Why does Keytruda (pembrolizumab) affect thyroid function?

Why Keytruda (Pembrolizumab) Affects Thyroid Function

Keytruda (pembrolizumab) causes thyroid dysfunction primarily through immune-mediated thyroiditis, where T-cell activation leads to autoimmune attack on the thyroid gland, often beginning with transient hyperthyroidism followed by permanent hypothyroidism.

Mechanism of Thyroid Dysfunction

Pembrolizumab is a PD-1 (programmed cell death protein-1) inhibitor that works by blocking immune checkpoints, which normally prevent excessive immune responses. When these checkpoints are blocked:

• The immune system, particularly T-cells, becomes disinhibited and can attack normal tissues, including the thyroid gland 1
• This leads to immune-mediated thyroiditis, which is primarily T-cell mediated rather than B-cell autoimmunity 1
• In most cases, the initial inflammation causes thyroid cell destruction, leading to release of stored thyroid hormone (transient hyperthyroidism), followed by permanent hypothyroidism as the gland becomes damaged 2

Epidemiology and Clinical Patterns

Thyroid dysfunction is one of the most common immune-related adverse events (irAEs) with pembrolizumab:

• Incidence rates:

  • Hyperthyroidism: 3.4% of patients receiving Keytruda 3
  • Hypothyroidism: 8% of patients receiving Keytruda 3
  • Higher rates in certain cancers (22% in resected NSCLC) 3

• Characteristic pattern:

  • Early onset (median 42 days after starting treatment) 2
  • Often begins with transient hyperthyroidism that evolves to permanent hypothyroidism 2, 4
  • Majority of cases are asymptomatic and detected through routine laboratory monitoring 2

Evidence of Autoimmune Mechanism

Research strongly supports an autoimmune etiology:

• Anti-thyroid antibodies are present in 80% of patients who develop thyroid dysfunction during pembrolizumab treatment, compared to only 8% in those who don't develop thyroid problems 2
• Diffuse increased 18FDG uptake on PET/CT is observed in patients with thyrotoxicosis who progress to hypothyroidism, consistent with inflammatory thyroiditis 4
• Pathology from thyroidectomy specimens shows severe thyroiditis 5

Clinical Implications and Management

The development of thyroid dysfunction requires specific monitoring and management:

• Regular thyroid function monitoring:

  • Check TSH and free T4 before every infusion for the first 3 months
  • Then every second cycle thereafter 1

• Management approach:

  • For hypothyroidism: Thyroid hormone replacement therapy is typically required and often permanent 3
  • For hyperthyroidism: Beta-blockers (propranolol or atenolol) for symptom control; rarely requires carbimazole or steroids 1
  • Unlike other immune-related adverse events, high-dose corticosteroids are generally not recommended for managing thyroid dysfunction 1

Prognostic Significance

Interestingly, the development of thyroid dysfunction may be associated with treatment efficacy:

• Patients who develop thyroid dysfunction during pembrolizumab treatment for NSCLC have shown significantly longer overall survival (hazard ratio 0.29) 2
• This suggests that thyroid autoimmunity may be a biomarker of enhanced immune activation and potentially better anti-tumor response

Important Clinical Considerations

• Pre-existing autoimmune thyroid conditions may predispose patients to more severe thyroid dysfunction with pembrolizumab 5
• Unlike other immune checkpoint inhibitors (such as ipilimumab which more commonly causes hypophysitis), PD-1 inhibitors like pembrolizumab predominantly affect the thyroid directly 1
• Thyroid dysfunction is usually manageable and rarely requires discontinuation of pembrolizumab therapy 3

Monitoring thyroid function is essential during pembrolizumab treatment, as early detection allows for appropriate management of thyroid dysfunction, ensuring optimal patient outcomes while continuing this important cancer therapy.