Table 4.

Management of Endocrine irAEs in Patients Treated With ICPis

4.0 Endocrine Toxicity
Counsel patients to inform their health care provider immediately if they experience any changes in their health since their last visit, especially any of the following:  Headaches that will not go away or unusual headache patterns  Vision changes  Rapid heartbeat  Increased sweating  Extreme tiredness or weakness  Muscle aches  Weight gain or weight loss  Dizziness or fainting  Feeling more hungry or thirsty than usual  Hair loss  Changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness  Feeling cold  Constipation  Voice gets deeper  Urinating more often than usual  Nausea or vomiting  Abdominal pain
4.1 Thyroid
4.1.1 Primary hypothyroidism
Definition: Elevated TSH, normal or low FT4
Diagnostic work-up
TSH and FT4 every 4–6 weeks as part of routine clinical monitoring on therapy or for case detection in symptomatic patients
Grading	Management
G1: TSH < 10 mIU/L and asymptomatic	Should continue ICPi with close follow-up and monitoring of TSH, FT4
G2: Moderate symptoms; able to perform ADL; TSH persistently > 10 mIU/L	May hold ICPi until symptoms resolve to baseline  Consider endocrine consultation  Prescribe thyroid hormone supplementation in symptomatic patients with any degree of TSH elevation or in asymptomatic patients with TSH levels that persist > 10 mIU/L (measured 4 weeks apart)  Monitor TSH even/6–8 weeks while titrating hormone replacement to normal TSH FT4 can be used in the short term (2 weeks) to ensure adequacy of therapy in those with frank hypothyroidism where the FT4 was initially low  Once adequately treated, should monitor thyroid function (at least TSH) every 6 weeks while on active ICPi therapy or as needed for symptoms to ensure appropriate replacement; repeat testing annually or as indicated by symptoms once stable
G3–4: Severe symptoms, medically significant or life- threatening consequences, unable to perform ADL	Hold ICPi until symptoms resolve to baseline with appropriate supplementation  Endocrine consultation  May admit for IV therapy if signs of myxedema (bradycardia, hypothermia)  Thyroid supplementation and reassessment as in G2
Additional considerations
For patients without risk factors, full replacement can be estimated with an ideal body weight-based dose of approximately 1.6 μg/kg/d
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting at 25–50 μg
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in asymptomatic patients to determine whether there is recovery to normal within 3–4 weeks
Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with a history of thyroiditis (initial thyrotoxic phase)
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated
4.1.2 Hyperthyroidism
Definition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine
Diagnostic work-up
Monitor TSH, FT4 every 4–6 weeks from the start of therapy or as needed for case detection in symptomatic patients
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (eg, ophthalmopathy)
Close monitoring of thyroid function every 2–3 weeks after diagnosis to catch transition to hypothyroidism in patients with thyroiditis and hyperthyroidism
Grading	Management
G1: Asymptomatic or mild symptoms	Can continue ICPi with close follow-up and monitoring of TSH, FT4 every 2–3 weeks until it is clear whether there will be persistent hyperthyroidism (see below) or hypothyroidism (see 4.1.1)
G2: Moderate symptoms, able to perform ADL	Consider holding ICPi until symptoms return to baseline  Consider endocrine consultation  β-Blocker (eg, atenolol, propranolol) for symptomatic relief  Hydration and supportive care  Corticosteroids are not usually required to shorten duration  For persistent hyperthyroidism (> 6 weeks) or clinical suspicion, work-up for Graves disease (TSI or TRAb) and consider thionamide (methimazole or PTU Refer to endocrinology for Graves disease
G3–4: Severe symptoms, medically significant or life- threatening consequences, unable to perform ADL	Hold ICPi until symptoms resolve to baseline with appropriate therapy  Endocrine consultation  β-Blocker (eg, atenolol, propranolol) for symptomatic relief  For severe symptoms or concern for thyroid storm, hospitalize patient and initiate prednisone 1–2 mg/kg/d or equivalent tapered over 1–2 weeks; consider also use of SSKI or thionamide (methimazole or PTU).
