” she says. “For this reason, we recommend the use of continuous glucose monitoring (CGM) as soon as possible after diagnosis to help our patients manage hyperglycemia and prevent hypoglycemia.”

Other considerations for treating physicians include:

• High-dose glucocorticoids do not reverse ICI-induced DM and should not be used for that purpose. In addition, high-dose glucocorticoids can precipitate diabetic ketoacidosis.
• Stopping ICI therapy does not restore beta cell function. Therefore, ICI therapy may be continued after initiation of insulin therapy and resolution of diabetic ketoacidosis, if it is recommended for optimal cancer treatment.
• Early consultation with endocrinology to diagnose and manage ICI-induced DM is critical.

ICI-Induced Thyroiditis

Thyroiditis is a relatively common irAE. It follows a typical pattern:

1. Painless, destructive thyroiditis occurs approximately 2–3 weeks after ICI combination therapy or 4–6 weeks after ICI monotherapy.
2. A hyperthyroid phase with high free thyroxine (FT4) and low thyroid-stimulating hormone (TSH) may last 3–6 weeks.
3. Conversion to permanent hypothyroidism (low FT4 and high TSH) often occurs at about 10–12 weeks post-ICI therapy.

Patients with pre-existing Hashimoto’s thyroiditis may develop a rapidly enlarging thyroid with initiation of ICI therapy due to an accelerated immune attack on the thyroid gland. Gland enlargement usually resolves spontaneously over 2–4 weeks, but for patients with pain or severe compressive symptoms, a short course of glucocorticoids can be used. In addition, these patients may progress directly to hypothyroidism without a preceding hyperthyroid phase.

Using FT4 and TSH to Diagnose ICI-Induced Thyroiditis

Diagnosis of ICI-induced thyroiditis is based mainly on FT4 and TSH levels measured routinely during each ICI therapy cycle. Other tests that can be considered on a case-by-case basis, but are not as helpful in diagnosing ICI-induced thyroiditis, include:

• Radioiodine uptake: Though often used for diagnosing autoimmune thyroid disease, radioiodine uptake testing can be burdensome for patients with cancer. In addition, interpretation of the test can be complicated in patients who receive frequent CT scans with iodinated contrast.
• Thyroid antibodies: The prevalence of thyroid antibodies, which ranges from 20–40% in patients with ICI-induced thyroiditis, is not a useful diagnostic tool. For patients who have prolonged hyperthyroidism, antibody tests can help diagnose the relatively rare possibility of concurrent Graves’ disease.
• Ultrasound: New onset ICI-induced thyroiditis can appear as a diffusely hypoechoic gland on ultrasound. Though this test is not required or recommended, it can give physicians a quick diagnosis when other indicators do not point to a clear diagnosis.

Levothyroxine Treatment During the Hypothyroid Phase of ICI-Induced Thyroiditis

During the hyperthyroid phase, most patients are asymptomatic and require only close monitoring. Symptomatic patients may receive a short course of a beta blocker, such as propranolol.

The transition from hyperthyroidism to hypothyroidism may occur over 4–6 weeks. The optimal time to start therapy with levothyroxine is just as FT4 drops to critical degree and TSH starts to rise. Because of the destructive nature of this condition and the potential for hepatotoxicity, there is no role for antithyroid drugs, such as methimazole or propylthiouracil, in the treatment of ICI-thyroiditis.

“Our research has shown a dose of 1.4 mcg/kg/day, or 1.2 mcg/kg/day for a very elderly patient, seems optimal,” says Dr. Lechner. “Though higher than we typically use for patients with Hashimoto’s disease, this dose adequately treats ICI-induced hypothyroidism and improves patients’ quality of life.”

ICI-Induced Hypophysitis

ICI-induced hypophysitis is defined as a new case of hypopituitarism, sometimes with pituitary enlargement. Among the pituitary hormones, ICIs most often affect adrenocorticotropic hormone (ACTH) production.

