13. Autoinflammatory diseases - classification, etiology, pathogenesis.

Autoinflammatory diseases - classification, etiology, pathogenesis.

Autoinflammatory diseases are a group of disorders characterized by spontaneous, recurrent episodes of systemic inflammation, without high-titer autoantibodies or antigen-specific T cells (which distinguishes them from autoimmune diseases).

Key Features

• Dysregulation of innate immunity (not adaptive immunity).
• Recurrent fevers, serositis, arthritis, rash.
• Elevated inflammatory markers (e.g., CRP, serum amyloid A).

Classification

1. 1 Hereditary (monogenic) autoinflammatory diseases

Caused by single gene mutations, typically inherited in an autosomal dominant or recessive pattern.

Examples

1. 2 Multifactorial (polygenic) autoinflammatory diseases

Involves multiple genetic and environmental factors.

Examples

• Systemic juvenile idiopathic arthritis (sJIA)
• Adult-onset Still's disease

Etiology

1. 1 Genetic factors

• Germline mutations in genes regulating innate immunity (e.g., NLRP3, MEFV).
• Most hereditary forms follow Mendelian inheritance patterns.

1. 2 Environmental factors (in polygenic forms)

• Infections.
• Trauma.
• Stress.

Pathogenesis

Innate immunity dysregulation

• Central mechanism is uncontrolled activation of inflammasomes (especially NLRP3 inflammasome).
• Inflammasomes are cytosolic multiprotein complexes that activate caspase-1 → cleavage and activation of pro-inflammatory cytokines (IL-1β, IL-18).

Key steps

1. Triggering event (e.g., spontaneous or minor stimuli).
2. Aberrant inflammasome activation.
3. Overproduction of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).
4. Systemic inflammation → fever, serositis, rash, arthritis.
5. Chronic inflammation can lead to secondary amyloidosis (especially with elevated serum amyloid A).

Clinical Features

• Recurrent fever episodes (often periodic).
• Serosal inflammation (peritonitis, pleuritis, pericarditis).
• Arthralgia or arthritis.
• Skin manifestations (urticarial or erythematous rash).
• Lymphadenopathy.
• Elevated acute-phase reactants during attacks.

Diagnosis

• Based on clinical criteria and genetic testing (in hereditary cases).
• Exclusion of infections, autoimmune diseases, and malignancies.

Treatment

• IL-1 inhibitors: anakinra, canakinumab (key therapy in many cases).
• Colchicine (especially in FMF).
• TNF inhibitors (in some syndromes like TRAPS).
• Corticosteroids (for acute flares).