Chapter 43 Rheumatic
Manual of Rheumatology and Outpatient Orthopedic Disorders
Chapter 43 Rheumatic Fever
Allan Gibofsky and John B. Zabriskie
Etiology and pathogenesis
The revised Jones criteria
Acute rheumatic fever (ARF) is the
used to describe a systemic rheumatic disease manifested clinically by a constellation of symptoms following pharyngeal streptococcal infection.
I. Etiology and pathogenesis.
The disease occurs as a sequela of streptococcal pharyngitis, and the latent period from infection to onset of disease varies from 2 to 6 weeks or longer. ARF is almost exclusively associated with
A strains causing pharyngitis, and rarely if ever
impetigo or kidney disease.
The available evidence suggests that the host's abnormal immune response, at both a cellular and humoral level, to streptococcal antigens cross-reactive with target
antigens is responsible for the pathologic damage. These cross-reactive antigens include the hyaluronic
of the streptococcus and a number of streptococcal antigens, including M
, that share antigenic
tropomyosin and myosin. Other antigenic determinants include renal, central nervous system, and skin antigens. A genetic basis for the disease has been suggested for more than 100
, and family studies
that gene inheritance is either autosomal recessive or dominant with limited penetrance. Whether susceptibility to rheumatic fever is associated with certain major histocompatibility complex (MHC) alleles is
, although associations with HLA-DR4 and HLA-DR2 have been
. Non-MHC markers have been described, and a monoclonal antibody called D8/17 identifies an antigen present on the B
of 100% of rheumatic fever
Both the prevalence and severity of rheumatic fever have declined dramatically during the last six decades in the United States and other developed
; however, a resurgence in new and recurrent cases
renewed attention. Changes in living conditions, nutrition, and virulence of the organism, in addition to antibiotic
of streptococcal pharyngitis, have all been suggested as reasons for the decreased incidence. The overall incidence of rheumatic fever in the United States is currently estimated to be less than 1 in 100,000 children of school age per year, but groups with poor standards of living have a much higher incidence. In some developing nations, the incidence of rheumatic fever remains high, 60 in 100,000 children (5 to 14 years old) per year or more. Rheumatic heart disease, a chronic sequela of rheumatic fever, is the most common cause of heart disease in persons under age 40 in these countries. Rheumatic fever thus represents a significant worldwide health problem.
III. Clinical presentation
Antecedent streptococcal pharyngitis
most commonly occurs 2 to 3 weeks before the onset of the symptoms of rheumatic fever. It may be mild, however, and a history of fever and sore throat cannot be elicited in all patients.
which has no specific pattern, is almost always present at the onset of an acute attack and fades away in days to weeks without antiinflammatory treatment. Fever resolves promptly with salicylate therapy.
with fever is the most common manifestation of ARF, occurring in 50% to 75% of cases. It usually involves the large peripheral joints,
the knees and ankles, but any joint may be affected. The arthritis, which occurs within 5 weeks of the streptococcal infection, when anti-streptococcal antibody titers are usually high, subsides without treatment in a few weeks and very rarely causes joint deformity. Carditis occurs less frequently in cases with severe arthritis.
without objective evidence of joint
may precede the development of synovitis. Severe arthralgia, especially if migratory, is an important diagnostic feature.
is the most important manifestation of ARF because it frequently leads to chronic valvular damage. In rare cases, it is a cause of death from cardiac failure or arrhythmias associated with myocarditis during an acute episode. Carditis occurs in 40% to 50% of attacks of ARF in some series, but this incidence seems to be
Chest pain or dyspnea
may occur with ARF, but these complaints are often not specific to cardiac involvement.
Significant new or changing murmurs,
described below, are characteristic of acute valvulitis and
from the murmurs of valvular stenosis or regurgitation that may be
later. They often disappear with resolution of acute inflammation.
Mitral valvulitis murmur
is blowing, high-pitched, holosystolic, and apical and transmits to the axilla. It must be distinguished from the click/murmur of the mitral valve prolapse syndrome, which has a mid-systolic click and late systolic murmur.
