What is the pathophysiology of rheumatic fever?

Pathophysiology of Rheumatic Fever

Rheumatic fever is an autoimmune disease triggered by group A streptococcal (GAS) pharyngitis, characterized by molecular mimicry where antibodies against streptococcal antigens cross-react with human tissues, particularly affecting the heart, joints, and central nervous system. 1, 2

Initiating Event: Group A Streptococcal Infection

• Rheumatic fever occurs as a delayed sequel to GAS throat infection (pharyngitis) in genetically susceptible individuals 1, 3
• The disease typically develops 2-3 weeks after the initial infection
• The infection triggers an abnormal immune response in susceptible hosts
• At least one-third of ARF cases result from asymptomatic streptococcal infections 1

Autoimmune Response and Molecular Mimicry

The core pathophysiological mechanism involves:

1. Molecular Mimicry: Structural similarities between GAS antigens and human tissues lead to cross-reactivity 2

   • Antibodies produced against streptococcal components recognize and bind to similar epitopes in human tissues
   • This cross-reactivity is the fundamental mechanism behind the autoimmune damage

2. Cross-Reactive Antigens: Several important cross-reactive relationships have been identified 4:

   • Cardiac, skeletal, and smooth muscle antigens
   • Heart valve fibroblast antigens
   • Neuronal antigens in basal ganglia
   • Group A carbohydrate-related determinants in connective tissues

3. Specific Molecular Triggers:

   • An octapeptide motif present in M and M-like proteins of streptococci can form autoantigenic complexes with human collagen IV 5
   • This interaction leads to the development of anti-collagen antibodies

Target Tissues and Clinical Manifestations

The autoimmune response primarily affects:

1. Cardiac Tissue:

   • Inflammation of the heart (carditis) can lead to valvular heart disease
   • Primarily affects mitral and aortic valves
   • Can present with new murmurs, heart failure, or pericarditis 1

2. Joints:

   • Migratory polyarthritis typically affecting large joints
   • Characterized by pain, swelling, and limited movement
   • Responds rapidly to anti-inflammatory treatment 1

3. Central Nervous System:

   • Sydenham's chorea: involuntary, purposeless movements and emotional lability
   • Results from antibodies targeting basal ganglia neurons 1

4. Skin:

   • Erythema marginatum: transient, non-pruritic rash with clear centers and rounded edges
   • Subcutaneous nodules: firm, painless nodules over bony prominences 1

Progression to Rheumatic Heart Disease

• Acute rheumatic fever can progress to chronic rheumatic heart disease (RHD)
• RHD can result from a single severe episode or multiple recurrent episodes 6
• Recurrences of ARF significantly increase the risk of severe cardiac damage 1
• Long-term damage primarily affects heart valves, causing stenosis or regurgitation
• Mitral valve is most commonly affected, followed by the aortic valve

Genetic Susceptibility

• Not all individuals infected with GAS develop rheumatic fever
• Genetic factors play a significant role in determining susceptibility
• Certain HLA types have been associated with increased risk
• Family history is an important risk factor

Diagnostic Considerations

Diagnosis of ARF requires evidence of:

• Preceding GAS infection
• Clinical manifestations according to the Jones Criteria:
  • 2 major manifestations OR
  • 1 major and 2 minor manifestations 1

Major manifestations include carditis, arthritis, chorea, erythema marginatum, and subcutaneous nodules.

Prevention Strategies

Prevention focuses on:

1. Primary Prevention: Proper identification and adequate antibiotic treatment of GAS pharyngitis 7
2. Secondary Prevention: Continuous antimicrobial prophylaxis for patients who have had ARF to prevent recurrences 7, 1

The pathophysiology of rheumatic fever underscores the importance of prompt treatment of streptococcal infections and long-term prophylaxis for those with a history of the disease to prevent the devastating cardiac complications.