With PD-1 and PD-L1 regimens, ACTH is the main hormone lost. CTLA-4 therapies are associated with broader hormone deficits. Loss of ACTH can cause secondary adrenal insufficiency and lead to several symptoms, such as:

• Abdominal pain
• Confusion
• Exhaustion, weakness
• Fatigue, lethargy
• Loss of appetite, nausea
• Low blood pressure, dizziness
• Low sodium
• Muscle aches
• Weight loss

An acute onset of these symptoms (adrenal crisis) can be life threatening and requires emergency care.

Using Cortisol and ACTH to Diagnose ICI-Induced Hypophysitis

Lab tests to detect secondary adrenal insufficiency include serum cortisol and ACTH. An MRI, which may or may not show an enlarged pituitary gland, is usually not necessary for diagnosis. It can be considered if the patient has neurological symptoms. When present, pituitary enlargement associated with ICI-hypophysitis typically resolves on its own within several months, says Dr. Lechner.

Physicians may consider an MRI if a patient has:

• Clinical concern for metastatic disease in the pituitary
• Multiple pituitary hormone deficits
• Symptoms due to pituitary enlargement, such as vision changes

Hydrocortisone Dosing for Treating ICI-Induced Hypophysitis 

Most patients with ICI-induced hypophysitis require long-term treatment with physiologic hydrocortisone. They can continue their ICI therapy.

The National Comprehensive Cancer Network (NCCN) guidelines recommend a daily dose of 20 mg hydrocortisone in the morning and 10 mg in the afternoon, which Dr. Lechner recommends. “We use higher hydrocortisone doses for ICI-induced hypophysitis than for Addison’s disease,” says Dr. Lechner. “This is because patients with cancer have more stress on their system.”

Patients with a new diagnosis of ICI-hypophysitis with adrenal insufficiency who are stable and ambulatory should receive an initial dose of 50–100 mg followed by daily physiologic replacement. Physicians should counsel patients on how to adjust their steroid dose for acute illness, procedures and surgeries.

If a patient presents with adrenal crisis, Dr. Lechner administers a one-time dose of 100 mg intravenous hydrocortisone (“stress dose steroids”) and triages to a setting with close medical care or hospital admission. Subsequent hydrocortisone doses should be tailored to the patient’s status and tapered to a physiologic replacement dose based on clinical response, often in conjunction with an endocrinologist.

As with ICI-DM and ICI-thyroiditis, stopping ICI therapy or use of high dose glucocorticoids has not been shown to reduce the long-term need for hormone replacement in patients with ICI-hypophysitis. High-dose glucocorticoids may be considered in patients with severe pituitary enlargement that causes compression of nearby structures, such as the optic chiasm.

Research Frontiers in Endocrine irAEs

Researchers are working to better understand endocrine irAEs, diagnose them earlier and treat them more effectively. Two exciting areas of investigation include:

Predicting Endocrine irAEs Based on Autoimmunity and Genetic Risk

Studies show that most patients with pre-existing thyroid autoantibodies — which includes about 10% of all females — progress to ICI-induced thyroiditis. Human leukocyte antigen (HLA) typing and polygenetic risk scores may also predict patients most likely to develop irAEs during ICI therapy.

Reducing Endocrine Toxicity of ICIs

Dr. Lechner’s research group is working on developing the next generation of immunotherapies that have fewer toxicities. One research strategy is to evaluate tissues of patients with endocrine irAEs to find out what’s causing the toxicity. These analyses have found interleukin (IL)-17- and IL-21-producing T cells in the thyroid tissues of patients with ICI-thyroiditis that are also present in other autoimmune diseases.

Using their knowledge about autoimmunity, the researchers tested whether IL-17 or IL-21 inhibitors given during ICI treatment could prevent irAEs in mouse models. Early results showed that IL-17 inhibitors might help prevent ICI-induced thyroiditis, while IL-21 inhibitors might help prevent ICI-induced thyroiditis and DM. However, more research is needed to assess these hypotheses.

“Through this collaborative work that includes basic and translational scientists and clinicians, we're making inroads,” says Dr. Lechner. 

Provider Education at Fred Hutch

Dr. Lechner’s presentation was the seventh in a series of multidisciplinary panel discussions to help providers better prevent, diagnose and treat irAEs. View Dr. Lechner’s entire presentation.

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