Management of Nivolumab-Induced Thyrotoxicosis
Beta-blockers should be started immediately for symptom control, nivolumab should be continued in most cases, and antithyroid drugs are rarely needed because this represents destructive thyroiditis that will transition to hypothyroidism within 4–8 weeks. 1
Immediate Symptomatic Management
Initiate beta-blocker therapy immediately (propranolol or atenolol) for patients presenting with palpitations, tremor, tachycardia, heat intolerance, or weight loss. 1 This provides rapid symptomatic relief while the thyrotoxic phase resolves spontaneously. 1
Do not start antithyroid drugs (carbimazole or methimazole) unless anti-TSH-receptor antibodies are positive, which occurs in only 16–26% of cases and indicates true Graves' disease rather than destructive thyroiditis. 1 The vast majority of nivolumab-induced thyrotoxicosis is painless thyroiditis, not Graves' disease. 2, 3
Decision to Continue or Withhold Nivolumab
Continue nivolumab therapy in the majority of patients, as thyroid dysfunction rarely mandates treatment interruption. 1 Thyrotoxicosis develops within 2–4 weeks of starting nivolumab and resolves within 4–6 weeks without stopping the drug. 2, 3
Withhold nivolumab only if the patient is markedly unwell with severe symptomatic hyperthyroidism that cannot be controlled with beta-blockers. 1 This is uncommon, as most cases are mild to moderate in severity. 4, 2
Monitoring Strategy and Anticipating Hypothyroidism
Check TSH and free T4 before every infusion for the first 3 months, then every second cycle for patients on 2-weekly dosing schedules. 1 This frequent monitoring is critical because the transition from thyrotoxicosis to hypothyroidism occurs rapidly—often within 6–8 weeks. 3
Recognize subclinical hyperthyroidism (low TSH with normal free T4) as a warning sign that precedes overt hypothyroidism. 1 When TSH begins to rise on two consecutive tests, this signals the destructive phase is ending and hypothyroidism is imminent. 1
Measure anti-TPO and anti-thyroglobulin antibodies when thyroid dysfunction is first identified; approximately 80% of clinically significant cases have positive antibodies. 1 Positive antibodies predict a higher likelihood of permanent hypothyroidism requiring lifelong levothyroxine. 1
Transition to Hypothyroidism and Levothyroxine Initiation
Start levothyroxine promptly once TSH rises, as hypothyroidism following nivolumab-induced thyroiditis is usually permanent. 1 The typical pattern is transient thyrotoxicosis (median TSH nadir at 51 days) followed by hypothyroidism (median TSH peak at 110 days). 4
Initial levothyroxine dosing is 0.5–1.5 µg/kg, with lower starting doses (25–50 µg daily) for elderly patients or those with cardiac disease. 1 Approximately 50% of patients who develop thyrotoxicosis will subsequently require long-term levothyroxine replacement. 4, 2
Continue immunotherapy even with subclinical hypothyroidism when patients experience fatigue or other symptoms; nivolumab does not need to be stopped for thyroid dysfunction. 1
Distinguishing Thyroiditis from Hypophysitis
If TSH falls on two consecutive tests while free T4 is normal or low, obtain a 9 AM cortisol to evaluate for hypophysitis rather than primary thyroid disease. 1 This pattern (declining TSH with normal/low free T4) suggests pituitary dysfunction, not thyroiditis. 1
Hypophysitis requires weekly cortisol monitoring and treatment with corticosteroids, not beta-blockers. 1 This is a critical distinction because starting levothyroxine before treating adrenal insufficiency can precipitate adrenal crisis. 5
Role of Corticosteroids in Thyrotoxicosis
Systemic steroids are required in only 9–20% of hyperthyroid episodes and are generally reserved for severe or painful thyroiditis. 1 Most cases of nivolumab-induced thyrotoxicosis are painless and do not require steroids. 2, 6
For painful thyroiditis, use a tapering course of prednisolone 0.5 mg/kg. 1 However, all five consecutive cases in one series were painless thyroiditis, suggesting pain is uncommon with nivolumab. 2
Special Considerations and Pitfalls
Recent iodinated contrast (CT scans) can transiently alter thyroid function tests; timing of imaging should be considered when interpreting results. 1 This is particularly relevant in cancer patients undergoing frequent imaging.
Nivolumab can cause biochemical interference on thyroid hormone assays, particularly free T4 measurements on certain immunoassay platforms (e.g., Siemens Centaur). 7 If free T4 results are discordant with TSH, consider retesting with a different assay method (e.g., Roche Elecsys) or performing polyethylene glycol precipitation to remove interfering antibodies. 7 This interference resolves after nivolumab discontinuation. 7
Thyroid dysfunction occurs in 5–10% of patients on anti-PD-1 monotherapy (nivolumab alone) and rises to approximately 20% when combined with ipilimumab. 1 The incidence is 23.3% in real-world cohorts. 4
In patients with non-small-cell lung cancer, nivolumab-induced thyroid dysfunction is associated with better overall survival (HR = 0.4,95% CI: 0.17–0.94; p = 0.035). 4 This suggests thyroid dysfunction may be a marker of immune activation and treatment response. 4
Clinical Pattern Summary
The typical sequence is: (1) thyrotoxicosis develops within 2–4 weeks of starting nivolumab 2, 3; (2) TSH nadir occurs around day 51 4; (3) thyrotoxicosis resolves within 4–6 weeks 2, 3; (4) hypothyroidism develops around day 110 4; (5) approximately 50% require lifelong levothyroxine. 4, 2 This pattern is consistent with destructive thyroiditis, not Graves' disease. 2, 6