What are the features of immune-mediated endocrinopathy in patients on biologic therapy, such as checkpoint inhibitors (e.g., ipilimumab, nivolumab)?

Features of Immune-Mediated Endocrinopathy in Patients on Biologic Therapy

Immune checkpoint inhibitors (ICIs) commonly cause endocrinopathies that have distinctive clinical, biochemical, and temporal features, with approximately 10% of patients developing clinically significant endocrine adverse events during treatment. 1

Timing and Incidence

• Median time to onset: 14.5 weeks (range: 1.5-130 weeks) 1
• Overall incidence rates:
  • Any endocrinopathy: ~10% of patients on ICIs 1
  • Thyroid dysfunction: 14% 2
  • Hypophysitis: 6-8% 2, 3
  • Autoimmune diabetes: 0.6% 2
• Combination therapy (ipilimumab + anti-PD-1) has higher risk (27%) compared to anti-PD-1 monotherapy (9%) 2
• Earlier onset with combination therapy (median 30 days) vs. ipilimumab alone (76 days) 2

Specific Endocrinopathies and Their Features

1. Thyroid Dysfunction

• Presentation patterns:

  • Primary hypothyroidism: Elevated TSH with low free T4 1
  • Thyroiditis: Often begins with transient thyrotoxicosis followed by hypothyroidism 1
  • Central hypothyroidism: Low TSH with low free T4 (suggests hypophysitis) 1

• Monitoring recommendations:

  • Anti-PD-1/PD-L1: TSH and free T4 every cycle for first 3 months, then every second cycle 1
  • Anti-CTLA-4 (including combinations): TSH and free T4 every cycle 1
  • A falling TSH across two measurements with normal/lowered T4 may suggest pituitary dysfunction 1

• Key feature: Unlike other immune-related adverse events, thyroid dysfunction rarely improves spontaneously and often requires permanent hormone replacement 4

2. Hypophysitis (Pituitary Inflammation)

• Predominant associations:

  • Most common with ipilimumab (CTLA-4 inhibitor): 1-16% depending on dose 1
  • Rare with anti-PD-1/PD-L1 monotherapy 1
  • Increased with combination therapy (9%) 2

• Clinical presentation:

  • Headache (85% of cases) 1
  • Fatigue (66% of cases) 1
  • Visual changes, especially visual field defects 1
  • Multiple pituitary hormone deficiencies:
    • Central hypothyroidism (>90% of cases) 1
    • Central adrenal insufficiency (majority of cases) 1
    • Hypogonadotropic hypogonadism 1
    • Panhypopituitarism in ~50% of cases 1

• Radiographic findings:

  • Pituitary enlargement on MRI 1
  • Stalk thickening, suprasellar convexity, heterogeneous enhancement 1
  • Resolution of enlargement typically occurs within 2 months 1

3. Autoimmune Diabetes Mellitus

• Presentation:

  • Polyuria, polydipsia, nausea, vomiting, abdominal pain, visual blurring 1
  • May present as diabetic ketoacidosis (DKA) 1, 5
  • Rapid onset with severe insulin deficiency 5

• Laboratory features:

  • Hyperglycemia with ketosis/ketoacidosis 5
  • Low C-peptide levels 5
  • Traditional autoantibodies (GAD, IA-2, ZnT8) may be negative 5

4. Adrenal Insufficiency

• Types:

  • Secondary (central): Due to hypophysitis with low ACTH and cortisol 1
  • Primary: Rare, with elevated ACTH and low cortisol 1

• Critical diagnostic point: Morning cortisol and ACTH measurements are needed to distinguish primary from secondary adrenal insufficiency 1

Diagnostic Approach

1. Regular screening:

   • TSH and free T4 every 4-6 weeks for asymptomatic patients 1
   • Morning cortisol measurements should be considered (every month for 6 months, then every 3 months for 6 months, then every 6 months for 1 year) 1
   • Glucose monitoring for diabetes 1

2. For symptomatic patients:

   • Always measure both primary hormone and corresponding pituitary hormone to localize disease 1
   • For thyroid: Check both TSH and free T4 (TSH alone may miss central hypothyroidism) 1
   • For adrenal: Morning cortisol and ACTH 1
   • For diabetes: Blood glucose, ketones, C-peptide, HbA1c 1

3. Imaging:

   • MRI of pituitary with dedicated pituitary cuts for suspected hypophysitis 1

Management Considerations

1. Critical sequencing for hormone replacement:

   • When multiple pituitary hormones are deficient, always replace hydrocortisone first before thyroid hormone 1
   • Replacing thyroid hormone first when cortisol is low can trigger adrenal crisis by increasing cortisol metabolism 1

2. Continuation of immunotherapy:

   • Unlike other immune-related adverse events, endocrinopathies can often be managed without discontinuing immunotherapy 1
   • Hormone replacement therapy is usually effective for symptom control 1

3. Permanence of effects:

   • Endocrine dysfunction is often permanent, with rare recovery of endogenous hormone secretion 3
   • Long-term hormone replacement is typically required 1

Special Considerations

• Multiple concurrent endocrinopathies can occur, especially with combination therapy 5
• Late endocrine dysfunction can develop even after treatment completion 1
• Atypical presentations are common with nonspecific symptoms that may be confused with cancer symptoms or other conditions 6
• High clinical suspicion is needed as traditional antibody testing may not be reliable for early-onset endocrinopathy 5

By understanding these distinctive features of immune-mediated endocrinopathies, clinicians can implement appropriate monitoring strategies and early interventions to minimize morbidity in patients receiving checkpoint inhibitor therapy.