402.3 🩺 內科專科考前版

402.3.0.1 📌 䞀頁重點

  • 22E updates:
    • Anti-IFN-α/ω antibodies = APECED-specific marker (vs anti-21-hydroxylase non-specific for AI alone)
    • ICI-induced endocrinopathies rising; T1DM fulminant with C-peptide → 0
    • Crinecerfont (CRF1 antagonist, FDA 2024) for classic CAH (relevant if 21-OH def part of APS-1)
    • AIRE-related autoimmunity model — important paradigm for understanding tolerance
    • Combined ICI (ipi + nivo, ipi + relatlimab) higher endocrine irAE rates
  • Taiwan: 健保 hormone replacement (HC, T4, insulin, fludrocortisone, Ca/VitD); 健保 anti-21-OH, anti-TPO, anti-GAD, anti-IF (條件); AIRE genetic 條件; FOXP3 genetic limited

402.3.0.2 🌟 Pearls (12)

402.3.0.2.1 APS-1 / APECED
  1. Anti-IFN-α/ω present in nearly all APS-1 patients; very specific (rare in other autoimmune)
  2. AIRE gene centrally promotes thymic expression of self-antigens (mTEC) for negative selection of autoreactive T cells
  3. Components develop over decades: candidiasis (early childhood) → hypoPTH (early to mid childhood) → Addison’s (variable, can be late)
  4. Asplenism in APS-1 → vaccine considerations
  5. Tooth enamel hypoplasia, nail dystrophy = ectodermal manifestations
402.3.0.2.2 APS-2 / Schmidt
  1. HLA-DR3 + DR4 combination = highest risk
  2. CTLA-4 polymorphisms confer additional risk
  3. MGW (myasthenia gravis) + vitiligo + alopecia common APS-2 components
  4. Premature ovarian insufficiency (POI): 5-10% APS-2 women; may precede other endocrine
  5. Celiac in APS-2 + T1DM ~ 5%; tissue transglutaminase screen
402.3.0.2.3 IPEX + ICI
  1. IPEX TNF-IL-2 storm: severe systemic immune dysregulation; HSCT only definitive
  2. ICI-induced T1DM can be fulminant (DKA at presentation, C-peptide undetectable, may not be GAD+ — different from classic T1DM)

402.3.0.3 📍 Taiwan + 健保

402.3.0.3.1 Replacement
  • 健保 hydrocortisone, prednisone, dexamethasone
  • 健保 fludrocortisone for AI
  • 健保 levothyroxine for hypothyroid
  • 健保 calcium + active Vit D (calcitriol) for hypoPTH
  • 健保 insulin for T1DM
  • 健保 testosterone, estrogen replacement
402.3.0.3.2 Lab + Antibodies
  • 健保 anti-21-hydroxylase (條件)
  • 健保 anti-TPO, anti-Tg, anti-TRAb 充分
  • 健保 anti-GAD, anti-IA-2 (T1DM 條件)
  • 健保 anti-IF, anti-parietal (PA 條件)
  • 健保 tissue transglutaminase (celiac)
  • Anti-IFN-α/ω: 自費 / 限制䞭心 (新, APS-1 specific)
402.3.0.3.3 Genetic
  • 健保 AIRE (APS-1 condition)
  • 健保 FOXP3 (IPEX 限制)
  • HLA typing for APS-2 limited
402.3.0.3.5 孞會 + 指匕
  • TES 內分泌孞會 + Endocrine Society APS Guideline 2018
  • DAROC (T1DM-related)
  • CTAOH (thyroid-related)
  • ASCO + Society for Immunotherapy of Cancer (SITC) ICI irAE guidelines

402.3.0.4 🎓 內專必懂 (12)

  1. APS-1 genetics + 3 triad + ectodermal
  2. AIRE function + central tolerance
  3. Anti-IFN-α/ω specificity for APS-1
  4. APS-2 polygenic + HLA-DR3/4
  5. APS-2 components evolution + surveillance
  6. Schmidt syndrome specifically
  7. IPEX X-linked FOXP3 + neonatal severe
  8. HSCT cure for IPEX
  9. ICI-induced endocrinopathies spectrum
  10. ICI T1DM fulminant vs classic
  11. Replacement order: cortisol always first
  12. Surveillance lifelong + family cascade

