Autoinflammatory Syndromes

Autoinflammatory Syndromes: Core Concepts - Fiery Fevers & Flares

• Primarily disorders of innate immunity (vs. adaptive in autoimmune).
• Pathogenesis: Dysregulated inflammasomes or cytokine pathways, leading to uncontrolled inflammation.
• Key pro-inflammatory cytokines mediating flares:
  • Interleukin-1β (IL-1β)
  • Tumor Necrosis Factor-alpha (TNF-α)
  • Interleukin-6 (IL-6)
• Clinical hallmarks: Recurrent, unprovoked episodes of:
  • High fever ("fiery fevers")
  • Serositis (e.g., pleuritis, pericarditis, peritonitis)
  • Various skin rashes (e.g., urticarial)
  • Arthralgia or arthritis
• Often have a strong genetic predisposition.

⭐ Autoinflammatory diseases are primarily driven by dysregulation of the innate immune system, unlike autoimmune diseases which involve the adaptive immune system (T and B cells).

Familial Mediterranean Fever (FMF) - Periodic Perils

• Genetic: Autosomal recessive, MEFV gene mutation (pyrin).
• Pathophysiology: Pyrin inflammasome dysregulation → ↑IL-1β.
• Features: Recurrent episodes (12-72 hrs) of:
  • Fever (abrupt, high-grade).
  • Serositis (peritonitis, pleuritis) → severe pain.
  • Arthritis (mono/oligo, lower limbs).
  • Erysipelas-like erythema (lower leg/foot).
• Labs: ↑ESR, CRP during attacks.
• Diagnosis: Tel Hashomer criteria; MEFV gene testing.
• Treatment:
  • Prophylaxis: Colchicine (0.6-1.2 mg/day, up to 2.4 mg/day) lifelong.
  • Acute attacks: NSAIDs.
• Complication: AA amyloidosis (renal failure).
• 📌 Mnemonic: FMF SCRIPT (Serositis, Colchicine/Complication-Amyloidosis, Recurrent fever, Inflammation markers, Pain-abdominal/chest, MEFV gene, Tel Hashomer criteria).

⭐ Colchicine is the mainstay of FMF treatment, effectively preventing attacks and the dreaded complication of AA amyloidosis.

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Other Key Monogenic Syndromes - Alphabet Soup Inflamed

Diagnostic & Management Principles - Cooling the Flames

• Clinical Suspicion: Recurrent, unexplained fevers & systemic inflammation (e.g., serositis, rash, arthritis).
• Investigations:
  • Inflammatory markers: ↑ CRP, ↑ ESR, ↑ SAA.
  • Genetic testing: Confirms specific syndromes (e.g., FMF, TRAPS); aids targeted therapy. Limitations: VUS, not all causative genes identified.
• Management Goals: Control inflammation, prevent organ damage (esp. amyloidosis), improve QoL.
  • Acute Flares: NSAIDs, corticosteroids.
  • Chronic/Prophylactic:
    • Colchicine (esp. FMF).
    • Biologics: IL-1 inhibitors (anakinra, canakinumab), IL-6 inhibitors (tocilizumab), TNF inhibitors.

⭐ Monitoring Serum Amyloid A (SAA) levels is crucial in chronic autoinflammatory diseases to assess disease activity and the risk of developing secondary AA amyloidosis.

High‑Yield Points - ⚡ Biggest Takeaways

• Autoinflammatory syndromes: Innate immunity dysregulation, not adaptive like autoimmune diseases.
• Key features: Recurrent fevers, systemic inflammation, often genetic.
• FMF: MEFV gene, colchicine prevents attacks and AA amyloidosis.
• CAPS: NLRP3 gene, IL-1 inhibitors (e.g., anakinra) are mainstay treatment.
• TRAPS: TNFRSF1A gene, prolonged fevers; corticosteroids or IL-1/TNF inhibitors may be used.
• HIDS/MKD: MVK gene, presents with high IgD (variable) and fevers.
• AA amyloidosis is a critical long-term complication across several syndromes if untreated.