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Rheumatic fever (RF) is a systemic autoimmune inflammatory disease that follows untreated or inadequately treated group A β-hemolytic streptococcal (GAS) pharyngitis. It primarily affects the heart, joints, skin, and central nervous system and may lead to Rheumatic heart disease (RHD) through progressive valvular damage.

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Epidemiology

• Primarily affects children aged 5–15 years
• More common in developing countries
• Latency: Usually occurs 2–3 weeks after streptococcal throat infection

Pathogenesis

• Molecular mimicry: Antibodies against streptococcal M proteins cross-react with host tissues (particularly the heart, joints, and CNS)
• Causes pancarditis (endo-, myo-, pericarditis), arthritis, chorea, and skin lesions

![Generation of an auto-reactive immune response: Following repeated infections with group A Streptococcus (Strep A), adhesion and invasion of pharyngeal epithelial cells activates both B and T cells. A loss of tolerance, together with molecular mimicry, likely contribute to an autoimmune response, which results in the major manifestations of acute rheumatic fever (ARF). MHC, major histocompatibility complex.

Carapetis, J. R. et al. Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Primers 2, 15084 (2016). Zühlke, L., Beaton, A., Engel, M. et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 12, 7 (2026). https://doi.org/10.1038/s41572-026-00685-y](attachment:1d40ce04-0b40-424f-a330-2d13d5179e07:41572_2026_685_Fig4_HTML.webp)

Generation of an auto-reactive immune response: Following repeated infections with group A Streptococcus (Strep A), adhesion and invasion of pharyngeal epithelial cells activates both B and T cells. A loss of tolerance, together with molecular mimicry, likely contribute to an autoimmune response, which results in the major manifestations of acute rheumatic fever (ARF). MHC, major histocompatibility complex.

Carapetis, J. R. et al. Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Primers 2, 15084 (2016). Zühlke, L., Beaton, A., Engel, M. et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 12, 7 (2026). https://doi.org/10.1038/s41572-026-00685-y

Clinical Features

Cardiac Involvement (Rheumatic Carditis)

• Most serious manifestation of RF
• Commonly affects mitral valve → leads to mitral stenosis or regurgitation
• May cause heart failure, murmurs, pericardial rub, or tachycardia out of proportion