Carey Coombs murmur
is mid-diastolic, low-pitched, and apical and often associated with the mitral valvulitis. It is best heard with the patient in the left lateral recumbent position and should be distinguished from the murmur of mitral stenosis.
murmur is a soft, high-pitched, decrescendo blow, heard immediately after the second heart sound along the left sternal border with the patient leaning forward. It must be distinguished from the murmur of a congenital bicuspid aortic valve.
by physical examination and serial chest roentgenograms.
Congestive heart failure
occurs more commonly in children under 6 years of age and in patients without severe arthritis.
when present, usually occurs in association with other features of rheumatic carditis. Pericarditis may be manifested by chest pain, friction rub, effusions, and electrocardiographic changes. Large effusions are rare.
Other cardiac findings
may include tachycardia at rest (out of proportion to fever) and a soft, dull, variable first heart sound secondary to a prolonged PR interval. Atrioventricular block is commonly seen in cases of ARF without other evidence of carditis or
rheumatic heart disease. It is thought to be a toxic manifestation of ARF and is not
indicative of carditis.
a rare manifestation of ARF, is a nonpruritic rash that begins as a pink macule and
outward in a sharp ring with central clearing or as serpiginous
lines. The rash is evanescent and rarely raised, blanches with pressure, is brought out by application of heat, and is distributed over the trunk and proximal extremities, never on the face, and rarely on the distal extremities. The rash may appear at any time in the course of ARF. Its appearance and resolution are unrelated to the course of other manifestations or to treatment. Rash secondary to drug reaction or systemic juvenile rheumatoid arthritis can usually be differentiated by the characteristics just mentioned and other associated clinical
are firm, nontender, nonpruritic,
located in crops of variable
over bony prominences and tendons without overlying skin discoloration. They are smaller and less persistent than those of rheumatoid arthritis. Nodules are a late and infrequent manifestation associated with severe carditis.
is a late manifestation of ARF and may follow other manifestations of ARF or may appear alone. It is characterized by involuntary, purposeless, abrupt, and nonrepetitive movements, muscular weakness, and emotional lability. The abnormal movements subside during sleep. When subtle, chorea is demonstrated when (a) squeezing the
's hand reveals an erratic milkmaid's grip, (b) raising the hand straight ahead causes pronation
of one or both arms, (c) extending the hands straight ahead causes spooning of the hand with wrist flexion and extension of fingers, and (d) protruding the tongue produces snakelike darting movements. Because the latent period from streptococcal infection to chorea is 1 to 6 months, anti-streptolysin O (ASO) titers and levels of acute-phase reactants may be normal. Investigation of other streptococcal antigens usually will reveal one or more with
titers in all but those patients with isolated chorea. The duration of chorea ranges from 1 week to 1 year, with an average of 3 months. Some patients with Sydenham's chorea have an antibody that reacts with
ganglia and cross-reacts with streptococcal
membranes. Sydenham's chorea must be distinguished from other neurologic entities, including Huntington's chorea, central nervous system lupus, Wilson's disease, and toxic drug
(especially to the phenothiazines).
IV. Laboratory studies
may be obtained by throat cultures (in about 25% of cases), and it is recommended that
successive cultures be taken before antibiotic treatment is begun. ASO antibodies are elevated in approximately 80% of cases, and serial serum samples should be drawn during the acute stage and 2 weeks later. Testing for anti-hyaluronidase, deoxyribonuclease B, and streptozyme titers
the documentation of a preceding streptococcal infection to 97%.
such as C-reactive protein, and the erythrocyte sedimentation rate reflect ongoing inflammation and are useful in monitoring response to therapy.
with streptococcal cell membranes are found in sera of ARF patients, but the test has not been standardized for routine use.
Serial chest roentgenograms
are important to reveal cardiomegaly as a sign of carditis.
may reveal the nonspecific atrioventricular block discussed in section
or changes of myocarditis and pericarditis.
is useful in
patients with bicuspid aortic
or mitral prolapse syndrome from those with rheumatic heart disease. It may also be used to evaluate pericardial effusion and myocardial function.
revised Jones criteria
(Table 43-1) indicate a high probability of ARF when evidence of a preceding streptococcal infection is found
with the presence of two major criteria; a diagnosis of ARF based on the presence of
one major criterion and two minor criteria is less definitive. The Jones criteria were developed to provide
and to minimize the overdiagnosis of ARF.