Additional considerations  Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. Hypothyroidism can be treated as above.  Graves disease is generally persistent and is due to increased thyroid hormone production that can be treated with antithyroid medical therapy.  Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves and should prompt early endocrine referral.
4.2 Adrenal - primary adrenal insufficiency
Definition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatremia and hyperkalemia with orthostasis and volume depletion due to loss of aldosterone
Diagnostic work-up for patients in whom adrenal insufficiency is suspected:  Evaluate ACTH (AM), cortisol level (AM)  Basic metabolic panel (Na, K, CO2, glucose)  Consider ACTH stimulation test for indeterminate results  If primary adrenal insufficiency (high ACTH, low cortisol) is found biochemically:   Evaluate for precipitating cause of crisis such as infection   Perform an adrenal CT for metastasis/hemorrhage
Grading	Management
G1: Asymptomatic or mild symptoms	Consider holding ICPi until patient is stabilized on replacement hormone  Endocrine consultation  Replacement therapy with prednisone (5–10 mg daily) or hydrocortisone (10–20 mg orally every morning, 5–10 mg orally in early afternoon)  May require fludrocortisone (0.1 mg/d) for mineralocorticoid replacement in primary adrenal insufficiency  Titrate dose up or down as symptoms dictate
G2: Moderate symptoms, able to perform ADL	Consider holding ICPi until patient is stabilized on replacement hormone  Endocrine consultation  Initiate outpatient treatment at two to three times maintenance (if prednisone, 20 mg daily; if hydrocortisone, 20–30 mg in the morning, and 10–20 mg in the afternoon) to manage acute symptoms.  Taper stress-dose corticosteroids down to maintenance doses over 5–10 days  Maintenance therapy as in G1.
G3–4: Severe symptoms, medically significant or life- threatening consequences, unable to perform ADL	Hold ICPi until patient is stabilized on replacement hormone  Endocrine consultation  See in clinic or, for after hours, make an emergency department referral for normal saline (at least 2 L) and IV stress-dose corticosteroids on presentation(hydrocortisone 100 mg or dexamethasone 4 mg (if the diagnosis is not clear and stimulation testing will be needed)  Taper stress-dose corticosteroids down to maintenance doses over 7–14 days after discharge  Maintenance therapy as in G1
Additional considerations  Primary and secondary adrenal insufficiency can be distinguished by the relationship between ACTH and cortisol. If the ACTH is low with low cortisol, then management is as per 4.3.  Patients on corticosteroids for management of other conditions will have low morning cortisol as a result of iatrogenic, secondary adrenal insufficiency. ACTH will also be low in these patients. A diagnosis of adrenal insufficiency is challenging to make in these situations (see next section on hypophysitis).  Emergent therapy for someone with suspected adrenal insufficiency is best done with dexamethasone as a stimulation test can still be performed. If the diagnosis is already confirmed, can use hydrocortisone 100 mg.  All patients need education on stress dosing and a medical alert bracelet for adrenal insufficiency to trigger stress-dose corticosteroids by EMS.  Endocrine consultation prior to surgery or any procedure for stress-dose planning.
4.3 Pituitary - hypophysitis
Definition: Inflammation of the pituitarywith varying effects on hormone function. Mostcommonly presenting with central adrenal insufficiency. May also have central hypothyroidism, diabetes insipidus, and hypogonadism.
Diagnostic work-up  Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and volume depletion with diabetes insipidus. Low testosterone or estradiol with low LH and FSH.  Testing:   Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes   Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females with fatigue, loss of libido, and mood changes   Consider MRI of the brain with or without contrast with pituitary/sellar cuts in patients with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes
Grading	Management
G1: Asymptomatic or mild symptoms	Considering holding ICPi until patient is stabilized on replacement hormones  Hormonal supplementation as needed, using dosing as above for primary hypothyroidism and adrenal insufficiency (eg, hydrocortisone 10–20 mg orally in the morning, 5–10 mg orally in early afternoon; levothyroxine by weight)  Testosterone or estrogen therapy as needed in those without contraindications  Endocrine consultation  Always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis  Follow FT4 for thyroid hormone replacement titration (TSH is not accurate)
G2: Moderate symptoms, able to perform ADL	Consider holding ICPi until patient is stabilized on replacement hormones  Endocrine consultation  Hormonal supplementation as in G1
G3–4: Severe symptoms, medically significant or life- threatening consequences, unable to perform ADL	Hold ICPi until patient is stabilized on replacement hormones  Endocrine consultation  Hormonal supplementation as in G1  Consider initial pulse dose therapy with prednisone 1–2 mg/kg oral daily (or equivalent) tapered over at least 1–2 weeks
Additional considerations  Be aware of the need to start corticosteroids first when planning hormone replacement therapy for multiple deficiencies  All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for adrenal insufficiency to trigger stress-dose corticosteroids by EMS  Corticosteroid use can cause isolated central adrenal insufficiency  Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions  Laboratory confirmation of adrenal insufficiency should not be attempted until treatment with corticosteroids for other disease is ready to be discontinued  For long-term exposure, consult endocrinology for recovery and weaning protocol using hydrocortisone.
