What are the CTCAE grades for immune checkpoint inhibitor–induced thyroiditis and the recommended management for each grade?

Immune Checkpoint Inhibitor-Induced Thyroiditis: CTCAE Grading and Management

For ICI-induced thyroiditis presenting as thyrotoxicosis, continue immunotherapy for Grade 1 patients with beta-blocker symptom control, hold therapy for Grade 2 until symptoms resolve, and discontinue for Grade 3-4 with hospitalization and endocrine consultation; for subsequent hypothyroidism, continue immunotherapy for Grade 1 (TSH 4.5-10), may continue or hold for Grade 2 (TSH >10 or symptomatic) with levothyroxine replacement, and hold for Grade 3-4 with urgent thyroid supplementation. 1

Thyrotoxicosis Phase (Initial Presentation)

Grade 1: Asymptomatic or Mild Symptoms

• Continue ICI therapy without interruption 1
• Initiate beta-blocker (atenolol or propranolol) for symptomatic relief of tachycardia, tremor, or anxiety 1
• Monitor TSH and FT4 every 2-3 weeks after diagnosis to detect transition to hypothyroidism, which occurs in most patients 1
• If thyrotoxicosis persists beyond 6 weeks, obtain endocrine consultation for additional workup 1

Grade 2: Moderate Symptoms, Able to Perform ADLs

• Consider holding ICI until symptoms return to baseline 1
• Obtain endocrine consultation for management guidance 1
• Prescribe beta-blocker for symptomatic control 1
• Provide hydration and supportive care 1
• For persistent thyrotoxicosis exceeding 6 weeks, refer to endocrinology for possible medical thyroid suppression 1

Grade 3-4: Severe Symptoms, Unable to Perform ADLs

• Hold ICI until symptoms resolve to baseline with appropriate therapy 1
• Mandatory endocrine consultation for all Grade 3-4 patients 1
• Initiate beta-blocker therapy 1
• Consider hospitalization for severe cases where inpatient endocrine consultation can guide additional medical therapies including steroids, SSKI (saturated solution of potassium iodide), or thionamides (methimazole or propylthiouracil), and possible surgery 1
• Provide aggressive hydration and supportive care 1

Hypothyroidism Phase (Subsequent or Primary Presentation)

Grade 1: TSH 4.5-10 mIU/L and Asymptomatic

• Continue ICI therapy without interruption 1
• Monitor TSH (with optional FT4) every 4-6 weeks as routine surveillance 1
• In asymptomatic patients with FT4 remaining in reference range during recovery phase of thyroiditis, monitoring before treating is acceptable to determine if recovery to normal occurs within 3-4 weeks 1

Grade 2: TSH Persistently >10 mIU/L or Moderate Symptoms

• May continue or hold ICI until symptoms resolve to baseline 1
• Obtain endocrine consultation for unusual presentations, concern for central hypothyroidism, or difficulty titrating therapy 1
• Prescribe levothyroxine supplementation for symptomatic patients with any TSH elevation or asymptomatic patients with TSH >10 mIU/L measured 4 weeks apart 1
• For patients <70 years old without cardiac disease or multiple comorbidities, initiate full replacement at approximately 1.6 mcg/kg/day using ideal body weight 1
• For patients >70 years old or frail with multiple comorbidities (including cardiac disease), start with lower dose of 25-50 mcg and titrate upward 1
• Monitor TSH every 6-8 weeks while titrating to goal TSH within reference range; FT4 can help interpret ongoing abnormal TSH as it normalizes faster 1
• Once adequately treated, repeat testing every 6-12 months or with symptom changes 1

Grade 3-4: Severe Symptoms, Myxedema, or Life-Threatening

• Hold ICI until symptoms resolve to baseline with appropriate supplementation 1
• Obtain endocrine consultation for rapid hormone replacement 1
• Hospital admission required for myxedema coma (bradycardia, hypothermia, altered mental status) 1
• Inpatient endocrinology consultation assists with IV levothyroxine dosing, steroids, and supportive care 1
• If uncertainty exists about primary versus central hypothyroidism, administer hydrocortisone before initiating thyroid hormone to prevent adrenal crisis 1
• Myxedema coma requires high level of care as a life-threatening emergency 1

Diagnostic Workup

Routine Monitoring

• Check TSH (with optional FT4) every 4-6 weeks for asymptomatic patients on ICI therapy 1, 2
• Continue monitoring post-ICI discontinuation, as 11.6% of monitored patients develop thyroid dysfunction after treatment cessation 3

Symptomatic Evaluation

• Measure both TSH and FT4 for case detection in symptomatic patients 1
• Add T3 testing for highly symptomatic patients with minimal FT4 elevations 1
• Low TSH with low FT4 indicates central hypothyroidism; evaluate for hypophysitis 1
• Consider TSH receptor antibody testing if clinical features suggest Graves' disease (ophthalmopathy, T3 toxicosis) 1, 4

Critical Clinical Pearls

Thyroiditis Natural History

• ICI-induced thyroiditis is typically self-limited, with initial hyperthyroidism resolving within weeks to either primary hypothyroidism (most common) or occasionally normal function 1
• The biphasic pattern (transient thyrotoxicosis followed by persistent hypothyroidism) is characteristic 2

Distinguishing Graves' Disease from Thyroiditis

• Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves' disease and require early endocrine referral 1
• Patients with existing or prior Graves' disease have 15.8% risk of hyperthyroidism with ICI therapy versus 0% in controls, necessitating careful differential diagnosis 4
• True Graves' disease is persistent and requires antithyroid medication, radioactive iodine, or surgery, unlike self-limited thyroiditis 1

Monitoring Pitfalls

• Development of low TSH on levothyroxine therapy suggests overtreatment or recovery of thyroid function; reduce or discontinue dose with close follow-up 1
• Elevated TSH during recovery phase of thyroiditis may not require treatment if FT4 remains normal and patient is asymptomatic 1
• Patients with abnormal TSH before ICI discontinuation and those receiving ≤9 months of therapy require more stringent post-ICI surveillance 3
• Nearly half (48.6%) of patients receive no post-ICI thyroid monitoring, leading to under-recognition of thyroid dysfunction 3

Prognostic Implications

• Overt thyroid dysfunction correlates with improved survival and treatment response, with Grade 2-4 hypothyroidism showing significantly higher remission rates than patients without thyroid dysfunction 5
• One-year survival rates are 64.9% for Grade 1,88.9% for Grade 2-4, versus 52.1% for patients without thyroid dysfunction 5