Jones criteria (revised) for guidance in the diagnosis of rheumatic fever
VI. Differential diagnosis
including septic arthritis, osteomyelitis, and subacute bacterial endocarditis, should be
out by appropriate culture. Lyme disease should be
, especially in areas where it is endemic.
particularly rubella arthritis, arthritis associated with hepatitis B infection, and infectious mononucleosis, should be considered.
rheumatoid arthritis, systemic lupus erythematosus, and vasculitis such as Henoch-Schnlein purpura may be differentiated on clinical and laboratory grounds.
Immune complex disease
induced by an allergic reaction to drugs may be suggested by history and by clinical features such as pruritic or urticarial rash.
Sickle cell hemoglobinopathies
may superficially resemble ARF but are not difficult to differentiate.
especially leukemias and lymphomas, can present with fever and acute polyarthritis.
Mucocutaneous lymph node syndrome (Kawasaki disease)
may initially resemble ARF, but the desquamating rash and absence of rising ASO titers should make differentiation possible.
treatment with penicillin, or erythromycin in case of penicillin allergy, is recommended for all patients in a standard 10-day course for streptococcal pharyngitis to eradicate
organisms. There is, however, no evidence that such therapy significantly alters the acute or chronic phase of the disease. Penicillin prophylaxis (see section
) is begun after the 10-day course of treatment to reduce the risk for
treatment provides symptomatic relief but does not appear to alter the duration of the attack or cardiac sequelae.
that are helpful include the following:
for the management of joint pains, especially while diagnostic evaluation is in progress and before antiinflammatory treatment is started.
Sodium restriction, digitalis, and diuretics
for heart failure. Digitalis should be used with caution, as myocarditis is almost invariably present.
are highly effective in controlling fever and arthritis but should not be used before an adequate period of observation allows a firm diagnosis to be established. A dosage of about 80 mg/kg daily in four divided doses, with a resultant blood level of 20 to 30 mg/dL, is usually effective in controlling fever, arthritis, and mild carditis when given for 2 weeks, followed by a dosage of about 60 mg/kg daily for 6 subsequent weeks.
have not been shown to be more effective than aspirin in reducing long-term cardiac damage. Nevertheless, they are often used to treat carditis, especially when congestive failure is present. Prednisone (1 to 2 mg/kg daily in divided doses) is used for 2 to 4 weeks. Salicylates are often added for an additional 4 to 8 weeks.
Treatment of chorea
includes keeping the patient in a quiet, protective environment and sedation with phenobarbital, diazepam, or chlorpromazine as needed. Valproic acid and haloperidol appear to be useful in reducing the severity of choreiform movements.
with penicillin G (250,000 U PO twice daily) or benzathine penicillin (1.2 million U IM every 4 weeks) clearly
the chance of recurrent rheumatic fever and progressive cardiac damage. In areas where high exposure to streptococci is expected and in all cases of valvular damage, the injections should be given every 3 weeks. Alternatively, the injection is given every 4 weeks with supplemental oral penicillin dosing during the last 10 days of each month. With penicillin VK (250 mg PO twice daily) in place of penicillin G,
from the intestinal
is improved and more
reliable. Benzathine penicillin prophylaxis has the advantage of ensured compliance, but cases of recurrent rheumatic fever have occasionally been reported, probably a consequence of individual differences in the pharmacokinetics of the drug. The penicillin-allergic patient may be treated with 250 mg of erythromycin twice daily. The minimum recommended duration of prophylaxis is 5 years from the last recurrence because recurrences are most common during this period. Recurrent attacks in
have been reported, however, and as long-term prophylaxis appears to be
, it is advisable to continue prophylaxis indefinitely. All patients with evidence of chronic rheumatic heart disease, regardless of age, should be on continuous prophylaxis because recurrent disease usually includes carditis.
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Rheum Dis Clin North Am
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders