- Clinical science
Rheumatic fever is an inflammatory sequela involving the heart, joints, skin, and central nervous system (CNS) that occurs two to four weeks after an untreated infection with group A streptococcus (GAS). The pathogenic mechanisms that cause rheumatic fever are not completely understood, but molecular mimicry between streptococcal M protein and human cardiac myosin proteins is thought to play a role. Because of the structural similarities between the two proteins, antibodies and T cells activated to respond to streptococcal proteins also react with the human proteins, causing tissue injury and inflammation. In addition to nonspecific symptoms (e.g., fever, malaise, and fatigue), patients present with symptoms involving the heart (pancarditis), joints (migratory polyarthritis), skin (subcutaneous nodules, erythema marginatum), and/or CNS (Sydenham chorea). The diagnosis of acute rheumatic fever is primarily a clinical one, and is based on the Jones criteria. Diagnostic evaluation in acute rheumatic fever typically shows elevated inflammatory markers, positive antistreptococcal antibodies, and valvular damage on echocardiogram. The first-line treatment is penicillin combined with symptomatic anti-inflammatory treatment, typically with salicylates or glucocorticoids (if salicylates are not effective). Acute rheumatic fever may be complicated by progressive, permanent damage to the heart valves (especially the mitral valve), resulting in chronic rheumatic heart disease. Preventing the cardiac complications of rheumatic fever is the goal of both primary prophylaxis (i.e., antibiotic therapy for GAS pharyngitis) and secondary prophylaxis (antibiotic administration following an episode of acute rheumatic fever.
- Delayed inflammatory complication of group A β-hemolytic streptococcal pharyngitis that usually occurs within 2–4 weeks of acute infection 
- One of the nonsuppurative complications of GAS pharyngitis
- Rheumatic heart disease refers to two clinical entities:
- The exact pathogenesis is not yet entirely understood.
- Most commonly accepted mechanism involves the following: /pharyngitis caused by GAS without antibiotic treatment → development of antibodies against streptococcal M protein → cross-reaction of antibodies with nerve and myocardial proteins (most commonly myosins) due to molecular mimicry → type II hypersensitivity reaction; → acute inflammatory sequela 
- Constitutional symptoms: fever, malaise, fatigue
- Joints: migratory polyarthritis
- Pancarditis (endocarditis, myocarditis, and pericarditis)
Valvular lesions: most commonly on high-pressure valves 
- Mitral valve (∼ 65% of cases)
- Aortic valve (∼ 25% of cases)
- Tricuspid valve (∼ 10% of cases)
- Dilated cardiomyopathy due to severe valvular disease, myocarditis
CNS: Sydenham chorea (involuntary, irregular, nonrepetitive movements of the limbs, neck, head, and/or face) 
- Clinical features
- Occurs 1–8 months after the inciting infection 
- Sometimes asymmetrical or confined to one side (hemichorea)
- Additional motor symptoms (e.g., ballismus, muscle weakness) and speech disorders (slurred or “jerky” speech)
- Neuropsychiatric symptoms (e.g., inappropriate laughing/crying, agitation, anxiety, apathy, obsessive-compulsive behavior)
- ♀ < ♂ (∼ 2:1)
- Pathophysiology: Streptococcal antigens lead to antibody production → antibodies cross-react with structures of the basal ganglia (particularly the striatum) and cortical structures → reversible dysfunction of cortical and striatal circuits
- Clinical features
- Subcutaneous nodules
Erythema marginatum: centrifugally expanding pink or light red rash with a well-defined outer border and central clearing.
- Painless and nonpruritic
- Location: The trunk and limbs are affected; the face is spared. May rapidly appear and disappear at different locations. 
Rheumatic heart disease tends to involve the high-pressure valves (i.e., the mitral and aortic valves).
The symptoms of acute rheumatic fever can be remembered by reading the JONES criteria (see “Diagnostics” below) as an acronym that replaces the “o” with a heart: J = Joints, ♥ = Pancarditis, N = Nodules, E = Erythema marginatum, S = Sydenham chorea
Diagnosis of acute rheumatic fever is based on the Jones criteria, which primarily describe the clinical findings of the condition. Evidence of a preceding GAS infection is also preferred (unless carditis or chorea are present). Laboratory tests and imaging may be necessary to assess any outstanding Jones criteria.
Jones criteria 
Two major criteria or one major plus two minor criteria or three minor criteria are required for diagnosis.
Low risk population
|High risk population|
Additional findings 
- Complete blood cell count
- Antibody/antigen tests: measure antibodies against metabolites of GAS
- Echocardiogram: may show mitral or aortic regurgitation
Myocardial findings 
- Aschoff bodies
- Anitschkow cells
- General measures: bedrest (especially important in patients with carditis)
- Antibiotics: to eradicate GAS 
- Anti-inflammatory therapy
Treatment of complications
- Heart failure: diuretics and conventional therapy (see “ ”)
- Myocarditis: monitoring and treatment for arrhythmias (see “ ”)
- Cardiac valve damage: Surgery or interventional reconstructive measures may be considered at least one year after the acute inflammatory phase.
- Sydenham chorea
- Cardiac involvement is the most important prognostic factor.
- Early death from rheumatic fever is usually due to myocarditis rather than valvular defects.
- Patients with a history of carditis (and possible post-inflammatory scarring and calcification) during an initial rheumatic fever episode are at high risk of developing valvular heart defects with recurrent episodes → rheumatic heart disease
- Primary prevention: prompt antibiotic treatment of GAS tonsillopharyngitis (e.g., penicillin V)
Secondary prevention: antibiotic prophylaxis
- Drug of choice: IM penicillin G benzathine (alternatively oral penicillin V)
- Immediately follows antibiotic treatment of acute rheumatic fever (see “Treatment” above)
- Duration depends on the risk and severity of the original episode; the longer-lasting option is usually chosen.