4.4 Diabetes
Definition:T2DM is a combination of insulin resistance and insufficiency that may require oral or insulin therapy. It may be newonsetor exacerbated during therapy for nonimmunologic reasons, such as corticosteroid exposure.   Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an insulin requirement
Diagnostic work-up  Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including measuring glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3–6 weeks thereafter. To guide the work-up in new-onset hyperglycemia, clinicians should consider a patient's medical background, exposure history, and risk factors for each subtype of DM.  Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and an assessment of the anion gap on a metabolic panel. Anti-glutamic acid decarboxylase, anti-islet cell, oranti-insulin antibodies are highly specific forautoimmune diabetes. Insulin and C-peptide levels can also assist in the diagnosis.
Grading	Management
Gl: Asymptomatic or mild symptoms; fasting glucose value > UlN (160 mg/dL); fasting glucose value > ULN (8.9 mmol/L); no evidence of ketosis or laboratory evidence of T1DM	Can continue ICPi with close clinical follow-up and laboratory evaluation  May initiate oral therapy for those with new-onset T2DM  Screen for T1DM ifappropriate, forexample, acuteonsetwith prior normal values or clinical concern for ketosis
G2: Moderate symptoms, able to perform ADL, fasting glucose value > 160–250 mg/dL; fasting glucose value > 8.9–13.9 mmol/L, ketosis or evidence ofT1DMatany glucose level	May hold ICPi until glucose control is obtained  Titrate oral therapy or add insulin for worsening control in T2DM  Should administer insulin for T1DM (or as default therapy if there is confusion about type)  Urgentendocrine consultation forany patient with T1DM; in theabsence of endocrinology, internal medicine may suffice  Consider admission for T1DM if early outpatient evaluation is not available or signs of ketoacidosis are present
G3–4: Severe symptoms, medically significant or life- threatening consequences, unable to perform ADL G3: > 250–500 mg/dL (> 13.9–27.8 mmol/L) G4: > 500 mg/dL (> 27.8 mmol/L)	Hold ICPi until glucose control is obtained on therapywith reduction oftoxicity to G1 or less  Urgent endocrine consultation for all patients  Initiate insulin therapy for all patients  Admit for inpatient management: Concerns for developing DKA, Symptomatic patients regardless of diabetes type, New-onset T1DM unable to see endocrinology
Additional considerations  Insulin therapy can be used as the default in any case with hyperglycemia.  Long-acting therapy alone is not usuallysufficient forT1DM, where halfof daily requirements are usuallygiven in divided doses as prandial coverage and half as long acting.  Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be estimated at 0.3–0.4 units/kg/d).  In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient’s daily requirements and can be used to more rapidly titrate basal needs. All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate.

Abbreviations: ACTH, adrenocorticotropic hormone; ADL, activities of daily living; CT, computed tomography; DKA, diabetic ketoacidosis; DM, diabetes mellitus; EMS, emergency medical services; FSH, follicle-stimulating hormone; FT4, free thyroxine; G, grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event; LH, luteinizing hormone; MRI, magnetic resonance imaging; PTU, propylthiouracil; SSKI, potassium iodide;T1DM, type 1 diabetes mellitus;T2DM, type 2 diabetes mellitus;TRAb, thyroid-stimulating hormone receptor antibody; TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin; ULN, upper limit of normal.