402.3.0.5 ⚙ APS Surveillance Schedule (內專)

402.3.0.5.1 APS-1
Annual / lifelong:
- Clinical exam (candidiasis, vitiligo, alopecia, ectodermal)
- Cortisol stim (Addison's surveillance)
- Ca + iPTH (hypoPTH)
- TSH + free T4 + anti-TPO
- Fasting glucose + HbA1c
- Anti-IF + B12 (PA)
- LFT (autoimmune hepatitis)
- Tissue transglutaminase (celiac)

Q5-10 yr:
- Sex steroids + LH/FSH (hypogonadism, POI)
- 25-OH Vit D, autoimmune marker panel

As needed:
- Fluconazole prophylaxis for candidiasis
- Vaccine if asplenic
402.3.0.5.2 APS-2
Annual / lifelong (after first dx):
- Cortisol stim if AI symptoms
- TSH + free T4 + anti-TPO
- Fasting glucose + HbA1c + anti-GAD/IA-2
- Anti-IF + B12
- Tissue transglutaminase (celiac)
- Sex hormone for women < 40 (POI)
- Anti-21-hydroxylase (Addison)
- Vitiligo, alopecia, MG screen

Family (first-degree relatives):
- Same panel, less frequent (q3-5 yr)
- Higher index of suspicion

402.3.0.6 ⚙ ICI Endocrine irAE Management (內專)

402.3.0.6.1 Thyroiditis
Clinical:
- Often asymptomatic on routine TFT
- Biphasic: transient hyperthyroid (1-3 mo) → hypothyroid (often permanent)
- TFT q4-6 wk on ICI

Hyperthyroid phase:
- Symptomatic: β-blocker
- 䞍 antithyroid drug (destructive, not autonomic)
- Self-limited

Hypothyroid phase:
- LT4 (start 1.6 ÎŒg/kg adult; lower in elderly)
- Continue ICI; thyroid component does not require ICI cessation
- Lifelong replacement (~ 80% permanent)
402.3.0.6.2 Hypophysitis
Clinical:
- 5-12 wk after ipilimumab (less frequent with PD-1)
- Headache, fatigue, nausea, visual changes
- Multi-axis: ACTH/cortisol, TSH/T4, LH/FSH, GH; rarely DI

Workup:
- AM cortisol + ACTH
- TSH + free T4
- LH + FSH + sex steroids
- IGF-1
- MRI sella (enlarged pituitary, peaks then atrophy)

Treatment:
- HC 15-25 mg/d immediately if cortisol low
- LT4 if T4 low (after cortisol replaced)
- Sex steroids per age
- High-dose steroid (1-2 mg/kg pred) ONLY for mass effect / vision (uncommon; no benefit for axis recovery)
- Continue ICI in most cases; multi-axis usually permanent
402.3.0.6.3 Adrenalitis (Primary AI from ICI)
Rare (~1% with combo)
- Hyperpigmentation + hyperK + hypoNa + 盎立 hypotension
- ACTH ↑ + cortisol ↓ + 21-OH Ab+
- Treatment: HC + fludrocortisone (stress doses + lifelong)
- Permanent
402.3.0.6.4 T1DM (ICI-induced)
Rare (~1%)
- Often FULMINANT presentation (DKA)
- C-peptide undetectable
- May not be GAD+ (different from classic T1DM autoimmunity)
- 30-60% precipitate in DKA at diagnosis
- Treatment: insulin lifelong (basal-bolus)
- Continue ICI possible
402.3.0.6.5 Hypoparathyroidism
Very rare
- Tetany, muscle cramp, low Ca
- Calcium + active Vit D + sometimes recombinant PTH

402.3.0.7 ⚙ APECED Anti-IFN-α/ω Significance

- Present in nearly 100% APS-1 patients
- Very specific (rare in other autoimmune)
- Useful diagnostic in suspected cases (2 of triad without genetic confirmation)
- Predates clinical disease in some carriers
- Possibly contributes to severe COVID-19 in selected (anti-IFN type I antibodies in critical COVID — overlap with APS-1)

⚠ AI 草皿。